Polymer-Based Nanomaterials for Photothermal Therapy: From Light

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Review

Polymer-Based Nanomaterials for Photothermal Therapy: From Light-Responsive to Multifunctional Nanoplatforms for Synergistically Combined Technologies Filippo Pierini, Pawe# Nakielski, Olga Urbanek, Sylwia Paw#owska, Massimiliano Lanzi, Luciano De Sio, and Tomasz Aleksander Kowalewski Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.8b01138 • Publication Date (Web): 19 Sep 2018 Downloaded from http://pubs.acs.org on September 21, 2018

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Biomacromolecules

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Polymer-Based

Nanomaterials

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Therapy: From Light-Responsive to Multifunctional

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Nanoplatforms

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Technologies

for

for

Synergistically

Photothermal

Combined

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Filippo Pierini,*† Paweł Nakielski,† Olga Urbanek,§ Sylwia Pawłowska, † Massimiliano

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Lanzi,‡ Luciano De Sio || and Tomasz Aleksander Kowalewski†

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†

Department of Biosystems and Soft Matter, Institute of Fundamental Technological

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Research, Polish Academy of Sciences, Warsaw 02-106, Poland

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§

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Polish Academy of Sciences, Warsaw 02-106, Poland

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‡

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Bologna, 40136 Bologna, Italy

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||

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Corso della Repubblica 79, 04100 Latina, Italy

Laboratory of Polymers and Biomaterials, Institute of Fundamental Technological Research,

Department of Industrial Chemistry “Toso Montanari”, Alma Mater Studiorum-University of

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome,

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Abstract. Materials for the treatment of cancer have been studied comprehensively over the

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past few decades. Among the various kinds of biomaterials, polymer-based nanomaterials

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represent one of the most interesting research directions in nanomedicine, because their

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controlled synthesis and tailored designs make it possible to obtain nanostructures with

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biomimetic features and outstanding biocompatibility. Understanding the chemical and

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physical mechanisms behind the cascading stimuli-responsiveness of “smart” polymers is

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fundamental for the design of multifunctional nanomaterials to be used as photothermal

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agents for targeted polytherapy. In this review, we offer an in-depth overview of the recent

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advances in polymer nanomaterials for photothermal therapy, describing the features of three

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different types of polymer-based nanomaterials. In each case, we systematically show the

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relevant benefits, highlighting the strategies for developing light-controlled multifunctional

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nanoplatforms that are responsive in a cascade manner and addressing the open issues by

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means of an inclusive state-of-the-art review. Moreover, we face further challenges and

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provide new perspectives for future strategies for developing novel polymeric nanomaterials

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for photothermally assisted therapies.

34 35 36

Keywords: polymer nanostructures; multifunctional nanomaterials, cascading stimuli-

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responsiveness; light-to-heat conversion; photothermal therapy; targeted polytherapy for

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cancer.

39 40 41


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Biomacromolecules

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1. Introduction

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Cancer is a class of more than one hundred diseases involving an out-of-control growth of

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abnormal cells in the human body.1 The number of people suffering from cancer is

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dramatically high. The World Health Organization (WHO) estimates that cancer is the second

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leading cause of death worldwide, and that it was responsible for 8.8 million deaths in 2015.2

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Moreover, it accounted for approximately 16% of all the world’s deaths in 2015 and it is

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expected to continue rising. The estimated annual worldwide cost of cancer to society, 1.16

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trillion US dollars, highlights the enormous impact that it has on global socioeconomic

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conditions.3

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Cancer has been recognized as a serious disease since ancient times. Hippocrates, the father of

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medicine, classified and studied several kinds of cancer more than 2,000 years ago. During his

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studies, he investigated different types of treatment, including the cauterization of surface

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tumors by using a hot metal, concluding in the end that “if a tumor cannot be cut, it should be

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burned. If it cannot be burned, then it is incurable”.4

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The theory that cancer may be cured by artificially controlling body temperature has been

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evaluated scrupulously over the last few decades. Many studies underlined the fact that

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normal and cancer cells have different responses to heat, and that temperatures over 42.5°C

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are actually cytotoxic for tumor cells.5 This concept paved the way to a new treatment called

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hyperthermia therapy.6 Conventional hyperthermia systems are designed to heat tissue to

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around 42.5-44.0°C in order to stimulate the immune system response for the non-specific

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immunotherapy of cancers and to induce the regression or complete disappearance of the

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cancer by direct cell damage.7 Unfortunately, in clinical conditions the use of hyperthermia as

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a stand-alone treatment of cancer has been proven ineffective.8 High temperatures can

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eliminate a large number of tumor cells, but it is difficult to heat the local tumor region

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without causing damage to the surrounding tissues. Hyperthermia exhibits several technical 3 ACS Paragon Plus Environment


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problems mainly related to the heating of relevant portions of the human body and to the

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serious side effects caused to patients.9 Lastly, this technique is only applied as an additional

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therapy, in combination with conventional cancer treatments (e.g. chemotherapy and

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radiotherapy).8

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The development of effective tumor treatments is one of the greatest challenges in healthcare

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today. Therefore, huge investments have been made in research with a view to developing

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new treatments or improving the already-existing ones. Scrupulous attention has recently been

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focused on the application of heat in cancer treatments, with the possibility to “burn” a tumor

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at the cellular level, thus reducing the main drawbacks of conventional hyperthermia. The key

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to the efficient and successful treatment of a tumor using heat is the development of a non-

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invasive therapy that leads to the local treatment of cancer cells only.10

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Photothermal therapy (PTT) is a newly developed and promising therapeutic strategy which is

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considered the natural evolution of conventional hyperthermia therapy, because it uses agents

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capable of physically reaching specific cancer cells and generating heat because of the

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interaction with light.11 PTT involves the use of nanometer sized materials that show high

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absorption in the near-infrared (NIR) region.12 This biological tissue-transparent radiation can

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penetrate living tissues without causing damage. The light absorbed by these nanomaterials is

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rapidly converted into heat, causing tumor cell apoptosis (Figure 1a) and avoiding the typical

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drawbacks of hyperthermia.10

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The development of future medical technologies capable of enhancing therapeutic efficiency

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and reducing their side effects will mainly be the result of the enormous scientific effort put

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into material science, which has led to the rapid development of nanotechnology.13 Today, the

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rapid expansion of this field has led to a generation of biomaterials with fascinating properties

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and activities.14 Unfortunately, the first generations of biomaterials already applied were

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designed without fully taking into consideration the fast and significant changes that occur in 4 ACS Paragon Plus Environment

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biological tissues. The possibility to use external stimuli to trigger changes in biomaterial

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properties affords a high level of control over the activities of implanted material over time,

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which is necessary for developing a new generation of biomedical materials.15 One of the

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main goals of nanomaterial sciences for biomedical application is that of developing

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biocompatible materials in which changes in properties and activities are triggered through

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artificial stimuli, such as light irradiation,16 magnetic,17 pH,18 thermal,19 and electrical

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stimulations.20

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The complex functions of living systems are mainly driven by regulation systems which

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provide feedback to stabilize such extremely dynamic and non-equilibrium systems.21 Nature

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uses different kinds of approaches to perform life processes precisely, based on response

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cascades.22 Nature has been a source of inspiration for scientists in the development of new

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technologies and materials, since it offers a wide range of multifunctional materials capable of

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responding to stimuli in a controlled way.23 In the past decades, biomimetic approaches have

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been used by scientists to develop stimuli-responsive materials which try to mimic nature.24

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Sensitive materials which respond to small environmental condition changes with dramatic

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material property variations are known as “stimuli-responsive” or “smart” or “intelligent”

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materials. Smart nanomaterials can be classified according to the stimuli they are sensitive to

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(e.g. temperature, pH, ionic strength, light, electric or magnetic field).25 Moreover, some of

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these materials can respond to a combination of different kinds of stimuli.26 Stimuli-

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responsive materials became essential in the area of biomedical applications in order to

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develop brand new diagnostic and therapeutic techniques, and especially nanomaterials, since

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nanotechnology shows remarkable potential in this field.27

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Nanomedicine is an extremely dynamic field and PTT, due to its non-invasive character for

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the selective treatment of tumors, is one of its most studied branches. Several scientific

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articles published by different research groups have proven the possibility to synthesize 5 ACS Paragon Plus Environment


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nanomaterials with interesting optical properties in the near-infrared region, such as the fast

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and efficient light-to-heat conversion that can be delivered to specific tissues. The unique

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optical properties of nanomaterials confirm the potential for the creation of new functional

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materials for photothermal cancer therapy.28 Recently, several kinds of nanomaterials that are

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good absorbers of NIR radiation have been developed. The first and most widely studied

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group of materials is composed of noble metal nanomaterials (e.g. gold and silver

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nanoparticles).29 The surface plasmon resonance – a phenomenon which leads to the

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collective excitation of electrons in these metal nanostructures – has been widely examined to

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strongly enhance the material’s optical response, such as the NIR radiation absorption,

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scattering, and conversion.30 Despite the huge efforts of the scientific community to improve

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metal nanomaterials for PTT, the accumulation of such metallic nanoparticles in the body and

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their potential health risk could be a problem that prevents the large-scale application of these

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nanomaterials.31 For this reason a number of research studies have been focused on the use of

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different structures, such as carbon nanomaterials. Carbon nanotubes, as well as graphene and

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its derivatives, have outstanding optical properties and have been indicated as potential

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therapeutic agents for PTT applications.32 However, the practical application of one- and two-

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dimensional carbon nanomaterials for nanomedicine is still open to doubt, since several

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studies have demonstrated their harmful effects on body tissues and cells due to their intrinsic

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toxicity and low biocompatibility.33

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In the light of potential advantages, the possibility to develop organic nanomaterials as PTT

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agents has recently attracted the attention of the scientific community (Figure 1b). Polymeric

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nanostructured materials have been widely applied in nanomedicine for various purposes such

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as tissue engineering,34 drug delivery,35 biosensors,36 antibacterial materials,37 and

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biointerfaces.38 Several kinds of polymer nanomaterials possess the main requirements

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necessary to be considered as potential PTT agents: suitable size and shape, dispersibility in 6 ACS Paragon Plus Environment

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Biomacromolecules

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an aqueous medium, light-to-heat conversion of NIR radiation, photostability, low

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cytotoxicity and accumulation in living tissues.39,

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application are not only more biodegradable and remain in the body for shorter periods of

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time after systemic administration than inorganic nanoparticles,41 but they also offer indirect

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advantages because of their synthesis and the possibility to apply further forms of treatment

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with a view to developing more advanced biomaterials.

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“Green chemistry” is an area of chemistry focused on the development of sustainable

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technologies for the production of materials by chemical strategies. “Green Polymer

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chemistry”, which is at the forefront of this innovative strand of work, has led to the

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development of a few encouraging viable synthetic strategies for suitable polymer synthesis.42

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Moreover, unlike inorganic nanomaterials, polymers can be easily processed using post-

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synthesis treatments for the preparation of nanomaterials with well-defined structures.

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Advanced techniques like electrospinning

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with great success to fabricate biomaterials for medical applications. Most importantly,

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tailored polymer-based nanomaterials could be designed to produce a cascade response to

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light stimulations.45 Using this nature-inspired mechanism, light irradiation activates the

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material response (e.g. heat generation), which acts as a “mediator” to trigger structural

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polymer transformations (e.g. expansion/contraction, chain mobility, crystallinity, or material

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rupture) and in turn gives novel material functionalities such as on-off switching of drug/gene

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delivery or signals for imaging purposes. This unique and fascinating property makes it

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possible to developed multifunctional materials which are able to combine photothermal

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therapy with other targeted cancer diagnostic and therapeutic treatments.46

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Polymer-based nanomaterials for PTT

and 3D-printing

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have already been applied


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Figure 1. (a) Scheme illustrating the biochemical mechanism resulting from nanomaterial-

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mediated photothermal therapy. Reprinted with permission from ref. 10. Copyright 2015

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American Chemical Society. (b) The number of published articles on polymer-based

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nanomaterials for photothermal therapy during the period 2006–2017, obtained from Web of

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Science database.

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The main aim of this review is to summarize the potential of polymer-based nanomaterials as

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photothermal cancer therapeutic agents for targeted polytherapy. We summarize the recent

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results in designing, fabricating, and testing different types of nanostructures which show a

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potential for developing multifunctional nanoplatforms thanks to their cascading

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responsiveness to light stimuli. Finally, we highlight the key points for the development of

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more effective nanomaterials and the emerging perspectives and challenges for future

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research from the viewpoint of material scientists.

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2. Conjugated Polymer Nanomaterials

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Conjugated polymers (CPs) are an important class of macromolecules having the π-electrons

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system delocalized over the whole polymeric main chain. Since the discovery of the doping of

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polyacetylene, many other new polymers, with a high structural versatility and stability in the

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neutral and the doped states, have been successfully synthesized and applied in different fields

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such as batteries,47 organic electronics,48 and solar cells.49 Moreover, these polymers have

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recently attracted great interest due to their biomedical applications.50

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Photothermal therapy exploits photo-absorbing agents which are able to efficiently convert

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the absorbed light into heat, in order to induce a local hyperthermia that results in irreversible

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damage for cancer cells. In a similar way, photodynamic therapy (PDT) uses photosensitizers

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to transfer coherent light energy to oxygen molecules, thus generating cytotoxic reactive

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oxygen species (ROS). While photosensitizers for PDT can also be activated using visible

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light, an important prerequisite for PTT is the use of CPs that absorb in the NIR region

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(650-1700 nm), since blood and tissues absorb in the UV-Vis spectral range. Recently, CPs

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have been successfully used for PTT and PDT in cancer thanks to their highly electronic-

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delocalized structures, which are particularly prone to absorbing light to be converted to heat,

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fluorescence, and other energies. Moreover, some CPs nanosystems show photoacoustic (PA)

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effects. Basically, they are able to absorb light, creating a thermally-induced pressure increase

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which generates ultrasonic waves (phonons). Phonons can be received by acoustic detectors to

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form high-resolution images of deep tumors.

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A new important class of CPs is D-A copolymers, which have a combination of electron-rich

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(ED) and electron-deficient (EA) moieties in their conjugated backbone. They usually show

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very low band-gap (π-π*) energy and long wavelength absorptions. Photons in the NIR-II

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region (950-1700 nm) provide more efficient tissue penetration ability than NIR-I photons



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(650-950 nm), when considering absorption and scattering effects in tissues. Moreover, the

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structural versatility of CPs makes the insertion of specific chromophores, photosensitizers, or

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other functional groups of biological interest (in the polymer main chain or in side chains)

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particularly simple. CPs are usually hydrophobic materials, but they can be effectively coated

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by hydrophylic polymers in order to achieve water-dispersable nanoparticles (NPs) for

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biomedical applications. CP NPs can also be loaded with a variety of photothermal agents,

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metallic NPs, and anticancer drugs by conventional nanoencapsulation strategies. Herein, we

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describe some examples of photothermal (PT) and photodynamic (PD) therapeutic CP

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nanosystems, together with recent developments in combinational drug-assisted therapy and a

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summary of currently-available studies involving the application of these multifunctional

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nanoplatforms is presented in Table 1.

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2.1 Polyaniline

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Polyaniline (PANI) can easily transit from emeraldine base (EB) state to emeraldine salt (ES)

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state in the presence of strong acids with a marked red-shift of its absorption maximum

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wavelength toward the NIR region. Molina et al. synthesized a thermoresponsive

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nanocomposite incorporating in-situ polymerized PANI.51 The dendritic nanogel, based on

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poly(N-isopropylacrylamide) (PNIPAM) crosslinked with 33% wt. of dendritic polyglycerol

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(dPG), was swollen in a solution of aniline and polymerized using (NH4)2S2O8. The final

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interpenetrated nanogel showed an excellent compatibility in physiological environments, and

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in vivo studies showed that mice tolerated an accumulated dose of 500 mg kg-1, which is able

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to inhibit A2780 tumor transplant growth by 55.3% after exposition to NIR laser light

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(distance: 5 cm, 5 min, 0.5 W maximum power). A simple method for preparing hybrid PANI

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NPs has been reported by Wang et al.52 EB PANI was doped with n-dodecylbenzenesulfonic

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acid (DBSA), yielding ES PANI, which was dissolved in CHCl3 and added to 10 ACS Paragon Plus Environment

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1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). After solvent evaporation, the thin

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film of Lipid-PANI NPs was conjugated with folic acid (FA) as the targeting ligand to

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enhance its tumor-targeting ability. FA-Lipid-PANI NPs showed high biocompatibility and

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stability in physiological environments and – owing to the strong absorbance in the NIR

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region (λmax=810 nm), which is ascribable to the presence of polarons in the conjugated PANI

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backbone – showed a relatively high photothermal conversion efficiency (η=25.6%) under

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laser irradiation at 808 nm. The in vitro cytotoxicity of NPs toward HeLa (human cervical

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cancer cells) reached nearly 70% at a NPs concentration of 100 µg ml-1 under 808 nm

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irradiation. Moreover, the local tumor temperature of HeLa tumor-bearing BALB/c mouse

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treated with tail injections of FA-Lipid-PANI NPs rapidly increased up to 50°C upon

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irradiation (@ 808 nm, 2 W cm-2, 5 min) and the tumor was completely eliminated after 10

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days.

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2.2 Polypyrrole

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Polypyrrole (PPy) is one of the most studied ICPs for PTT applications thanks to its strong

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absorbance in the NIR region. Recently, Bharathiraja et al. have developed PPy NPs using

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astaxanthin (Astx) conjugated bovine serum albumin (BSA) as a coating agent

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(PPy@BSA-Astx).53 They used Astx, a natural keto-carotenoid pigment, as a photosensitizer

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to generate ROS (reactive oxygen species) under 808 nm laser irradiation. At a power density

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of 0.3 W cm-2 for 15 min they observed a significant reduction of MDA-MB-231 cell

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viability, depending on the nanoparticle concentration, which is ascribable to the

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photodynamic toxic effect on breast cancer. Moreover, PPy@BSA-Astx NPs in water solution

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at 50 µg mL-1 concentration showed a high photothermal efficiency imputable to PPy,

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enabling the possibility to reach 57°C in 5 min at 1 W cm-2 power density. NPs were also



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screened for ultrasound signal generation under 808 nm laser irradiation, revealing their

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ability to generate PA signals even at low concentrations (10 µg mL-1). Since the NIR II

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window offers a high efficiency in tissue penetration owing to the reduced photon scattering

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and lower tissue background, Wang et al. recently prepared ultrathin PPy nanosheets with

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improved absorption at 1064 nm

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second NIR window (Figure 2).54 PPy is a low-cost, biocompatible, photostable conjugated

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polymer which can be easily doped up to high levels with a controlled doping process by

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means of Fe(III) inorganic salts. A layered iron oxychloride template was used to obtain

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ultrathin PPy nanosheets in which the CP was in its doped, low-bandgap, high-wavelength

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absorption bipolaron state. The as-synthesized nanosheets were coated with 1,2-distearoyl-sn-

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glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000),

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obtaining highly stable physiological dispersions for biomedical applications. PPy nanosheets

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exhibited high in vitro and in vivo photothermal ablation ability toward cancer cells in the

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NIR II window. Their photothermal conversion efficiency was 55.6% at 808 nm and even

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higher (64.6%) at 1064 nm; in vitro studies revealed that 80% of MDA-MB-231 human breast

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adenocarcinoma cells were killed when exposed to a 1064 nm laser beam (1.0 W cm-2, 10

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min). Moreover, the use of PPy nanosheets permitted the effective PT ablation of tumors in

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nude mice at depths of 8 and 6 mm, by means of 1064 and 808 nm laser sources respectively,

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suggesting promising applications of these nanomaterials for effective deep-tissue PTT.

(ε=27.8 L g-1 cm-1) to be used as PT agents in the


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Figure 2. (a) Schematic illustration of the preparation of PPy nanosheets. (b) Fluorescent

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images at different time points post intravenous injection of PPy nanosheets. (c) Infrared

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thermographic images of tumor-bearing mice after intravenous injection of PBS and PPy

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nanosheets after irradiation by a 1064 nm laser. Reprinted with permission from ref. 54.

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Copyright 2018 American Chemical Society.

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2.3 Polythiophene

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Polythiophene (PTh) derivatives usually exhibit excellent photostability, light-harvesting

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ability, easy synthesis, and facile functionalization with different substituents. Ren et al.

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successfully synthesized a new organic compound by covalently linking 2-N,N’-bis(2-

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(ethyl)hexyl)perylene-3,4,9,10-tetra-carboxylic acid bis-imide to a thienylvinylene oligomer,

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obtaining a conjugated copolymer (C3) with excellent photothermal properties, thanks to the

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presence of benzene rings and conjugated double bonds (Figure 3a).55 C3 was coprecipitated 13 ACS Paragon Plus Environment


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with PEG-PCL and indocyanine green (ICG) in order to obtain encapsulated multifunctional

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nanospheres with an average diameter of 50 nm. When PEG-PCL-C3-ICG NPs distilled water

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solution was exposed to 808 nm laser irradiation for 10 min, the temperature increased from

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25°C up to 47°C, confirming the strong PT effect. Moreover, multifunctional encapsulated

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NPs exhibited a low cytotoxicity and an efficient ROS production in vitro for PDT treatment

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of oral squamous cell carcinoma (OSCC). Additionally, HSC tumor-bearing mice injected

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with NPs and exposed to laser radiation (@808 nm, 2 W cm-2, 8 min) showed a remarkable

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tumor volume reduction. The persistence of conjugated polymer nanoparticles (CPNs) could

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be a threat to human body. In fact, an important challenge for the use of CPNs for in vivo

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theranostic is to prevent accumulation of nanoparticles in the body. Recently, Lyu et al.

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developed a biodegradable conjugated polymer which can be gradually broken down into

300

small fragments in presence of the oxidative species normally abundant in the biological

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environment.56

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tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)-dithiophene]-5,5′-diyl-alt-vinylene} (DPPV) (Figure

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3b), the presence of vinylene bonds in the main chain not only enhances its biodegradabilty

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and biocompatibility, but also increases the photothermal conversion efficiency and the mass

305

absorption coefficient, for a superior antitumor efficacy. Moreover, DPPV showed an intense

306

PA activity, for a more effective imaging capability. The PTT conversion efficiency of

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DPPV/PLGA-PEG NPs reached a notably high value of 71% (@ 808 nm, 0.3 W cm-2),

308

among the best values recorded for photothermal theranostic agents. Antitumor effect of

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DPPV PEGylated NPs was evaluated by measuring the volumes of tumors induced by

310

injecting 4T1 mammary carcinoma cells in living mice, resulting that the tumor growth was

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effectively inhibited during the whole tested period. Finally, the ex-vivo histological data

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evidenced that no significant histopathological lesions or abnormalities were observed for the

In

the

synthesized

poly{2,2′-[(2,5-bis(2-hexyldecyl)-3,6-dioxo-2,3,5,6-


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main vital organs of treated mice, owing to the good biodegradability and organically benign

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composition of the employed CPNs.

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316 317

Figure 3. (a) Synthetic route of C3. Reprinted with permission from ref. 55. Copyright 2017

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American Chemical Society. (b) Synthesis of DPPV ((i) Pd2(dba)3 and tri(o-tolyl)phosphine,

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toluene, 100°C, 24 h) and schematic illustration of DPPV/PLGA-PEG NPs. Reprinted with

320

permission from ref. 56. Copyright 2018 American Chemical Society.

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2.4 CPs containing organic light-absorbing dyes

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Porphyrins are strong light-absorbers, showing an absorption band around 400 nm (Soret

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band) and two Q-bands around 510 and 540 nm. Recently, Wang et al. reported on the

325

synthesis of polymeric NPs loading ICG, Pt(II)-meso-tetra(pentafluorophenyl)porphyrine

326

(PtTFPP) and poly(9,9-di-n-octylfluorenyl-2,7-diyl) (PFO) (Figure 4).57 The simultaneous

327

presence of a photo-sensitizer (PtTFPP), an organic semiconducting polymer acting as two-

328

photon antenna (PFO), and a NIR-absorbing photothermal dye (ICG) in the same nanoparticle

329

led to a strong photothermal performance under 808 nm laser irradiation and a high 1O2



Page 16 of 84

330

generation efficiency under NIR light exposition, thus making the assembled multifunctional

331

therapeutic nanoplatform particularly promising for cancer treatment.

332 333

Figure 4. Schematic illustration of multifunctional ICG-PtTFPP NPs. Reproduced from ref.

334

57. Republished with permission of Royal Society of Chemistry, Copyright 2017; permission

335

conveyed through Copyright Clearance Center, Inc.

336 337

2.5 D-A conjugated polymers

338

D-A conjugated polymers are very useful materials for photothermal cancer therapy. Indeed,

339

their HOMO-LUMO gap can be easily tuned by the choice of the suitable electron

340

donor/electron acceptor moieties. Cao et al. recently designed a thieno-isoindigo derivative-

341

based

342

bis(5-oxothieno[3,2-b]pyrrole-6-ylidene)benzodifurandione

343

3,3’-didodecyl-2,2’-bithiophene (BT) units acted as EA and ED, respectively (Figure 5a).58

344

The polymer, with a very low bandgap (1.24 eV) and a λmax at 1107 nm, was formulated into

345

nanoparticles using an amphiphilic diblock copolymer to enhance its solubility in aqueous

346

environments. The obtained NPs showed a spherical morphology with a diameter of about 45

semiconducting

polymer,

PBTPBF-BT,


in (BTPBF)

which

the

and

the

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Biomacromolecules

347

nm and a remarkable mass extinction coefficient of 89.3 mL cm-1 mg-1 at 1064 nm, in the NIR

348

II region. NPs have been evaluated as PT agents by exposing MDA-MB-231 cells to a 1064

349

nm laser at a power density of 0.42 W cm-2. After 10 minutes, more than 50% of the cancer

350

cells were killed using a NPs concentration of 3.75 µg mL-1. In vivo activity was tested on

351

MDA-MB-231 tumor-bearing mice which were injected with a PBTPBF-BT NPs dose of 30

352

µg per mouse and exposed to 1064 nm laser light for 10 min at 0.42 W cm-2. The tumor

353

growth was completely inhibited and only black scars were observed at the original tumor

354

sites at 14 days post-treatment. Jiang et al. synthesized a conjugated copolymer with

355

alternated cyclopentadithiophene (ED) and benzothiadiazole (EA) units. Hydrophilic PEG

356

chains were grafted onto hydrophobic CP backbone leading to water-soluble NPs.59 The

357

presence of CP in NPs gave them some important properties: an intense PT activity, a strong

358

NIR fluorescence, and the ability to interact with the aromatic anticancer Doxorubicin (DOX)

359

through hydrophobic π-π interactions. Yuan et al. also described the preparation of a

360

multifunctional nanoplatform by combining DOX with a PT conjugated polymer based on

361

thiadiazoloquinoxaline EA units alternated with functionalized fluorene ED units.60 The use

362

of a NIR laser-responsive amphiphilic brush copolymer as the encapsulation matrix allowed

363

for an efficient phototriggered drug release. The obtained NPs were also surface-modified

364

with cyclic arginine-glycine-aspartic acid (cRGD) tripeptide in order to increase their

365

accumulation within cancer cells. Feng et al. designed an organic NP-based theranostic

366

platform using two D/A copolymers: poly[9,9-bis(2-(2-(2-methoxyethoxy)ethoxy)-ethyl)

367

fluorenyldivinylene]-alt-4,7-(2,1,3-benzothiadiazole) (PFVBT), with bright red fluorescence

368

and high ROS production, and poly[(4,4,9,9-tetrakis(4-(octyloxy)phenyl)-4,9-dihydros-

369

indacenol-dithiophene-2,7-diyl)-alt-co-4,9-bis(thiophen-2-yl)-6,7-bis(4-(hexyloxy)phenyl)-

370

thiadiazolo-quinoxaline] (PIDTTTQ), with a broad absorption in the NIR region.61 The two

371

copolymers were coencapsulated to form CP NPs using a PEG matrix, and an anti-HER2



372

affibody was attached to the nanoparticle surface through surface conjugation. The obtained

373

multifunctional theranostic NPs showed high fluorescence (η=23%) and light-to-heat

374

conversion efficiency (47.6%), and an excellent targeting ability toward HER2 overexpressed

375

SKBR-3 breast cancer cells. A D-A porphyrin-containing conjugated polymer showed the

376

absorption peak at 799 nm, good biocompatibility and photostability, and a very high PT

377

conversion efficiency (63.8%).62 The in vitro cancer cell ablation activity of its NPs was

378

satisfying, since at the concentration of 5 mg L-1, almost 80% of MDA-MB-231 human breast

379

cancer cells were killed under laser irradiation at 0.75 W cm-2 for 10 min. Conjugated

380

oligomers often exhibit a better-defined structure and a higher degree of purity and synthetic

381

reproducibility than their conjugated polymer analogs. Cai et al. recently developed novel D-

382

A conjugated oligomer-based NPs with high PT activity and biocompatibility and an excellent

383

contrast when used for PA imaging of sentinel lymph nodes.63 An efficient NIR II PT

384

conversion was obtained using the new D-A conjugated polymer TBDOPV-DT.64 It contained

385

a thiophene-fused benzodifurandione-based oligo(p-phenylenevinylene) (TBDOPV) as EA

386

unit and 2,2’-bithiophene (DT) as ED moiety (Figure 5b), and showed an absorption peak at a

387

very long wavelength (1093 nm), a high biocompatibility, and a highly efficient photothermal

388

conversion through 0.2 cm of pig skin tissue (33% of transmittance).

389

390


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Biomacromolecules

391

Figure 5. (a) Schematic illustration of PBTPBF-BT NPs. Reprinted from ref. 58. Copyright

392

2017, with permission from Elsevier. (b) Chemical structure of TBDOPV-DT polymer.

393

Reprinted with permission from ref. 64. Copyright 2017 American Chemical Society.

394

Huang and coworkers reported on the synthesis of a theranostic agent based on

395

benzo[1,2-c;4,5-c’]bis[1,2,5]thiadiazole-4,7-bis(9,9-dioctyl-9H-fluoren-2-yl)thiophene

396

(BBT-2FT) to take advantage of the high EA characteristics and strong light absorption of

397

benzo-bis-thiadiazole (BBT) derivatives.65 The conjugated molecule contained fluorene

398

moieties as ED groups and a BBT unit as electron-acceptor. The presence of hypervalent

399

sulfur atoms in quinoidal structures in the conjugated backbone ensured high NIR absorption

400

in the NIR II therapeutic optical window. By coprecipitating the conjugated molecule in the

401

presence of the block copolymer PEG-b-PCL, they obtained BBT-2FT NPs, which showed

402

high PA signal intensity and PT conversion efficiency (η=40%). When CPs are encapsulated

403

into NPs and suspended in aqueous media, their aggregation can reduce the overall

404

fluorescence and the ROS generation ability. However, some types of weakly emissive NPs

405

show the opposite phenomenon, being induced to emit by aggregate formations. Another D-A

406

conjugated polymer architecture for PTT was proposed by Li et al.66 PBIBDF-BT copolymer

407

showed in its structure the EA isoindigo derivative bis(2-oxoindolin-3-ylidene)-benzodifuran-

408

dione (BIBDF) and the ED unit bithiophene (BT). NPs were obtained by emulsifying the

409

conjugated polymer with the amphiphilic copolymer mPEG-b-PHEP and showed a high

410

antitumor efficiency toward

411

0.5 W cm-2, 10 min). A higher activity was reached when PBIBDF-BT NPs were coloaded

412

with doxorubicin, since NIR irradiation was capable of efficiently triggering DOX release

413

from PBIBDF-BT@NPPPE/DOX nanoparticles. Combining D-A conjugated polymer with

414

wide-absorption organic dyes can be an efficient way to improve the light-absorbing ability of

415

the polymer to further enhance its theranostic properties, especially for PT applications.

MDA-MB-231 tumors in mice by irradiation (808nm,



416

Recently, for the first time, Zhang et al. introduced a light-harvesting unit on a D-A

417

polymer.67 The semiconducting polymer was obtained by the copolymerization of 5,6-

418

difluoro-4,7-bis[5-(trimethylstannyl) thiophen-2-yl]benzo-2,1,3-thiadiazole as an EA and 5,5′-

419

dibromo-4,4′-bis(2-octyldodecyl)-2,2′-bithiophene as an ED in the presence of a porphyrin-

420

pyrene pendant as a side-branch unit. The obtained copolymer was nanoprecipitated with

421

HOOC-PEG-COOH and PMHC18-mPEG copolymers to increase the water dispersibility and

422

size stability of the resulting biocompatible

423

semiconducting polymer nanoparticles NPs. As expected, the spherical-shape NPs showed a

424

very high photothermal conversion (η=62.3%) and a strong fluorescence for PA imaging-

425

guided PTT. Mice injected with A549 human lung cancer cells achieved 100% tumor

426

elimination using a dose of 15 mg kg-1 of NPs under laser irradiation (630 nm, 0.8 W cm-2, 10

427

min). Although many polymeric photothermal agents have shown great potential for cancer

428

treatment, they are often assembled in unstable nanostructures which can degrade in short

429

times. Chang et al. recently synthesized a new D-A copolymer: 4,8-bis[5-(2-

430

ethylhexyl)thiophen-2-yl]-2,6-bis(trimethylstannyl)benzo[1,2-b:4,5-b′]dithiophene-6,6′-

431

dibromo-N,N′-(2-ethylhexyl)isoindigo (BDT-IID) with a strong absorption in the 650-700 nm

432

range.68 Polymer dots, with spherical morphology and an average diameter of 18 nm, were

433

obtained by coprecipitating BDT-IID and poly(styrene-co-maleic anhydride) (PSMA).

434

Polymer dots (Pdots) aqueous dispersions were very stable and no aggregation was observed

435

even after 30 days while they showed an enhanced photostability. NPs dispersions in water at

436

a concentration of 100 µg mL-1 were irradiated using a laser source (@ 660 nm, 200 mW cm-

437

2

438

still maintained the ability to increase the temperature to the same level, denoting an excellent

439

photostability of the employed chromophoric system. Moreover, since the measured

440

photothermal conversion efficiency was particularly high (45%), the prepared nanomaterials

electron donor–acceptor conjugated

) reaching a temperature of 53.2°C after 600 s. Even after seven irradiation cycles, the Pdots


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Biomacromolecules

441

were also examined as PT agents for tumor therapy. Animal tests were carried out on MCF-7

442

tumor-bearing mice injected with BDT-IID Pdots and subjected to irradiation under the

443

previously described conditions. The results showed a marked tumor inhibition when

444

compared to the control group mice. More importantly, no appreciable signs of organ

445

damages or inflammatory lesions could be observed on major organs as a consequence of the

446

PTT treatment. All the aforementioned results demonstrated that the BDT-IID Pdots are

447

particularly promising for nanotheranostic applications. A few novel nanoplatforms based on

448

Pdots for tumor phototherapy has been developed by the Wu research group.69,70 Recently,

449

Chen et al. designed a conjugated polymer-based nanocarrier for enhanced anticancer PTT by

450

integrating a diketopyrrolopyrrole-dithiophene (DPP-DT) derivative with an amphiphylic

451

polymer (polystyrene-grafted ethylene oxide functionalized with carboxyl groups) used as the

452

encapsulation matrix.69 DPP-DT NPs (Pdots) were prepared starting from semiconducting

453

polymer solutions at different concentrations, observing that NPs with larger sizes were

454

recovered when the concentration of the solution was increased. Interestingly, the wavelength

455

of the absorption peak of Pdots was strongly dependent on their size and also on the

456

molecular weight of the semiconducting polymer. This very versatile system was capable of

457

tuning its optical absorption by simply acting on particle morphology and on the mean

458

conjugation length of the conjugated polymer. PEGylated polymer dots showed high PT

459

conversion efficiency (>50%), photostability and therapeutic performance. Mice bearing H22

460

or 4T1 tumors were injected with coated Pdots (1.0 mg kg-1) and subsequently exposed to

461

laser irradiation

462

inhibited, leaving only black scars at the original tumor sites which faded in about 10 days.

463

Fluorescence imaging technique, offering high temporal resolution, safety and sensitivity at a

464

low cost, has been extensively investigated for the purpose of diagnostics and therapeutic of

465

diseases. Conjugated Pdots have been widely accepted as a promising class of fluorophores

(@ 808 nm, 0.5 W cm-2, 5 min) and tumor growth was strongly



466

due to their intense brightness and nontoxic features. Moreover, these particles could emit in

467

the NIR region acting as local sources of activation for PTT agents. Wu et al. synthesized

468

polymer-blended Pdots of a green-light-harvesting polymer (poly[(9,9-dioctylflurenyl-2,7-

469

diyl)-co-(1,4-benzo-{2,1’,3}-thiadiazole)] (PFBT)) as the ED unit and a deep-red emitting

470

polymer

471

95:5 (PF-DBT5)) as the EA unit.71 Pdots showed a high absorption in the visible range and

472

high quantum yield in deep-red emission. PF-DBT5, PFBT and an amphiphilic polymer

473

(PSMA) were cocondensed giving highly fluorescent polymeric blend dots (PBdots) which

474

exhibited a quantum yield of 0.56, the highest value reported so far for polymer dots. PBdots

475

were then covalently conjugated to a peptide ligand CTX, a tumor-targeting agent with a

476

strong affinity for neuroectodermal tumors. PBdots-CTX were able to traverse the blood-brain

477

barrier and selectively target ND2:SmoA1 tumors in mice. They also proved to be photostable

478

during the in vivo fluorescence signal recording, but no evident fluorescence was observed in

479

mice blood 72 h after injection, indicating a good clearance of this new type of NP platform.

480

Among fluorescence imaging techniques, NIR fluorescence has been successfully employed

481

for clinical image-guided cancer surgery. In fact, NIR fluorescent probes (λ>700 nm) are

482

particular promising since they allow in vivo bioimaging with high penetration depth and

483

minimal auto-fluorescence interference. Chen et al. developed a novel semiconducting

484

polymer by incorporating a NIR emissive porphyrin unit and other monomers into one

485

polymeric backbone, using Suzuki-coupling reaction.72 The aim of the authors was to obtain a

486

new polymeric system with a large absorption coefficient in the visible region and an efficient

487

promotion of the cascade energy transfer to the NIR unit. The synthesized polymer (NIR800),

488

showing an intense emission at 800 nm with a narrow bandwidth, was further blended with

489

(poly[(9,9-dioctylflurenyl-2,7-diyl)-co-(4,7-bis(4-hexylthiophen-2-yl)-2,1,3-

490

benzothiadiazole)] (PFDHTBT) as a donor polymer, to enhance the energy-transfer via

(poly[(9,9-dioctylflurenyl-2,7-diyl)-co-(4,7-di-2-thienyl-2,1,3-benzothiadiazole)]


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Biomacromolecules

491

Förster mechanism. The blended Pdots showed a broad absorption range (from 500 to 600

492

nm) and an enhanced quantum yield (15%) for the narrow band emission. The PEGylated

493

Pdots evidenced a long blood-circulation time and were selectively accumulated to the lymph

494

nodes and tumors, allowing to obtain high resolution fluorescence mapping for image-guided

495

surgery.

496

Table 1. A summary of studies on the use of conjugated polymer PTT nanoplatforms in

497

cancer polytherapies.

Polymer

Wavelength of laser (nm)

Laser power density (W cm-2)

Radiation time (min)

Temp. reached (°C)

Cell line

Animal model

Ref.

PNIPAMdPG/PANI

785

-

20

42

A2780

Female nude mice

51

FA–Lipid– PANI

808

2

5

50

HeLa

Female BALB/c mice

52

PPy@BSAAstx

808

1

5

57

MDA-MB231

-

Ppy

1064

1

10

55

MDA-MB231

BALB/c nude mice

54

PEG-PCLC3-ICG

808

2

8

47

HSCs

Nude mice

55

DPPV

808

0.3

5

51

4T1 and RAW264.7

BALB/c mice

56

ICGPtTFPP

808

1

5

48

HepG2

PBTPBFBT

1064

2

5

56.4

MDA-MB231

Female BALB/c nude mice

58

DSPN5

808

1

6

60.9

4T1

BALB/c mice

59

TTTQ/DOX

800

1

10

56

MDA-MB231

-

PFVBT/PI

808

0.5

2

60

SKBR-3

Nude


-

53

57

60 61


Page 24 of 84

DTTTQ

mice

PorCP

808

0.75

10

66

HeLa and MDA-MB231

Zebrafish

62

N4

808

0.8

8

64

MDA-MB231 and NIH-3T3

-

63

TBDOPVDT

1064

0.98

1

107

-

Pig skin

64

BBT-2FT

808

1.77

10

62

HeLa

-

65

PBIBDFBT

808

1

10

55

MDA-MB231

Female BALB/c nude mice

66

PPor-PEG

630

0.8

10

50

HeLa

Male nude mice

67

BDT-IID

660

0.2

10

58.8

MCF-7

Male nude mice

68

DPP-DT

808

0.5

5

62

MCF-7 and HeLa

Female nude mice

69

498 499 500

3. Polymer-Functionalized Nanoparticles

501

Polymer functionalization of nanoparticles is a widely used technique for stabilizing

502

biomaterials and preventing their aggregation. In the case of metal and semiconducting

503

nanoparticles, the inter-particle attractive forces are especially strong. Moreover, it is very

504

important to prevent the attractive interactions of such nanoparticles with the components

505

found in body tissues. This is why these nanoobjects should be fully dispersed and stable.

506

Polymer functionalization is a successful strategy for enhancing the stability of colloidal

507

dispersions.73 Several coating strategies of functionalization using polymers are well-known.

508

One of the most useful strategies is the end-grafting of polymer chains onto the nanomaterial


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Biomacromolecules

509

surface. The formation of a polymer brush at the colloidal interface is one of the most

510

efficient methods used for colloidal dispersion stabilization.74

511

In this section we focus on the functionalization of nanoobjects by using different kinds of

512

polymers, which help to improve the chemical, physical, and biological properties of

513

nanomaterials for photothermal therapy, and endow the synthesized materials with novel and

514

unexpected functionalities.

515

3.1 PEGylation

516

Nanomaterial functionalization with poly(ethylene glycol) (PEG) is one of the most common

517

methods used to modify the surface of nanoparticles and give them stability in water,

518

biocompatibility, and other interesting features. Literature has many examples of the use of

519

this polymer to functionalize particles for biomedical applications.75 Some of them have

520

shown that during in vivo tests, nanoparticles functionalized with PEG demonstrate

521

remarkable properties such as the reduced clearance through the reticuloendothelial system of

522

the organism and the passive targeting of tumors because of the retention effect and enhanced

523

permeability. Similarly, PEGylation allows a long circulation time for NPs in the

524

bloodstream,76 while on the other hand, this technique is not useful for developing

525

multifunctional nanomaterials for polytherapy applications. These functionalized particles

526

have been investigated in numerous studies to prove their effective use as active agents for

527

photothermal therapy.

528

Li et al. proposed PEG-functionalized copper nanowires as new photothermal therapy

529

agents.77 The PEGylation chemical process consisted of adding 200 mg of PEG to 15 mg of

530

copper nanowires dispersed in 15 mL of THF. The mixture was stirred at 50°C for 4 h. The

531

functionalized nanomaterials have been characterized by higher flexibility than uncoated

532

wires and, after implantation, they are intertwined around cancer cells. Thanks to this, the



533

irradiated material transmits the generated heat to cells and effectively cause cancer ablation

534

(Figure 6a). Tests have been conducted on colon tumor-bearing mice. PEGylated

535

nanomaterials have been intratumorally injected and NIR irradiation conducted by using a

536

NIR laser (808 nm) with a power density of 1.5 W cm-2. After 6 minutes of irradiation, the

537

temperature increased rapidly above 50°C, and the suppression of tumor growth and necrosis

538

have been observed (Figure 6b).

539 540

Figure 6. (a) Scheme representing the use of PEGylated copper nanowires as a photothermal

541

agent for cancer therapy. (b) Tumor volume of CT26-bearing BALB/c mice after PEGylated

542

copper nanowires after photothermal ablation. Reprinted with permission from ref. 77.

543

Copyright 2016 American Chemical Society.

544 545

O’Neal and his co-workers used PEG-coated nanoshells for treating murine colon carcinoma

546

cells.78 To prepare PEGylated nanoshells, PEG with a terminal thiol group was added to gold-

547

silica nanoshells in deionized water. After the intravenous injection of PEGylated nanoshells

548

and their six-hour circulation in the body, mice have been illuminated with a 808 nm diode

549

laser (4 W cm-2) for 3 minutes. During the first 30 seconds, the temperature reached 50ºC.

550

After 10 days of nanoshell treatment, a complete resorption of the tumor has been observed.

551

At 90 days of post-treatment, all mice were healthy and without tumors. Similarly, gold 26 ACS Paragon Plus Environment

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Biomacromolecules

552

nanoshell agents functionalized with PEG have been developed by Hirsch et al.79 Yang et al.

553

have studied the possibility of using PEGylated conjugated nanographene sheets for the

554

photothermal therapy of murine breast tumors.80 The PTT agent preparation included the

555

attachment of amine-terminated branched PEG to graphene oxide sheets via amide formation.

556

Mice have been treated with 20 mg kg-1 of PEGylated nanosheets. After exposure to 2 W cm-2

557

of 808 nm NIR laser, the tumor surface temperature increased up to 50ºC. The Authors have

558

demonstrated that this treatment had completely eliminated 4T1 murine breast tumors and had

559

led to a 100% mouse survival. In comparison to non-functionalized gold nanorods, the

560

properties of PEGylated nanosheets seem to be similar in terms of administration routes

561

(intravenous), injected doses (20 mg/Kg), NIR laser densities requirements (2 W cm-2), and

562

irradiation term (5 min). Interestingly, in vivo tests also show relatively low retention in

563

reticuloendothelial systems and a highly efficient passive tumor targeting.

564

Cyanine (Cy) is an organic dye with high extinction coefficient in the NIR window which has

565

been widely adopted as a drug in PTT therapy. Lin et al. prepared a poly(heptamethine) Cy-

566

containing derivative (CyP) using a one-pot multicomponent reaction.81 CyP was

567

encapsulated into NPs using PEG-PLA copolymer obtaining high Cy-loading nanospheres

568

with an average diameter of 50 nm. CyP@PEG-PLA NPs were stable in aqueous solutions for

569

half a year, showed a PT conversion of 12% and caused irreversible tumor cellular damage in

570

mice with HeLa tumors upon 808 nm light irradiation for 30 min after injection of 150 µL of

571

a 200 µg mL-1 NPs solution.

572 573

3.2 Chitosan functionalized nanomaterials

574

Chitosan is a natural cationic polymer which is characterized by properties that are significant

575

for

biomaterials:

non-toxicity,

biodegradability,

and


biocompatibility.

Chitosan


576

functionalization of nanoparticles for PTT has several advantages. Indeed, chitosan coatings

577

protect nanoparticles, avoiding irreversible coalescence and improving their optical stability,

578

thus rendering photothermal ablation more effective. Chitosan-based coating significantly

579

changes the surface property of nanoobjects. Chitosan is an excellent agent for nanoparticle

580

biocompatibilization and stabilization, but it can also be useful as a scaffold structure for

581

anchoring the antibodies and proteins needed for selective cellular targeting.82 Thanks to the

582

presence of amino groups, chitosan can be applied to drug or DNA delivery systems, since it

583

can be ionically crosslinked to multivalent elements. Due to its properties, chitosan has

584

already been widely used for coating metal nanomaterials such as gold and silver

585

nanoparticles.83

586

Boca et al. have focused on the study of photothermal activation in chitosan-coated silver

587

nanotriangles (Chit-AgNTs) for treating human lung cancer cells (NCI-H460).82 Chit-AgNTs

588

have been prepared by triggering the reaction of silver nitrate in chitosan solution. Cells have

589

been incubated with Chit-AgNTs and irradiated by a laser at different power densities for 10

590

min at 800 nm. The Authors found that the rate of cell mortality in the presence of Chit-

591

AgNTs is higher than in the presence of thiolated poly(ethylene) glycol-capped gold

592

nanorods. Cytotoxicity tests have shown that Chit-AgNTs are efficiently uptaken by cancer

593

cells, while exhibiting good biocompatibility for healthy human embryonic cells.

594

Zhuang et al. have synthesized gold nanoparticles coated with chitosan or O-carboxymethyl

595

chitosan (CMCS), and studied them as therapeutic agents for the photothermal ablation of

596

cancer cells, such as the hepatocellular carcinoma cell line (HepG2) and human dermal

597

fibroblast cells (HDF).84 The particle functionalization procedure relies on mixing chitosan or

598

CMCS with as-synthesized gold particle suspensions. During in vitro tests, HepG2 and HDF

599

cell lines have been incubated in a medium containing CN or CMCS gold nanoparticles for

600

2 h. Cells have been exposed to 817 nm NIR laser (5 W cm-2) for 2 min. The highest 28 ACS Paragon Plus Environment

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Biomacromolecules

601

efficiency of the photothermal ablation has been observed for the cells treated with

602

gold/chitosan nanoparticles. Almost 100% of HepG2 and 90% of HDF cells have been killed

603

after the laser treatment.

604 605 606 607

3.3 Peptide functionalization of nanoagents

608

The diagnosis and treatment of cancer diseases at the cellular level would be greatly enhanced

609

by the ability of multifunctional nanomaterials to deliver active probes and therapeutic agents

610

into specific cells and cellular compartments. The cell nucleus is the most desired target for

611

cancer therapies. Targeted nuclear delivery of diagnostic probes and therapeutics could

612

improve disease detection and treatment. The goal of several research studies is to further

613

examine the ability of multipeptide nanoparticle conjugates to target cell nuclei. Observations

614

suggest that the most efficient nuclear targeting may result from the use of peptides attached

615

to a single vector. Combining this type of strategy with other types, such as photothermal

616

therapy, offers greater possibilities for developing effective cancer cell eradication methods.

617

Peptide layers screen the undesirable inorganic surface of nanoparticles behind an organic

618

shell, endowing the nanoagents with the needed cell-entering properties together with the

619

required optical properties.73

620

Daniels et al. have presented new approaches for the synthesis of pH Low Insertion Peptide

621

(pHLIP) and PEG-coated spherical and spiked gold nanoparticles for the enhancement of

622

radiation damage during NIR thermal therapy.85 It has been shown that pHLIP peptides are

623

excellent for targeting acidic tumors, and their use makes it possible to deliver therapeutic

624

agents speciﬁcally to the cancer cells inside tumors. The irradiation by an 805 nm laser of 29 ACS Paragon Plus Environment


625

multispiked gold nanoparticles coated with PEG and pHLIP led to a time- and concentration-

626

dependent increase in temperature. The developed pHLIP-coated nanoparticles can ﬁnd

627

applications in targeted photothermal therapies of tumors.

628

The possibility of fabricating graphene oxide decorated with gold nanoparticles by using

629

thermostable antimicrobial nisin peptides as functionalizing agents has been presented by

630

Otari et al. 86 This nanocomposite has been used as an agent in photothermal therapy, showing

631

an enhanced photothermal activity compared to gold nanoparticles, thanks to the presence of

632

reduced graphene oxide (rGO). Nisin peptide has a wide range of antimicrobial activities

633

against gram-positive microorganisms. During in vitro tests, cells have been treated with the

634

synthesized nanocomposite and irradiated using an 800 nm laser (at a power density of 0.5 W

635

cm-2). The photothermal effect of nanocomposites on MCF7 breast cancer cells caused the

636

inhibition of approximately 80% of the cells after a 5 min irradiation.

637

Tan et al. have demonstrated that the lycosin-I-conjugated spherical gold nanoparticles

638

(LGNPs), lycosin-I-modified gold nanorods (LGNRs), and gold nanorods (GNRs) showed an

639

efficient cellular internalization efficiency toward cancer cells, also displaying an

640

unprecedented selectivity over noncancerous cells.87 LGNRs and LGNPs have been examined

641

as platforms for cancer photothermal therapy. In vitro tests have been carried out using HeLa

642

cells previously incubated with LGNRs or peptide-modified gold nanorods (PGNRs) and

643

near-infrared irradiation (808 nm) at a power density level of 2 W cm-2 or 5 W cm-2. In vivo

644

experiments using BALB/c nude mice with xenograft tumor were performed by intravenously

645

injecting LGNRs, PGNRs and sterile PBS three times, with a time interval of 3 days. The

646

cancer sites of each mouse have been irradiated by a 808 nm laser at power density of 3.54 W

647

cm-2 for 5 minutes at a time point of 24 and 48 hours after each injection. LGNRs exhibited

648

selective intracellular translocation toward cancer cells and an efficient photothermal effect

649

under near-infrared (808 nm) irradiation, which consequently effectively killed cancer cells in 30 ACS Paragon Plus Environment

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Biomacromolecules

650

vitro and in vivo. Therefore, the established LGNPs and LGNRs possessed great potential in

651

cancer-targeted delivery and photothermal therapy.

652 653

3.4 Functionalization with nucleic acids

654

The functionalization of nanoparticles with nucleic acids has many advantages, offering the

655

possibility to combine photothermal therapy with gene therapy.88 The aim of gene therapy is

656

to treat cancer by using nucleic acids to inhibit the expression of genes which drive tumor

657

progression. Small interfering RNA (siRNA) is one of the main types of nucleic acids useful

658

in gene regulation. Its function is the suppression of gene expression, which triggers the

659

degradation of RNA molecules inside the cytoplasm of cells. This way, the production of the

660

encoded disease-associated protein is stopped.89

661

Nanomaterial surface functionalization with siRNA has been used in the study presented by

662

Wang et al.

663

photothermal agent showed the ability to deliver siRNA oligos targeting the BAG3 gene,

664

which efficiently blocked the heat-shock response. Gold nanorod-siRNA agents have been

665

prepared by combining anionic-charged siRNA oligos with gold nanorods whose surface was

666

previously modified by negatively-charged poly(sodium 4-styrenesulfonate) (PSS) and

667

positively-charged

668

experiments, Cal-27 cells have been treated with functionalized gold nanorods for 24 h and

669

irradiated by a 810 nm wavelength laser at different power densities. In the case of in vivo

670

tests, mice infected with tumors have been injected with a gold nanorod-siRNA sol, and

671

irradiated by the 810 nm laser with a energy density of

672

treatment, the tumors have been extracted and analyzed (Figure 7). In vitro and in vivo studies

673

demonstrated the ability of the siRNA-functionalized nanomaterials to overcome

90

They have modified gold nanorods using siRNA and the developed

poly(diallyldimethylammonium

chloride)


(PDDAC).

In

in

vitro

600 J cm-2. 18 days after the


674

thermoresistance and produce the maximal tumoricidal effect with minimal damage to normal

675

tissues. The inhibition of BAG3 expression makes cancer cells more vulnerable to

676

chemotherapy or radiotherapy, thereby eliminating their therapeutic resistance and enhancing

677

therapeutic efficacy.

678 679

Figure 7. (a) Tumor growth percentage from different groups during the first 18 days after

680

Gold nanorod-siRNA treatment. (b) Photographs of tumors 18 days after G1-G5 treatments.

681

Reprinted from ref. 90. Copyright 2015, with permission from Elsevier.

682 683

Braun and co-workers have used gold nanoshells modified with siRNA for gene silencing.

684

They have used a NIR laser to control the release of siRNA from nanoshells.91 It has been

685

shown that the intense local heating by pulsed lasers causes vesicle rupture, which allows the

686

drug delivery through membranes. In order to study the system efficiency, the Authors used a

687

GFP-expressing cell line and the combination of siRNA release with nanoshell-induced

688

endosome rupture has been explored. Cells incubated with nanoshell-siRNA have been

689

irradiated by a 800 nm pulsed laser with a power density of 3.5 W cm-2. All samples showed

690

high viability, but the GFP level for laser-exposed nanoshell-siRNA showed a gene silencing

691

of about 80% . 32 ACS Paragon Plus Environment

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Biomacromolecules

692

The use of pulsed near-infrared laser irradiation for the release of nucleic acid from gold

693

nanoparticles has also been investigated by Takahashi et al.92 They used plasmid DNA

694

immobilized on gold nanorods modified by phosphatidylcholine (PC-GNRs). DNA-PC-GNR

695

sols under irradiation with a 1064 nm laser. The results showed that only tens of seconds of

696

NIR laser irradiation are necessary to induce DNA plasmid release. Such a rapid release is

697

very beneficial for minimizing unwanted photochemical damage.

698

Another exciting application of photothermal therapy combined with gene therapy is the

699

possibility to treat not only cancer, but even diseases caused by microbial infections. The use

700

of aptamer-functionalized gold nanoparticles (Apt@Au NPs) and gold nanorods (Apt@Au

701

NRs), for the inactivation of Methicillin-resistant Staphylococcus aureus (MRSA) by targeted

702

photothermal therapy, has been reported on by Ocsay et al.93 The DNA aptamer was

703

specifically selected to MRSA cells and used for targeted therapy. Au NRs and Au NPs acted

704

as convertors for transducing NIR radiation to heat for the photothermal inactivation of cells.

705

Mixtures of aptamer-functionalized nanoparticle or nanorod sols and the cell solution were

706

incubated for 1 h, and then illuminated using a single-mode NIR laser with 808 nm

707

wavelength at 1.1 W cm-2 power density. Results showed that both Apt@Au NPs and

708

Apt@Au NRs specifically bound to MRSA cells, but only Apt@Au NRs effectively

709

inactivated MRSA cells through hyperthermia due to their longitudinal absorption of NIR

710

radiation and photothermal conversion. The Authors also observed that the MRSA Apt@Au

711

NRs are very effective and promising nanosystems for specific cell recognition and in vitro

712

PTT. Au NRs have multiple functions, serving as a nanoplatform for aptamer immobilization

713

and also providing multivalent effects for increasing the binding strength of aptamer for the

714

targeting of MRSA cells; moreover, they act as photothermal agents to inactivate cells with

715

the heat generated under NIR irradiation.



716

The functionalization of nanoparticles used in photothermal therapy offers the possibility to

717

combine this therapy with other innovative therapeutic methods, such as chemotherapy,

718

immunotherapy, and gene therapy. The use of appropriate modifications not only increases

719

the therapeutic effectiveness, but also prevents damage to healthy cells and tissues. The

720

studies described clearly demonstrate the great efficiency of polymer-functionalized

721

nanoparticles in killing cancer cells. Some recent studies, however, have shown that

722

photothermal therapy is always accompanied by a heat shock response. This effect shields

723

cancer cells from hyperthermia damage, consequently decreasing its therapeutic efficacy.

724

Usually, to increase therapeutic efficacy, a larger administration dose or higher irradiation

725

power is necessary, causing severe side effects due to the overheating of neighboring normal

726

tissues. The use of gene therapy combined with phototherapy is a fascinating candidate for

727

solving this problem. Killing cancer cells without inducing cellular thermoresistance by

728

photothermal therapy is one of the biggest challenges in this field.

729 730


Page 34 of 84

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Biomacromolecules

731

4. Polymer Matrix Composites

732

Polymer matrix composites are materials formed from at least two different types of

733

components, e.g. polymer matrix and ceramic/metal nanofillers.94 In these materials, the

734

polymer matrix is a hosting network, while nanofillers are the photothermal agents. The

735

objective of composite development is to create new materials which will combine the

736

advantages of both components at the same time. Today, the latest trend of cancer treatment is

737

the development of techniques based on a combination of various treatment methods (e.g.

738

combined chemo- and photothermal therapy) which operate locally. Local treatments make it

739

possible to maximize the bioactive molecule concentration in the cancer area, while

740

minimizing the drug toxicity for other tissues. This type of treatment has been considered

741

much more effective than conventional chemotherapy.95

742

Various delivery systems such as drug-loaded fibers or hydrogel have been studied for local

743

therapy in recent years.96,97 As we have already pointed out, however, a single cancer

744

treatment method is not sufficient, because of both the inefficient drug permeability in the

745

cancer site, and the drug resistance of tumor cells.98 Therefore, thermally responsive polymer-

746

matrix composites are a promising solution because they can easily host drugs and

747

photothermally-active particles. Moreover, because of the polymer responsivity, the final

748

material can be used as an on-off switch for drug release under NIR irradiation.99 In the case

749

of drug release, the hyperthermia effect of photothermal therapy not only kills cancer cells,

750

but also increases drug penetration into the tumor site.100,

751

caused by the non-target accumulation occur, together with an unsatisfactory anticancer

752

efficiency.100 However, drug release is still a not entirely controllable process. Furthermore,

753

additional advantages of the use of polymers in biomedical applications stem from the

754

biodegradable nature of these materials.102

101


In this case, the side effects


755

The properties of polymer composites (e.g. mechanical properties, degradation rate, and drug

756

release) are highly dependent on structural morphology at the molecular level, such as

757

crystallinity fraction or crystallite size, and polymer chain structure. It is worth remembering

758

that polymer structure is characterized by temperature-dependent features. When surface

759

plasmon resonance (SPR) is induced in the polymer composite, due to the inclusion of

760

inorganic nanofillers, energy is transferred from the particle to the surrounding polymer

761

matrix, causing local polymer melting and, consequently, leading to changes in its structure.94,

762

103-105

763

described by Viswanath et al. 103 They demonstrated that a low annealing temperature reached

764

during the photothermal process led to the maximum polymer crystallinity in a shorter

765

annealing time than with conventional annealing procedures (Figure 8). Gold nanoparticles

766

embedded into polymer matrixes are localized heat sources which make it possible to

767

manipulate crystallinity, crosslinking, or chemical reactions. Using this nature-inspired

768

cascade approach, the internal structure of polymer matrix composites can be altered at any

769

point in their life cycle by photothermal treatments. Indeed, light responses can act as

770

mediator signals which generate material structural transformations and, in turn, offer

771

additional functionalities (e.g. on-off release of bioactive molecules) to the material.99, 102, 106

The effect of photothermal heating on the polymeric structure has been extensively

772


Page 36 of 84

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Biomacromolecules

773 774

Figure 8. Images of poly(ethylene oxide) (PEO) spherulites observed through a cross-

775

polarized optical microscope of: (a) melt-crystallized gold nanoparticle:PEO film; (b, c, d)

776

after conventional annealing at 60 °C and after photothermal process; (e, f, g) at different time

777

points; (h) crystallinity; (i) spherulite density as a function of annealing time for gold

778

nanoparticle:PEO melt-crystallized films. The annealing was conducted by conventional and

779

photothermal heating. Reprinted with permission from ref. 103. Copyright 2013 American

780

Chemical Society.

781 782

Today there are only a few scientific papers devoted to polymer matrix composites. They are

783

briefly described in the following paragraphs.

784



Page 38 of 84

785

4.1 Hydrogels

786

Hydrogels are three-dimensional constructs formed by hydrophilic polymers, in which the

787

polymer chains are crosslinked physically or chemically to form a network. The capability to

788

accumulate large amounts of water is a characteristic feature for hydrogels, which may reach

789

up to 90% of their bulk mass. High water content, softness, flexibility, and biocompatibility

790

make hydrogels very similar to natural tissues. At the same time, this type of material has

791

certain limitations, e.g. toxic crosslinking agents which may remain in the bulk,

792

inhomogeneity of nanoparticle dispersion, or poor mechanical properties.107 Moreover, a few

793

hydrogels are responsive to different kinds of environmental condition changes, like pH or

794

temperature. Thermosensitive hydrogels are characterized by lower and upper critical solution

795

temperatures (LCST, UCST), which indicate the temperature points of hydrogel state

796

transitions. Some hydrogels formed for controlled drug release show a LCST slightly above

797

body temperature. When the temperature of the copolymer exceeds the LCST, the hydrogel

798

collapses and releases any components suspended in the hydrogel matrix.107-109 Hydrogels are

799

currently used for manufacturing various medical devices, such as contact lenses, tissue

800

engineering scaffolds, drug delivery systems, and wound dressings.107 The application of this

801

type of material for photothermal cancer therapy was recently explored by several scientists.99,

802

110-112

803

Hydrogel materials for cancer therapy have been developed and studied by Conde et al.

804

These Authors proposed the use of one single hydrogel patch capable of combining gene,

805

drug, and photothermal therapies all at the same time. This hydrogel contains nanofillers such

806

as gold nanorods and gold nanospheres. Nanorods have been functionalized with appropriate

807

biomarkers, in order to enhance their uptake by cancer cells. These biomarkers made it

808

possible to eliminate the problem connected with the absorption by healthy cells and the

809

strong hypothermia impact on them. Using confocal microscopy and proper labeling 38 ACS Paragon Plus Environment

99

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Biomacromolecules

810

techniques, the Authors proved that nanoparticles are more effectively absorbed by CRC cells

811

(cancer cells) than 3T3 fibroblasts. MTT assay also confirmed the decreased tumorgenicity of

812

CRC cells after laser irradiation. The hydrogel formed using poly(amidoamine) and the

813

abovementioned particles was analyzed in in vivo tests using mouse models (Figure 9). It has

814

been shown that the designed hydrogel nanocomposite is a good material for nanoparticle and

815

drug delivery into cancers, as well as an effective carrier for the quick diffusion of therapeutic

816

agents into cancer cells. However, some questions concerning implantation procedure (e.g.

817

depth, insertion, and fixation) still remain under debate. Moreover, the rapid changes in the

818

material structure and its consequent possible damage after reaching the LCST point, which

819

facilitates the quick release of drugs, remains an unsolved problem.

820 821

Figure 9. (a) Schematic of the smart hydrogel–nanoparticle patch with drug–siRNA

822

nanoparticle conjugates (drug–gold nanorods and siRNA–gold nanospheres) for local gene

823

and drug release designed by Conde et al.99. (b) Fluorescence and thermographic images of

824

hydrogel patches. (c) Thermographic surveillance of the photothermal heating of hydrogel



Page 40 of 84

825

patches in mice (nD5) 72 h after the first NIR treatment. Reprinted by permission from

826

Springer

827

http://www.nature.com/nmat/

Nature,

ref.

99.

Copyright

2016,

Macmillan

Publishers

Limited.

828 829

In order to improve the implantation of hydrogel composites, injectable materials should be

830

taken into consideration. Xing et al. have described an injectable, self-healing hydrogel with

831

self-assembly biomacromolecules.110 In this study, natural polymers such as collagen, elastin,

832

or silk fibroin have been used. The interactions between polymer gelators and nanoparticles

833

have been used to assemble tunable and self-healing polymeric materials. Additionally,

834

nanoparticles play a key role in tuning mechanical properties, while the polymeric matrix

835

remains a good environment for water-soluble drug diffusion. The Authors extensively

836

described the healing mechanism of this hydrogel, focusing on the gold nanoparticle-collagen

837

interaction. It has been proven that intratumoral-injected hydrogel sustained in situ and that

838

the drugs were successfully released.

839

A few studies reported that the process of selective treatment of cancer cells by hyperthermia

840

needs to be improved.111 The hydrogel composite formed with spinach extract, reduced

841

graphene oxide, gold nanocages (AuNCs), and fluorouracil (5-FU) effectively increased the

842

temperature and released the drug, leading to a successful reduction in HeLa cell proliferation.

843

But as it was shown, CHO cells, used as a control, also exhibited a reduced proliferation. This

844

effect is due to the rGO and/or AuNC release, which additionally affects CHO cell

845

proliferation. The Authors, however, only presented profiles for 5-FU, without showing data

846

on rGO or AuNCs release.111 In this case, the effectiveness and targeting ability of the active

847

compound could be modified by appropriate biomarkers as proposed by Conde et al. 99


Page 41 of 84 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

848

For hydrogels, as well as for any other type of 3D materials, implantation remains a crucial

849

problem. A good idea for the proper placement of hydrogel composite components is the in

850

situ crosslinking. Zhang et al. have explored this type of strategy with a view to synthesize a

851

novel hydrogel for synergistic cancer therapy.113 The hydrogel has been formed by

852

poly(ethylene glycol) double acrylates (PEGDA), a titanium dioxide/multiwall carbon

853

nanotube (TiO2@MWCNT) nanocomposite, which acts as a photoinitiator and photothermal

854

agent for cancer multi mechanism therapy, while DOX has been applied as a model drug.115

855

The proposed material showed a certain recyclability, which may be important for successful

856

treatments, and a long-lasting drug release. However, the reported data also showed that

857

limited UV or NIR light penetration may be an additional problem. Because of these reasons,

858

this material may not be suitable for deeply located tissue treatments.114, 115

859

An injectable drug delivery system which provides photothermal transduction activity was

860

proposed by Zhou et al.

861

(SWNTs), PNIPAM hydrogel, and doxorubicin. The combination of hyperthermia therapy

862

and controlled DOX release gave a higher cancer suppression rate on gastric cancer xenograft

863

mouse models than did free DOX, and without detectable organ toxicity. However, the

864

application of rGO or carbon nanotubes in medical treatments seems to be yet uncertain. The

865

release profiles, accumulation in tissues, and cytotoxicity are constantly studied, and at the

866

same is still unclear.117, 118

867

Polymer matrix composites in the form of hydrogels may be successfully used as medical

868

materials for combined cancer therapy (chemo- and photothermal therapy). Some problems

869

concerning the nature of these materials should also be solved. Furthermore, the accurate

870

control of the heating under NIR irradiation to avoid damaging the hydrogel structure and the

871

fast drug release will be the biggest challenge in this field.

116

The developed system contains single-wall carbon nanotubes



872

4.2 Fibrous membranes

873

Polymer membranes already play a significant role in fields such as water purification, fuel

874

cells, cell scaffolds, and wound dressings. Membranes may be formed by various techniques

875

e.g. melt electrospinning 119 or electrospinning,120-124 solvent casting and particles leaching 125

876

or freeze-drying.126 In the case of polymer matrix composites for photothermal cancer therapy,

877

however, just a few of these have been investigated. Nonwovens can be fabricated by various

878

techniques, thus making it possible to obtain fibers with diameters ranging from dozens of

879

nanometers to a few micrometers.120-124 Fibrous nanomaterials are promising materials for

880

medical applications such as photothermal cancer therapy, due to their highly active surface

881

area, to which drugs or particles can be attached.

882

The concept of using fibers for photothermal therapy is quite new, and only a few papers have

883

been published recently on this subject. Zhang et al. proposed poly-L-lactic acid (PLLA)

884

composite nanofibers loaded with multiwalled carbon nanotubes (MWCTs) and

885

doxorubicin.102 Moreover, in this scientific work, polytherapy (chemo- and photothermal

886

therapy) has been suggested for cancer treatment and the on-off switching mechanism of drug

887

release was described. PLLA has a low glass-transition temperature (Tg) of around 60°C.

888

Since the human body temperature is under the Tg of PLLA, the as-prepared material is in its

889

glassy state and the polymer chain mobility is limited. Therefore, the release of DOX from the

890

fibers is rather slow (5-8% per 12 h, depending on pH). After irradiation, however, a great

891

deal of heat is efficiently generated by MWCNTs. When the temperature exceeded the PLLA

892

Tg, the mobility of the polymer chain increased, enhancing the drug release (20% per 2 h after

893

30 minutes of irradiation). This work proved that nanofibers can effectively combine two

894

cancer treatment methods, while delivering drugs effectively and locally. This material can be

895

easily used for the treatment of skin cancer, but its implantability remains uncertain.


Page 42 of 84

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Biomacromolecules

896

Furthermore, as was described in the previous paragraph, the problem connected with the

897

MWCNT cytotoxicity is still unsolved.

898

Nonwovens for photothermal therapy were also analyzed by Shao et al.127 Locally produced

899

energy was an effect of the bismuth selenide (Bi2Se3) irradiation. In this work, Bi2Se3

900

nanoplates were incorporated into the poly(lactide) fiber matrix and tested as photothermal

901

agents (Figure 10).

902 903

Figure 10. (a) Scanning electron microscope (SEM) and transmission electron microscopy

904

(TEM) images of PLLA and Bi2Se3/PLLA membranes. (b) Infrared thermographic maps and

905

time-dependent temperature increase in the tumor-bearing nude mice irradiated by an 808 nm

906

laser. (c) Temperature growth during the irradiation of PLLA and Bi2Se3/PLLA membranes.



907

(d) Corresponding growth curves of tumors in different groups of mice after NIR laser

908

irradiation. Reprinted with permission from ref. 127. Copyright 2017 American Chemical

909

Society.

910 911 912

The Authors showed that composite fibers effectively increase the temperature of the

913

medium, while killing HeLa cancer cells. In this case, however, one important issue should be

914

further taken into consideration: the Authors did not present data concerning bismuth selenide

915

release from fibers before and after irradiation, nor on its cytotoxicity for non-cancer cells. If

916

such a significant temperature increase appears during irradiation, PLLA molecule mobility is

917

increased and nanoplates may be easily released to the environment.128 This problem is not

918

visible when analyzing monocultures of HeLa cells, because target cells are logically

919

successfully killed. However, in co-culture, such as in in vivo conditions, both healthy and

920

cancer cells coexist. In this case, it is hard to say if either only local hypothermia is

921

responsible for cell death or if the cytotoxicity of bismuth selenide is also a cause of it.127 The

922

concept of selectively attaching biomarkers could be used in this case, as was done by Conde

923

et al. 99 to limit bismuth selenide effects on healthy cells.

924

Additionally, nanofibers may be surface-functionalized in order to introduce bioactive

925

components for treatment purposes.129 However, the attached substances should be carefully

926

selected in order to avoid inducing cytotoxic effects.118 Moreover, it should be remembered

927

that surface-functionalized fibers show very different particle/drug release kinetics and

928

photothermal effect efficiency than do bulk loaded fibers.

929

Various technologies are available today to fabricate fibers on a mass scale. Most of them use

930

polymer solutions or melted polymers. This may be problematic if biologically active 44 ACS Paragon Plus Environment

Page 44 of 84

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Biomacromolecules

931

molecules for combined therapy are to be added to fibers. Aggressive solvents or high

932

temperature could cause the degradation of these components. To summarize, the

933

implantation procedure of nonwovens, their degradation in in vivo conditions, and the

934

influence of solvent traces should be further investigated.

935

Only a few scientific articles on polymer nanocomposite membranes with different

936

morphologies for photothermal therapy have been published recently.130-132 Li et al. fabricated

937

polydimethysiloxane (PDMS) membranes containing gold nanoparticles which have been

938

synthesized by the in situ method.130 In the case of composite membranes with nanoparticles,

939

the potential segregation of components may occur, thus leading to a higher intensity of the

940

NIR radiation needed for photothermal effects. To avoid this problem, Li et al. decided to use

941

in situ polymerization. Wet and dry samples of the proposed composites have been studied. It

942

has been demonstrated that the amount of remaining solvent traces affects the intensity of the

943

photothermal effects. Upon laser irradiation, wet membranes reached lower temperatures than

944

dry membranes. The Authors explained that, most likely, the heat generated by gold

945

nanoparticles is dissipated throughout the entire system (both the remaining solvent and the

946

polymer matrix) in wet membranes, resulting in a lower temperature of these materials

947

compared to dry membranes.131, 132 The data presented may help to understand the differences

948

in the efficiency of photothermal effects in the previously mentioned hydrogels or nonwoven

949

materials.

950

Up to this time, various forms of polymer matrix composites for photothermal cancer

951

treatment have been investigated. As can be seen, all of them show significant advantages, i.e.

952

are good vehicles for drugs and nanoparticles, and induce localized hyperthermia, but they

953

also have a few disadvantages: a not fully controlled drug release and a limited implantation

954

localization and depth. In spite of this, polymer matrix composites are the most promising



955

materials for the development of functional materials for the combined chemo- and

956

photothermal therapy of cancer.

957 958 959

5. New Trends

960

In the fight against cancer, compared with traditional therapeutic approaches (e.g.

961

chemotherapy, radiotherapy and immunotherapy), PTT exhibits very unique advantages such

962

as selective targeting and minimal invasiveness. PTT has the capability to destroy cancer cells

963

in the primary tumor (mainly if localized in superficial tissues) and to combat the initial stage

964

of cancer metastasis. Moreover, PTT can effectively destroy cancer stem cells and tumor

965

initiating cells avoiding metastatic propagation to distant organs. It is important to say that

966

PTT can kill cancer cells via cellular necrosis, enabling an inflammatory responses that can

967

affect the efficacy of the same treatment. To overcome this issue, it has been demonstrated the

968

possibility to trigger the PTT heat in such a way to induce apoptosis (does not generate an

969

inflammatory process) rather than necrosis.10 On the other hand, at the current stage PTT fails

970

if applied after the metastatic process has taken place, such as in presence of aggressive

971

tumors involving important organs or tissues which are already far away from the primary

972

tumor. To overcome this issue, novel nanoplatforms able to efficiently combine PTT with

973

other therapies to exert a stronger impact in presence of metastasis has been combines. In this

974

framework, photoresponsive nanoagents have been exploited for combined PTT-

975

immunotherapy.133 Results have shown that nanotubes-based PTT could modulate the

976

adaptive immune responses for the treatment of metastatic cancers. PTT agents could not only

977

be used for photothermal tumor destruction but also act as immunological adjuvants

978

promoting the maturation of dendritic cells and production of anti-tumor cytokines. These


Page 46 of 84

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Biomacromolecules

979

data prove that after photothermal ablation of the primary tumor, the induced immunological

980

responses are able to inhibit a secondary tumors as well as lung metastasis. Another approach

981

is based on the fact that, cellular dysfunctions due to radiation are mediated by the

982

microvascular endothelial damage and that therefore chemical vascular disrupting agents

983

could be effective in combination with radiation therapy for the tumor vascular disruption.

984

The use of these agents are promising materials to improve therapeutic outcome and

985

extending their applicability to tumors that barely respond to standard therapies. Kunjachan et

986

al. proposed a dual-targeting strategy to improve tumor blood vasculature radiation outcome

987

by inducing vascular damage.134 This study, experimentally validated the hypothesis that

988

tumor-specific vascular disruption could be mediated by the administration of targeted

989

nanoparticle followed irradiation which could be easily extended to PTT nanoplatforms.

990

The development of novel nanomaterials for photothermal therapies is evolving rapidly.

991

Current strategies concern not only monotherapies such as the NIR-controlled heating of

992

cancerous cells with, for example, gold nanorod nanoparticles. The novel advanced medical

993

treatments require the development of combined therapies using NIR illumination for

994

inducing chemotherapeutic drug release or photodynamic therapy. One of the emerging

995

techniques used for the formation of multifunctional biomaterials is electrospinning. In this

996

method, a polymer solution is stretched by electrostatic forces which develop between a

997

needle, connected to a high voltage supply, and a grounded collector in order to form ultra-

998

thin fibers. Moreover, due to the nanosized fiber diameter, the developed materials show

999

structural similarity to the naturally produced proteins and polysaccharide complexes present

1000

in the extracellular matrix (ECM), positively influencing cellular proliferation and activity.121

1001

As we will show in this paragraph, electrospinning can combine all the properties of the

1002

abovementioned materials, conjugated polymers can be electrospun, while the electrospun

1003

nanomaterial surface can be easily functionalized, and it is even possible to fabricate 47 ACS Paragon Plus Environment


1004

composite nanomaterials to develop novel heat generating devices. One of the best examples

1005

of this is the development of CaTiO3:Yb,Er nanofibers co-conjugated with Rose Bengal (RB)

1006

and gold nanorods.135 The incorporated RB served as the photodynamic therapy agent, while

1007

the gold nanorods attached to the nanofiber surface were responsible for the hyperthermia

1008

effect. Additionally, upconversion photoluminescence (UCPL) of CaTiO3:Yb,Er nanofibers

1009

was used to excite RB and gold nanorods, so photodynamic and photothermal therapy could

1010

occur simultaneously, during the irradiation with a laser source (λ=980 nm) with a deeper

1011

tissue penetration. The combination of several treatments is particularly significant due to the

1012

resulting synergistic effect that shrinks the tumors and stops the metastatic spread of cancer,

1013

in which cells escape from the primary tumor and form new ones. Moreover, every

1014

monotherapy has its own side effects; therefore, combining different therapeutic approaches

1015

can help eliminate heterogeneous cancer cells that cannot be treated with single

1016

chemotherapeutic agents due to drug resistance.

1017

The rise of new strategies in the treatment of tumors is essential for the complete eradication

1018

of cancer cells from the body. PTT is a promising method for increasing temperature to a

1019

level that induces the apoptosis of cancer cells via localized hyperthermia; on the other hand,

1020

this method also makes it possible to trigger other processes that could also help eliminate

1021

cancer cells. One of these methods is the on-off release of drugs. For instance, Park et al. have

1022

described an experiment in which fibrous polycaprolactone (PCL) materials containing phase-

1023

changeable fatty acids and indocyanine green were illuminated with NIR light.136 Upon NIR

1024

illumination, the temperature of the material increased above the melting point of the fatty

1025

acids, thus causing a greater drug release from the material. This strategy could limit the

1026

harmful impact of chemotherapeutic drugs, being more beneficial for patients’ health.

1027

Another interesting functionality that could help clinicians in assessing the response to

1028

treatment is the monitoring of the drug release from the implanted biomaterial itself.137 The 48 ACS Paragon Plus Environment

Page 48 of 84

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Biomacromolecules

1029

incorporation of Yb3+/Er3+ into CaTiO3 nanofibers helped control the release of doxorubicin;

1030

additionally, the amount of this kind of bioactive molecule could be easily assessed optically

1031

by evaluating the intensity ratio of green to red emissions of UCPL nanofibers under

1032

irradiation with a 980 nm laser. Another innovative strategy is the simultaneous capture and

1033

killing of cancer cells described by Mauro et al.138 They have functionalized the surface of

1034

PCL fibers with graphene oxide. This allowed the selective capture of circulating tumor cells

1035

and upon irradiation of NIR light, the temperature increase eradicated them photothermally.

1036

This is a potential tool not only for eliminating metastatic cells, but also for the early detection

1037

of cancer cells thanks to the fluorescence properties of this material. In any case, while the

1038

idea of capturing and eradicating circulating tumor cells with NIR light is promising, the long-

1039

term consequences of using graphene oxide in implantable nanomaterials are not well known.

1040

The abovementioned hybrid scaffold could be implanted under the patient’s skin, thus making

1041

it more accessible for NIR light illumination. However, new PTT agents are necessary for

1042

treating inaccessible tumors with light in the NIR I region.

1043

As mentioned in the previous paragraph, numerous photothermal agents, especially

1044

nanomaterials with strong absorbance in the tissue-transparent NIR I (650-950 nm), region

1045

have been studied extensively for use in PTT. The low penetration depth of laser light is one

1046

of the limiting factors which permit treating superficial cancers only, such as skin and breast

1047

tumors. The illumination of tissues by lasers operating in the NIR II window (950-1700 nm)

1048

offers a higher light penetration depth. One of the most fascinating examples of this is the use

1049

of CaTiO3:Yb,Er nanofibers which, thanks to the UCPL, emit light-activating photosensitizers

1050

and heat-generating agents, leading to a synergistic effect of photodynamic and photothermal

1051

therapies, while irradiated with a 980 nm laser.135, 137 Nanomaterials filled with nanoagents

1052

which absorb light in the NIR II region, have a high aspect ratio, and present upconversion



Page 50 of 84

1053

photoluminescence could potentially be used for the formation of theranostic medical devices,

1054

opening new possibilities for the simultaneous diagnosis and efficient treatment of tumors.

1055

6. Conclusions and Future Perspectives

1056

From the very beginning, inspiration from nature has proved to be very helpful for the

1057

development of advanced materials with novel and unpredictable properties, looking at the

1058

mechanisms involved in life processes as they occur in nature, but with an in-depth

1059

knowledge of material sciences. Proper design and application of theranostic biomaterials

1060

based on polymer PTT agents require a deep understanding of the features that distinguish

1061

them from other smart materials. Polymer-based PTT nanoplatforms offer many advantages,

1062

such as ease of fabrication, biocompatibility and especially the possibility to tune their

1063

cascaded responsive properties in order to trigger other local cancer treatments such as

1064

chemo-, gene-, or photodynamic therapy.

1065

This review provides an overview on the progress made towards the production of different

1066

types of polymer-based multifunctional nanomaterials for PTT. Three main material classes

1067

have

1068

nanoparticles and polymer matrix composites. All of them are composed by different types of

1069

polymers and the processes used in responding to light stimulation in a controlled cascade-

1070

like fashion are based on different mechanisms, therefore every described class presents

1071

specific advantages and shortcomings.

1072

In summary, conjugated polymers are highly versatile materials which can be synthesized

1073

through well-established reactions (e.g. click chemistry, copolymerization, ester-coupling and

1074

polycondensation). Moreover, they can be functionalized after polymerization in order to

1075

introduce novel functional groups. This makes these polymers ideal building blocks for

1076

materials with enhanced light-to-heat conversion (e.g. improving the light-harvesting ability

been

identified:

conjugated

polymer

nanomaterials,


polymer-functionalized

Page 51 of 84 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

1077

in the second NIR window). Additionally, conjugated polymers such as polythiophene

1078

derivatives can be easily modified in order to increase their water solubility. Conjugated

1079

polymers can be modified to finally form copolymers with D-A properties and they can be

1080

combined with wide-absorption organic dyes to further increase their photothermal

1081

conversion efficiency. Conjugated polymers in the form of nanoparticles can help control the

1082

drug release process; they can also improve the treatment efficacy and, at the same time,

1083

could minimize the side effects of, for example, chemotherapies. Moreover, nanoparticles, in

1084

addition to transporting a drug cargo, can also be bound to target cells and generate signals for

1085

imaging purposes as well as generating ROS to perform PTT and PDT simultaneously.

1086

However, several challenges need to be addressed before these nanosystems can find a

1087

clinical application: low photothermal conversion efficiency and low photostability in vivo,

1088

for instance. Another issue is the fast renal clearance of nanomaterials and their over-

1089

accumulation in non-targeted tissues, which may trigger additional serious side effects.

1090

Therefore, we can conclude that platforms based on conjugated polymers have shown

1091

outstanding light-material interaction properties as well as exceptional multifunctional

1092

performance, but the interaction of these materials with body tissues should be the subject of

1093

further investigations before they can be considered as biomaterials suitable for potential

1094

applicability to clinical oncology.

1095

The surface functionalization of PTT nanoparticles by polymers was initially explored in

1096

order to stabilize nanomaterials and to increase their biocompatibility prolonging their

1097

circulation within the body and avoiding the direct contact of body tissues with the metal or

1098

inorganic surface of the particles. Recently, nanoparticle capping by biomolecules such as

1099

peptides or nucleic acids was used to create multifunctional platforms able to combine PTT

1100

with other advanced cancer therapies (e.g. gene therapy) activated by the interaction of the

1101

nanomaterials with the NIR radiation. This intriguing methodology created new opportunities 51 ACS Paragon Plus Environment


1102

in the biomedical field. However, it is worth pointing out that the presence of functional

1103

polymer layers around PTT nanoagents does not allow a significant improvement of the

1104

efficiency of the photothermal effect, since it is mainly driven by the core features.

1105

Polymer matrix composites are the last class of nanomaterials that has been explored in this

1106

well-detailed overview. These materials have been investigated in depth only in the last

1107

decade, but their scientific interest is growing quickly, because of the possibility to combine

1108

the advantages of both aforementioned material classes. Therefore, in this case it is possible to

1109

improve both light-material interaction and biocompatibility as well as obtaining several new

1110

functionalities driven by the polymer matrix modification (e.g. crystallinity) which occurred

1111

during heat generation. Noteworthy, PTT hydrogel-based nanoplatforms, because of their

1112

intrinsic high water content, softness and flexibility (very similar to natural tissues), have

1113

great potential for the development of fully biocompatible multistimuli-responsive and

1114

versatile theranostic nanomedicine platforms. Most importantly, polymer composites can be

1115

easily processed by electrospinning in order to form nanofibrous platforms, paving the way to

1116

the development of tissue-engineered scaffolds and localized smart drug delivery systems,

1117

which is the most valuable perspective in the field. Today the incorporation of drugs with

1118

photothermally active agents in the polymer nanofiber matrix leads to distinct and synergistic

1119

chemo-photothermal therapies while, at the same time, providing an ideal environment for

1120

tissue regeneration after cancer removal. The use of nanocomposites for this purpose is still in

1121

the initial stages, therefore accurate pharmacokinetics and pharmacodynamics data are still

1122

unavailable. Consequently, systematic and rigorous in vivo evaluations, especially regarding

1123

the degradability, toxicity and long term side effects of nanomaterials, are needed; but they

1124

have not yet been thoroughly performed because of the complexity of the processes of

1125

nanomaterial biodistribution and elimination from the body.

1126 52 ACS Paragon Plus Environment

Page 52 of 84

Page 53 of 84 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

1127

Author Information

1128

Corresponding Author

1129

*E-mail: [email protected]

1130

Author Contributions

1131

The manuscript was written through contributions of all authors. All authors have given their

1132

approval to the final version of the manuscript.

1133

Notes

1134

The authors declare no competing financial interest.

1135

Acknowledgment

1136

This

1137

2015/19/D/ST8/03196.

work

was supported

by the National Science Centre (NCN) grant no.

1138 1139

Abbreviations

1140

WHO, World Health Organization; PTT, photothermal therapy; NIT, near-infrared; CPs,

1141

conjugated polymers; PA, photoacustic; PDT, photodynamic therapy; ROS, reactive oxygen

1142

species; ED, electron-rich; EA, electron-deficient; NPs, nanoparticles; PT, photothermal

1143

photodynamic; PANI, Polyaniline; EB, emeraldine base; ES, emeraldine salt; PNIPAM ,

1144

poly(N-isopropylacrylamide); dPG, dendritic polyglycerol; DBSA, n-dodecylbenzenesulfonic

1145

acid; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; FA, folic acid; DOX, doxorubicin;

1146

PPy, polypyrrole; Astx, astaxanthin; BSA, bovine serum albumin; DSPE-PEG2000, 1,2-

1147

distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; PTh,

1148

polythiophene; ICG, indocyanine green; OSCC, oral squamous cell carcinoma; CPNs,

1149

conjugated polymer nanoparticles; DPPV, poly{2,2′-[(2,5-bis(2-hexyldecyl)-3,6-dioxo-

1150

2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)-dithiophene]-5,5′-diyl-alt-vinylene};

1151

PtTFPP, Pt(II)-meso-tetra(pentafluorophenyl)porphyrine; PFO, poly(9,9-di-n-octylfluorenyl53 ACS Paragon Plus Environment


1152

2,7-diyl);

PFBT,

poly[(9,9-dioctylflurenyl-2,7-diyl)-co-(1,4-benzo-{2,1’,3}-thiadiazole)];

1153

TPP, tetraphenylporphyrin; Cy, Cyanine; CyP, poly(heptamethine) Cy-containing derivative;

1154

BTPBF, bis(5-oxothieno[3,2-b]pyrrole-6-ylidene)benzodifurandione; BT, 3,3’-didodecyl-

1155

2,2’-bithiophene; cRGD, cyclic arginine-glycine-aspartic acid; PFVBT, poly[9,9-bis(2-(2-(2-

1156

methoxyethoxy)

1157

PIDTTTQ,

1158

2,7-diyl)-alt-co-4,9-bis(thiophen-2-yl)-6,7-bis(4-(hexyloxy)phenyl)-thiadiazolo-quinoxaline];

1159

TBDOPV, thiophene-fused benzodifurandione-based oligo(p-phenylenevinylene); DT, 2,2′-

1160

bithiophene;

1161

fluoren-2-yl)thiophene; BBT, benzo-bis-thiadiazole; BIBDF, bis(2-oxoindolin-3-ylidene)-

1162

benzodifuran-dione; BT, bithiophene; BDT-IID, 4,8-bis[5-(2-ethylhexyl)thiophen-2-yl]-2,6-

1163

bis(trimethylstannyl)benzo[1,2-b:4,5-b′]dithiophene-6,6′-dibromo-N,N′-(2-

1164

ethylhexyl)isoindigo; PSMA, poly(styrene-co-maleic anhydride); Pdots, polymer dots; DPP-

1165

DT, diketopyrrolopyrrole-dithiophene; PF-DBT5, poly[(9,9-dioctylflurenyl-2,7-diyl)-co-(4,7-

1166

di-2-thienyl-2,1,3-benzothiadiazole)]; PBdots, polymeric blend dots; PFDHTBT, (poly[(9,9-

1167

dioctylflurenyl-2,7-diyl)-co-(4,7-bis(4-hexylthiophen-2-yl) -2,1,3-benzothiadiazole)]; PEG,

1168

poly(ethylene glycol); Chit-AgNTs, chitosan-coated silver nanotriangles; CMCS, O-

1169

carboxymethyl chitosan; HepG2, hepatocellular carcinoma cell line; pHLIP, pH Low

1170

Insertion Peptide; rGO, reduced graphene oxide; LGNPs, lycosin-I-conjugated spherical gold

1171

nanoparticles; LGNRs lycosin-I-modified gold nanorods; GNRs, gold nanorods; PGNRs,

1172

peptide-modified gold nanorods; siRNA, small interfering RNA; PSS, poly(sodium 4-

1173

styrenesulfonate); PDDAC, poly(diallyldimethylammonium chloride); PC-GNRs, gold

1174

nanorods modified by phosphatidylcholine; Apt@Au NPs, aptamer functionalized gold

1175

nanoparticles; Apt@Au NRs, aptamer functionalized gold nanorods; PEO, poly(ethylene

1176

oxide); LCST, lower critical solution temperature; UCST, upper critical solution temperature;

ethoxy)-ethyl)

fluorenyldivinylene]-alt-4,7-(2,1,3-benzothiadiazole);

poly[(4,4,9,9-tetrakis(4-(octyloxy)phenyl)-4,9-dihydros-indacenol-dithiophene-

BBT-2FT,

benzo[1,2-c;4,5-c’]bis[1,2,5]thiadiazole-4,7-bis(9,9-dioctyl-9H-


Page 54 of 84

Page 55 of 84 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

1177

AuNCs, gold nanocages; 5-FU, fluorouracil; PEGDA, poly(ethylene glycol) double acrylates;

1178

TiO2@MWCNT, titanium dioxide/multiwall carbon nanotube; SWNTs, single wall carbon

1179

nanotubes; PLLA, poly-L-lactic acid; MWCTs, multiwalled carbon nanotubes; Tg, glass

1180

transition temperature; Bi2Se3, bismuth selenide; SEM, scanning electron microscope; TEM,

1181

transmission electron microscopy; PDMS, polydimethysiloxane; ECM, extracellular matrix;

1182

RB, Rose Bengal; UCPL, upconversion photoluminescence; PCL, polycaprolactone.

1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197



Page 56 of 84

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Figure 1. (a) Scheme illustrating the biochemical mechanism resulting from nanomaterial-mediated photothermal therapy. Reprinted with permission from ref. 10. Copyright 2015 American Chemical Society. (b) The number of published articles on polymer-based nanomaterials for photothermal therapy during the period 2006–2017, obtained from Web of Science database. 178x60mm (300 x 300 DPI)

ACS Paragon Plus Environment

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Figure 2. (a) Schematic illustration of the preparation of PPy nanosheets. (b) Fluorescent images at different time points post intravenous injection of PPy nanosheets. (c) Infrared thermographic images of tumorbearing mice after intravenous injection of PBS and PPy nanosheets after irradiation by a 1064 nm laser. Reprinted with permission from ref. 54. Copyright 2018 American Chemical Society. 178x119mm (300 x 300 DPI)



Figure 3. (a) Synthetic route of C3. Reprinted with permission from ref. 55. Copyright 2017 American Chemical Society. (b) Synthesis of DPPV ((i) Pd2(dba)3 and tri(o-tolyl)phosphine, toluene, 100°C, 24 h) and schematic illustration of DPPV/PLGA-PEG NPs. Reprinted with permission from ref. 56. Copyright 2018 American Chemical Society. 178x75mm (300 x 300 DPI)


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Figure 4. Schematic illustration of multifunctional ICG-PtTFPP NPs. Republished with permission of Royal Society of Chemistry, from ref. 57, Copyright 2017; permission conveyed through Copyright Clearance Center, Inc. 178x80mm (300 x 300 DPI)



Figure 5. (a) Schematic illustration of PBTPBF-BT NPs. Reprinted from ref. 58. Copyright 2017, with permission from Elsevier. (b) Chemical structure of TBDOPV-DT polymer. Reprinted with permission from ref. 64. Copyright 2016 American Chemical Society. 178x50mm (300 x 300 DPI)


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Figure 6. (a) Scheme representing the use of PEGylated copper nanowires as a photothermal agent for cancer therapy. (b) Tumor volume of CT26-bearing BALB/c mice after PEGylated copper nanowires after photothermal ablation. Reprinted with permission from ref. 77. Copyright 2016 American Chemical Society. 178x65mm (300 x 300 DPI)



Figure 7. (a) Tumor growth percentage from different groups during the first 18 days after Gold nanorodsiRNA treatment. (b) Photographs of tumors 18 days after G1-G5 treatments. Reprinted from ref. 90. Copyright 2015, with permission from Elsevier. 178x75mm (300 x 300 DPI)


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Figure 8. Images of poly(ethylene oxide) (PEO) spherulites observed through a cross-polarized optical microscope of: (a) melt-crystallized gold nanoparticle:PEO film; (b, c, d) after conventional annealing at 60 °C and after photothermal process; (e, f, g) at different time points; (h) crystallinity; (i) spherulite density as a function of annealing time for gold nanoparticle:PEO melt-crystallized films. The annealing was conducted by conventional and photothermal heating. Reprinted with permission from ref. 103. Copyright 2013 American Chemical Society. 177x113mm (300 x 300 DPI)



Figure 9. (a) Schematic of the smart hydrogel–nanoparticle patch with drug–siRNA nanoparticle conjugates (drug–gold nanorods and siRNA–gold nanospheres) for local gene and drug release designed by Conde et al.99. (b) Fluorescence and thermographic images of hydrogel patches. (c) Thermographic surveillance of the photothermal heating of hydrogel patches in mice (nD5) 72 h after the first NIR treatment. Reprinted by permission from Springer Nature, ref. 99. Copyright 2016, Macmillan Publishers Limited. http://www.nature.com/nmat/ 177x108mm (300 x 300 DPI)


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Figure 10. (a) Scanning electron microscope (SEM) and transmission electron microscopy (TEM) images of PLLA and Bi2Se3/PLLA membranes. (b) Infrared thermographic maps and time-dependent temperature increase in the tumor-bearing nude mice irradiated by an 808 nm laser. (c) Temperature growth during the irradiation of PLLA and Bi2Se3/PLLA membranes. (d) Corresponding growth curves of tumors in different groups of mice after NIR laser irradiation. Reprinted with permission from ref. 127. Copyright 2017 American Chemical Society. 177x149mm (300 x 300 DPI)



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Polymer-Based Nanomaterials for Photothermal Therapy: From Light

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