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Polydopamine-Based Multifunctional (Nano)materials for Cancer Therapy Rados#aw Mrówczy#ski ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b08392 • Publication Date (Web): 08 Aug 2017 Downloaded from http://pubs.acs.org on August 9, 2017

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ACS Applied Materials & Interfaces

Polydopamine-Based Multifunctional (Nano)materials for Cancer Therapy Radosław Mrówczyńskia* a

NanoBioMedical Centre, Adam Mickiewicz University in Poznan, Umultowska 85, 61-614 Poznan, Poland *Corresponding author, E-mail: radosław.mrówczyń[email protected] Abstract Since Lee published a pioneering paper about polydopamine (PDA), application of that polymer in a number of areas has grown enormously in the last 10 years and still is growing. PDA's spectacular success can be attributed to its unique features i.e. simple preparation protocol, strong adhesive properties, easy and straightforward functionalization and biocompatibility. Therefore, this polymer has attracted the attention of a vast group of scientists, including those working in the field of nanomedicine. In consequence, polydopamine has been merged with various nanostructures that differ in size and nature, which has resulted in novel types of multifunctional nanomaterials that have recently been extensively exploited in nanomedicine and particularly in cancer therapy. The aim of this article is to offer insight into the latest achievements (up until the end of 2016) in the field of synthesis and application of nanomaterials based on polydopamine and their application in cancer therapy. The conclusions regarding the application of polydopamine-based nanoplatforms in this area and future prospects are given at the end. Keywords: polydopamine, nanomaterials, nanomedicine, multifunctional nanoparticles, cancer therapy

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1. Introduction Cancer is the name for a large family of diseases which share the following features, termed the “six hallmarks of cancer”: 1. Cell growth and division absent the proper signals 2. Continuous growth and division even given contrary signals 3. Avoidance of programmed cell death 4. Limitless number of cell divisions 5. Promoting blood vessel construction and 6. Invasion of tissue and formation of metastases.1 It is predicted by the World Health Organization that cancer will take a heavy toll on human life in the near future since in 2012 alone 14 million new cancer cases were recorded and this number is going to increase by 70 % over the next two decades. Thus, there is still a great need to develop new formulations which allow doctors to fight cancer effectively. In recent years nanotechnology has emerged as a promising field that can provide necessary and efficient tools to fight against cancer. It has been shown that nanomaterials can effectively deliver chemotherapeutics to cancer cells, overcoming the effect of multi-drug resistance (MDR), which is responsible for the failure of conventional chemotherapy.2-3 Thus, a new branch of research called nanomedicine was established, which deals with the medical application of nanotechnology, including cancer therapy.4-5 Tremendous progress has been made in the last few years in the field of synthesis of multifunctional nanoparticles (MFNP), which have produced excellent results in anticancer therapy.6 First of all, latest-generation MFNPs have the advantage over lower-generation nanocarriers because they can serve as a platform for the simultaneous delivery of therapeutics (e.g. chemotherapeutics and genetic material) and contrast agents, which renders them theranostic tools.7-8 At present, such nanotheranostic platforms are mostly based on inorganic nanoparticles, carbon nanomaterials, liposomes, micelles and polymeric nanoparticles or hybrid materials obtained from given categories. As scientists aim to prepare new and more efficient MFNPs, it is a big challenge to engineer them in the proper way


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so that they combine all the desired modalities in a single system. Thus, the appropriate choice of core material for the synthesis of MFNPs is extremely relevant, because it can already provide one of the required attributes i.e. the core can be a contrast agent. Moreover, the coating on MFNP should provide it with facile functionalization, biocompatibility, colloidal stability and additional attributes e.g. photothermal properties. Additionally, MFNPs can be modified with targeting ligands, which enhances their internalization in infectious cells with improved specificity.9 Generally, nanoparticles can accumulate in tumors via the enhanced permeability retention effect (EPR) in a passive manner due to leaky tumor vessels. However, this strategy lacks selectivity and does not lead to the expected high accumulation of nanomaterials inside the treated area. Hence, in modern MFNPs active targeting resulting in concertation increase inside the cancer cells is applied, which results in a superior therapeutic outcome and diminished side effects. Moreover, properly tailored MFNPs can be applied in combined therapy e.g. chemotherapy with photothermal therapy, gene delivery with photothermal therapy or co-delivery of various therapeutic molecules by a single system, which is emerging as a new paradigm in nanomedicine.10-14 What is also of importance is the final price of MFNPs. In principle, the preparation costs of multifunction materials are higher than those of lower-generation materials. However, in the light of recent reports on the ratio between costs and usefulness, it is clear that multifunctional nanohybrids have an advantage over lower-generation nanomaterials, even though their production costs are higher.15 Nevertheless, cheap and effective synthetic methods of multimodal nanomaterials are demanded in order to make them marketable. Polydopamine is a mussel-inspired polymer which was introduced by Lee et al. in 2007.16 Since that time it has found a wide application in many areas of material chemistry and biomedicine.1718

Successful use of polydopamine for the constriction of intriguing materials can be attributed to



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a set of unique features. Firstly, polydopamine possesses strong adhesive properties, which allow virtually any type of material to be covered, including hydrophobic Teflon, noble metals and different groups of nanoparticles.16,19 Secondly, PDA coating has been proved to be biocompatible.20-22 Thirdly, the broad scope of strategies towards PDA modification has been developed, therefore covered surfaces can be easily modified with a wide range of molecules including polymers and biomolecules or metals.23-24 Recently, the Click reaction has joined the toolset for PDA versatile surface functionalization.25-26 It is worth to highlight that PDA is known to bind to nearly all transition and radioisotope. This allow to fix on nanomaterials both important metals ions and radioisotope vesting them contrast properties or capability to be used in radioisotope cancer therapy. This feature can be also use for water purification from heavy metals (CrVI, HgII, PbII, CuII) and radioisotopes as well.27 Moreover the site of metal chelation in polydopamine may vary according to the metals ions nature. In consequence, not only oxygen atoms from PDA are involved in binding of metals but also nitrogen atoms can contribute to this process too. Finally, PDA has been recognized as an efficient photothermal agent28, which has great significance since photothermal therapy can be combined with other therapeutic approaches, resulting in an improved therapeutic effect. Therefore, PDA fulfills all the requirements regarding a versatile functional coating for multimodal theranostic nanomaterials. In addition, the preparation cost of PDA shell is low as it can be obtained via simple dip protocol under basic conditions (mostly TRIS buffer) from dopamine under air access, which significantly reduces preparation costs. Indeed, polydopamine has attracted the attention of many scientific groups as promising material for the preparation of multifunctional nanomaterials for cancer therapy and has been extensively used in this area, especially in the last 3-4 years. (see Table 1) PDA-based nanomaterials have been demonstrated to show outstanding therapeutic performance both in vitro and in vivo,


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allowing the simultaneous exploitation of therapeutic and diagnostic modalities fundamental for a theranostic approach and resulting in them being seen as a rising star in nanomedicine. Thus, the aim of this review is to summarize the synthesis and application of the latest theranostic materials for cancer therapy based on PDA, where this polymer plays a crucial role in vesting the multifunctionality of coated materials. Moreover, selected nanoplatforms where the potential multimodal character was not fully explored will also be presented, as they can be rediscovered as MFNP in near future. The prefix 'nano' is in parentheses in the title of the article, because some PDA-coated materials or structures made from pure PDA exceed 100 nm, which is the basic condition to consider them as nanoscale objects. Nevertheless, such materials have been successfully applied in cancer therapy, which is why they were included in this text. The article starts with a description of PDA particles and their application in cancer therapy. Next, merging PDA with several groups of nanomaterials including magnetic and gold nanostructures, rare earth nanoparticles, carbon nanotubes and graphene, micelles and liposomes is discussed. Finally, fusing PDA with other metallic and polymeric nanoparticles is presented. A summary and conclusion regarding developments in this field are given at the end. I am convinced that this article will provide a comprehensive overview of the field of MFNP for cancer therapy based on PDA and will fill the existing gap in the literature in this important area. 2. Polydopamine (nano)particles and hollow spheres Polydopamine particles in nanoscale (below 100 nm) or above can be obtained simply by polymerization of dopamine under basic conditions and air access. However, the crucial issue is to control their size and morphology, which are both affected by the reaction of pH29 and additives like alcohols.30 PDA particles usually range from 40 to 300 nm depending on the



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conditions applied. One of the smallest particles was obtained using reverse emulsion polymerization in the presence of surfactants, which resulted in 25 nm mere PDA nanoparticles.31 The second type of PDA structure are hollow particles, which are synthesized using the template method, where the sacrifice core is removed after polymerization of PDA. In this approach, silica particles or polystyrene beads are frequently employed and these are subsequently extracted by HF and THF, respectively. Recently, it has been shown that PDA capsules can be fabricated by polymerizing dopamine on emulsion droplets made from toluene and THF under mild conditions.32 The interest in the application of mere PDA structure in nanomedicine started to grow following the report by Li et al. proving their excellent photothermal properties.28 Further modification of mere PDA structures with chemotherapeutics, targeting ligands and/or contrast agent allowed them to evolve into advanced theranostic platforms, which have been successfully applied in in vitro and in vivo. For instance, Li et al. prepared PDA particles with a diameter of 120 nm loaded with doxorubicin (DOXO) and modified with a PEG chain bearing targeting ligand – RGD peptide.33(See Figure 1) The authors proved that the material bearing RGD ligand exhibited superior internalization and delivered the drug more efficiently to cancer cells than without RGD moiety. Moreover, NIR irradiation combined with chemotherapy (CT) in vivo resulted in an enhanced synergistic therapeutic effect since tumor regrowth was not observed even after 50 days. It is worth highlighting that these advanced materials could be employed in imaging by means of the photoacoustic imaging (PAI) technique, thus its theranostic potential was fully exploited.


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Figure 1 Schematic illustration of preparation-modified PDA particles bearing targeting ligand and DOXO. Reprinted with permission from reference 33. Copyright 2017 Elsevier

A similar approach was used by Wang et al., who prepared PDA nanoparticles with a diameter below 100 nm and loaded them with (DOXO) or 7-ethyl-10-hydroxycampothecin (SN38).34 These drugs were attached to a carrier via π-π interaction and probably hydrogen bonding, but no targeting ligand was attached to this material. Interestingly, it was found that DOXO could be loaded in higher amounts than SN38. However, in release tests it was found that under NIR irradiation the SN38 release was higher than in the case of DOXO. Synthesized nanocomposites were examined under in vitro conditions on several cancer cell lines and finally they were checked in vivo. These experiments showed that combined photothermal therapy (PTT)-(CT) was necessary to enhance tumor suppression and revealed that PTT made a major contribution to effective killing of cancer cells. In another example, Dong et al. attached indocyanine green (ICG) to PDA particles, which improved their NIR absorption properties at low concentrations and simultaneously enhanced the photostability of ICG in comparison to its unbound form.35 In the next step DOXO and Mn2+ were deposited on PDA particles, thus linked PTT-CT therapy on 4T1 cells could be performed simultaneously with T1-weighted MRI. Multifunctional PDA particles for PTT and MRI were also synthesized by Hu et al. in a similar way to the example given above. However, here Fe2+ ions served as contrast imaging agent



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instead of Mn2+. In addition, functionalization with PEG assured improved stability of nanocomposite.36 Due to the NIR absorption, this material allows photoacoustic imaging to be performed. It is worth highlighting that ICG increased the photothermal properties of PDA almost 6 times. Therefore, this nanomaterial could be successfully applied in thermal ablation of cancer cells in vitro and in vivo. Moreover, the tumor growth was completely inhibited only when NIR irradiation was applied on PDA particles with ICG. Tumor reemission was observed after 3 days when thermal therapy was carried out only with mere PDA particles. An interesting structure based on mere PDA and metal organic framework (MOF) was reported by Chen et al. The authors deposited Fe2+ ions on PDA particles, making use of the chelating abilities of catecholic groups and then they performed the growth of MOF shell by repeating the reaction with trimesic acid.37 (See Figure 2) The materials obtained had a high active surface, thus the loading capacity of DOXO was as high as 2.562 mmol g-1. Furthermore, the material obtained exhibited contrast properties in MRI, hence therapeutic and diagnostic functions could be provided in one system. As in previously described reports, it was found that both CT and PTT provides the best results in killing cancer cells due to the additive effect of CT and PTT.


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Figure 2 Schematic view of the preparation of multifunctional PDA structure with a MOF shell and its further application in combined PTT-CT therapy. Reprinted with permission from reference 37. Copyright 2017 Elsevier

PDA particles could be embedded in hydrogel by GhavamiNejad et al. They served as a photothermal agent for killing cancer cells and due to the local temperature increase they were able to release DOXO “on demand” from the polymer matrix.38 DOXO could be replaced by bortezomib (BZT), which exhibited a negligible release from particles under NIR irradiation, but could be released in an acidic environment. Thus, the nature of the material could be easily tuned and controlled by external stimuli. Moreover, an additional therapeutic effect of PTT and CT on colon cancer cells was presented. A different approach towards combined therapy was proposed by Zhang et al., who, instead of using a dual approach PTT-CT, modified PDA nanoparticles with chlorince6 (Ce6) by linking free amino groups of PDA with carboxylic groups of Ce6 using EDC coupling protocol, which resulted in multimodal particles for PTT and photodynamic therapy (PDT).39(See Figure 3) Immobilization of Ce6 on PDA particles enhanced Ce6 internalization, which allowed more ROS to be generated upon laser irritation at 670 nm and together with superb photothermal properties of PDA gave rise to more effective therapeutic results both in vitro and in vivo. Unfortunately, this interesting material lacked targeting ligand or imaging capabilities that could increase its functionality.



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Figure 3 (a) Schematic view of the PDA-Ce6 nanoparticles preparation procedure (b) TEM image of PDA nanoparticles (c) representative TEM image of the prepared PDA-Ce6 nanoparticles. Reprinted with permission from reference 39. Copyright 2015 ACS

PDA particles stabilized with PEG were used to carry DOXO and

131

I, emitting strong beta

particles for combined radioisotope therapy (RIT) and CT in accordance with Zhong et al.40 The authors also modified PDA particles with 99m Tc in order to run single-photon emission computed tomography (SPECT). Therefore, the properties of the materials could be tuned by choosing the proper radioisotope. Even though one can suspect a similar mechanism of deposition for these two elements on the PDA surface, the authors hypothesized that

99m

Tc was fixed to PDA via

interaction with catecholic groups of polydopamine, while linkage of

131

I was attributed to

electrophilic substitution in a PDA benzene ring, since the reaction was carried out in the presence of chloramine T, which could result in oxidation of I to I-. An enhanced therapeutic effect on the breast cancer cell line was found when CT and RIT were performed at the same time. This novel multimodal structure lacked active targeting and its internalization was based


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only the EPR effect. Nevertheless, it was demonstrated that this platform performed well in cancer therapy, both in vitro and in vivo. A radiophotodynamic approach was demonstrated by Yu et al. who functionalized polydopamine particles with Ce6 and curcumin.41 This dual strategy towards cancer therapy resulted in an improved therapeutic effect similar to other combined approaches. Moreover, in vivo studies confirmed that this structure could serve as an efficient multifunction platform for cancer therapy. Meng’s group demonstrated that PDA hollow spheres can be successfully filled in with ionic liquids (IL) and utilized either in a thermal ablation of tumor using microwave (MW)42 or combined therapy MW-CT with DOXO loaded on a carrier.43(See Figure 4 and 5) Even though the approaches seem to be similar, the PDA hollow particles differed in size. In the first case, particles of around 500 nm were synthesized using SiO2 templates, while in the second case, smaller particles around 140 nm were employed. However, both materials absorbed MW due to the presence of IL, as the author claims, and could successfully generate hyperthermia at low particle concertations. High efficiency in destroying cancer cells was demonstrated on the HepG2 cell line and in vivo on xenograft model. These tests proved that linked therapy was superior to the single treatment approach. Moreover, these materials were also used in imaging by means of a photoacoustic method exploiting near infrared absorption properties of PDA.

Figure 4 Schematic view of synthesis of PDA hollow sphere with ionic liquids. Reprinted with permission from reference 42. Copyright 2016 ACS



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Figure 5 a) Photothermal properties of PDA hollow particles@IL under NIR irradiation b) distribution of PDA hollow particles@IL in the organs c) Infrared thermal images showing the temperature change during irradiation of PDA hollow particles @IL in vivo. Reprinted with permission from reference 42 Copyright 2016 ACS

In another example, Cho et al. synthesized PDA particles modified with Gd3+ ions and silica shell.44 This additional coating allowed fluorescent molecule tetramethylrodamine to be deposited and prevented from fluorescence quenching, which could occur because of PDA. These particles could be utilized in dual T1-weight MRI and fluorescent imaging. Moreover, their PTT properties gave rise to effective thermal ablation of prostate cancer cells, which demonstrated in vivo on a xenograft model. Even though it seems that combined anticancer therapies give better results than singular ones, Miao et al. reported that single PTT performed with PDA particles gives excellent results as well. Moreover, modification of PDA particles with metal ions e.g. Mn2+ or Fe3+ provides theranostic platforms capable of performing both therapy and diagnosis by means of MRI.31, 45 (See Figure 6)


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Figure 6 (a) (b) SEM and TEM image of multifunctional PDA particles with Mn2+ and PEG chains c) schematic view of the preparation of PDA nanoparticles with an Mn2+ and PEG chain. (d) temperature change under NIR irradiation. Reprinted with permission from references 45. Copyright 2015 ACS

There are reports showing that PDA particles or hollow particles could be applied as efficient carriers for various chemotherapeutics. However, their potential application in combined therapy or imaging was not taken into consideration at that time. Nevertheless, they are fine structures with great potential and one can assume that they can be “rediscovered” as MFNPs for cancer therapy. For instance, Cui et al. tailored a cleavable hydrazone linker to join a DOXO and PDA capsule, which allowed the drug to be released in a pH controlled manner.46 (See Figure 7) The use of this carrier provided better anticancer performance than unbound DOXO, probably due to enhanced internalization of the carrier inside the cancer cells.



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Figure 7 Schematic illustration of the preparation of polydopamine hollow particles with “on demand” drug releases in a pH-dependent manner. Reprinted with permission from references 46. Copyright 2013 ACS

In another example published by Cheng et al., PDA hollow particles were functionalized with polyethylene imine (PEI) followed by the addition of folic acid via an EDC coupling protocol.47 Finally, DOXO was loaded inside the particles obtained and the material was tested in vitro on an HeLa cell line, showing promising activity in anticancer therapy. Ho et al. showed that PDA particles below 100 nm are capable of carrying campotchecine to Hela and A549 cells. The authors showed that particle size could be tuned by changing the pH of the polymerization reaction.29 3. Magnetic nanoparticles Iron oxide magnetic nanoparticles (MNP) are a group of nanomaterials that can be obtained in different sizes and shapes by means of well-established and relatively cheap protocols. Moreover, they simplify the purification step during the preparation of complex materials, since they can be collected by an external magnetic field. What is important to note is that magnetic nanoparticles can be exploited as a magnetic resonance imaging (MRI) contrast agent, which makes them important for the “diagnostic” part of nanotheranostic materials.48 There are great expectations for these particles and their application in nanomedicine, as they can be magnetically guided to cells or tissues affected, and it is supposed that this will increase the active targeting capability and prevent the spread of nanoparticles in an undesired way.49 Moreover, superparamagnetic nanoparticles can be used to generate local hyperthermia through the application of an altering magnetic field.50 Therefore, this class of materials is of greatest interest to numerous scientific groups dealing with multifunctional nanomaterials, because they allow many desired factors to be fused into one material in a simple manner.


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PDA has been merged with two types of magnetic nanomaterials, either with MNPs with a diameter of less than 20 or clusters whose size varies from 50 to more than 100 nm. For instance, Mrówczyński et. al showed that MNP@PDAs of around 8 to 10 nm in size can serve as efficient nanocarriers for the DOXO to HeLa cell cancer line.51 The loading of DOXO on nanoparticles was 0.46 mg/g, which was higher than in the case of mere PDA spheres, but lower than for rare earth nanoparticles covered with PDA and modified with PEG. A different strategy was reported by Hashemi-Moghaddam et al., who performed polymerization of PDA in the presence of MNP and 5-flourocuracil (FU).52 They obtained nanoparticles loaded with chemotherapeutics which were applied in magnetic guided therapy on a mouse breast cancer model. Their in vivo studies showed that the application of an external magnetic field enhanced the accumulation of composites inside the tumor mass and reduced the side effects of anticancer drug, consequently increasing the lifespan of the animals. The same group reported a similar approach towards imprinting of PDA with DOXO.53 Nanoparticles were checked in vivo in mice for breast adenocarcinoma. DOXO linked the nanoparticles with high efficiency, but its release profile shows a burst release in the first 8 to 10 hours. Another set of data proved enhanced accumulation of nanoparticles in the tumor when a magnetic field was applied. Unfortunately, MRI and NIR irradiation experiments were not performed, so the full potential of these nanoparticles was not explored, which could result in a significant increase in the impact of these materials. A truly multifunctional nanoplatform was presented by Lin et al., who functionalized PDAcoated magnetic nanoparticles with an ssDNA probe for intracellular mRNA, while at the same time these were shown to be an effective agent for photothermal therapy of the breast cancer cell MCF-7.54 Subsequently, nanoparticles were used in the photoacoustic imaging and MRI of these cells. (See Figure 8)



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Figure 8 (a) Schematic view of the preparation of Fe3O4@PDA (b) RNA detection with functionalized Fe3O4@PDA (c) General scheme of the application of Fe3O4@PDA for intracellular mRNA detection and multimodal imagingguided photothermal therapy. Reprinted with permission from references 54. Copyright 2014 ACS

Ming et al. proposed a magnetic cluster built from superparamagnetic nanoparticles covered with PDA obtained under commonly applied conditions.55 Such structures were used for killing the HepG2 and HeLa cells under NIR irradiation. The composites were approximately 50 nm and were coated with a 4 nm layer of PDA. It is worth highlighting that this composite exhibited improved photothermal properties in comparison to uncoated magnetic clusters. The authors explained that magnetofection had a huge influence on the internalization of the nanostructures obtained and gave rise to better results in photothermal therapy by increasing the nanoparticle concentration inside the cells. The effect of magnetic guiding on the uptake of nanocomposites by cells was visualized by MRI experiments, because synthesized nanomaterials exhibited high


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contrast properties. Later research of the same group showed that such nanostructures functionalized with PEG and indocyanine green can be applied in vivo for the effective killing of liver cancer cells under NIR irradiation, as well as a contrast agent for MRI.56 (See Figure 9)Their synergistic effect of fusing ICG with PDA-coated magnetic clusters was observed, as ICG showed better photostability than its free form and at the same time the photothermal properties of PDA-coated nanostructures were elevated. Moreover, the magnetic-guide strategy led to an improved therapeutic effect. In addition, MRI was used to monitor the accumulation of composites inside the tumor.

Figure 9 Schematic view of the preparation of smart PDA coated magnetic nanoclusters and their in vivo use. Reprinted with permission from reference 56. Copyright 2017 Elsevier

Similar platforms were synthesized by Zheng57(See Figure 10 and 11) and Ge58, who carried out an experiment on a living model to show the superb PTT properties of magnetic clusters obtained in the treatment of various type of cancer. Even though the final structures were similar in both approaches, they differed in terms of the synthetic methods used for their preparation, which



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affected their sizes and PDA thickness, and further PTT and contrast properties. For example, a cluster obtained by Ge et al. had high T2 relaxivity, as high as 230.5 mM-1s-1, while particles obtained by Zheng exhibited T2 relaxivity 78.1 mM-1s-1. Studies on the photothermal properties used different laser power, so it is not possible the compare their effectiveness. Both structures could be applied in thermal ablation of tumors in vivo with high efficiency.

Figure 10 (a) Schematic illustration of the synthesis of Fe3O4@PDA composite. TEM images of clustered Fe3O4 with various amounts of PDA particles (b) 37.8% (c) 42.5% (d) 48.2% and (e) 56.1%. The bar is 200 nm. Reprinted with permission from references 57. Copyright 2015 ACS

Figure 11 Infrared thermal images of Fe3O4, PDA, and Fe3O4@PDA with a dose of 50 µg of an injected A549 tumor sample under NIR laser irradiation (λ = 808 nm; 6.6 W cm−2) for 0−180 s. Reprinted with permission from references 57. Copyright 2015 ACS


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In a different approach Liu et al. demonstrated that catecholic groups presented in PDA-coated MNP can be employed to immobilize the anticancer drug bortezomib (BTZ) via boron ester formation. The drug could then be released from the carrier in a pH responsive manner, since the boron ester group was cleaved under acid pH. However, the authors did not report any biological studies or physical properties i.e. contrast properties, so the potential of this material for theranostic at that time was unexplored.59 4. Gold nanostructures Gold nano-sized structures are of great interest of numerous scientists, because their shape and size can be tuned by reaction parameters. In consequence, one can control their physical parameters, thus further influencing their biological applications. Importantly, they are biocompatible and a wide range of structures including spheres, nanorods and nanostars are available according to well established protocols.60-63 All these features were key to their successful application in nanomedicine as novel drug carriers. Even though that they have been studied for many years, they are still the focus of a great deal of attention, especially in the field of advanced theranostic nanomaterials for cancer therapy. Excellent and comprehensive reviews of this class of materials, dealing with their chemistry and bioapplication, are available, therefore these issues will not be discussed.64-66 Here we will focus on coating different gold nanostructures with PDA and advances in their further application for cancer treatment. One of the earliest reports regarding the use of gold nanostructure with a PDA shell comes from Black et al., who showed a preparation of gold nanorods (GNR) with a PDA layer exhibiting strong longitudinal plasmon resonance, which was versatile for NIR absorption in the important biological window.63 The nanorods obtained were around 60 nm in length and with a PDA layer of approximately 10 nm, which was then functionalized with anti-EGFR antibodies. In consequence, modified gold nanorods showed improved performance in PTT on various cell lines



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in comparison to particles without targeting moiety and PDA, because antibodies significantly enhanced the uptake of nanoparticles by the cancer cells, which further promoted NIR absorption. Moreover, optical tomography could be applied to track these structures, thus material could serve in dual-mode therapy and diagnosis. Recently, the application of GNR@PDA in the synthesis of advanced nanotheranostic tools has been explored by Wang67 and Zhang.68 In Wang’s report, GNR@PDA were synthesized in two step protocol. In the first step a CTAB layer on GNRs was replaced by PEG chains in order to prevent aggregation of GNR. Further GNRs were functionalized with a PDA shell and PEG chains followed by loading either methylene blue or DOXO. (See Figure 12) These materials were found to produce superb anticancer activity in combined PTT-PDT or CT-PTT as demonstrated in vitro and in vivo. Here a dual therapeutic approach was found out to be superior to the singular method and provided extraordinary enhancement in anticancer therapy. Synthesized GNR@PDA exhibits very strong photothermal properties in very low concentrations (nM). Moreover, DOXO release from the nanocarrier was performed in a pH-dependent manner and could be intensified by NIR irradiation.


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Figure 12 Schematic illustration of synthesis of GNRPDA-MB and GNR-PDA-DOX nanocomposites, respectively. a) Absorption spectra of CTAB-coated GNRs (GNR-CTAB) and PEGylated GNRs (GNR-PEG). (b) Absorption spectra of GNR-PDA with shell thicknesses of 15, 20, and 30 nm (GNR-PDA0.1, GNR-PDA0.5, and GNR-PDA1), and PDA solutions with dopamine concentrations of 0.1, 0.5, and 1 mg/mL (PDA0.1, PDA0.5, and PDA1).(c−f) Representative TEM images of GNR-CTAB (c), GNR-PDA0.1 (d), GNR-PDA0.5 (e), and GNR-PDA1 (f). (g) Hydrodynamic size distributions of GNR-CTAB and GNR-PDA1. (h) Digital photographs of GNR-PDA and GNR-PDA-PEG in three different dispersions from left to right: water, PBS, and DMEM (+10% FBS) at 0 and 24 h. Scale bars, 100 nm. Reprinted with permission from reference 67. Copyright 2016 ACS

In another strategy Zhang synthesized GNR@PDA followed by deposition of platinum, RGD peptide (targeting ligand) and

125

I on the surface. Such a complex structure was stable in

biological media and both multimodal cancer therapy and SPECT/CT imaging could be performed. (See Figure 13) Additionally, a targeting function assured selectivity towards cancer cells, as proved by two-photon confocal microscopy, which had a great influence on combined therapy, since more efficient removal of cancer cell was observed for this structure in contrast to nanocomposite without targeting moiety. Essentially, coating with PDA prevents cytotoxicity of starting CTAB gold nanorods and provided negligible toxicity of the theranostic nanoplatforms prepared. In vivo experiments confirmed that linking chemotherapy (platinum) with NIR



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hyperthermia employing the multimodal nanostructure obtained was the most effective therapeutic approach to destroy cancer cells.

Figure 13 Schematic illustration of the RGD-125IPt-PDA@GNRs probe preparation procedure. Reprinted with permission from references 68. Copyright 2016 ACS

In addition to GNRs, gold nanostars (GNS) have also been employed in the preparation of a novel nanoplatform where coating with PDA was found to add value to the material. For instance, Du et al. presented 50 nm GNS@PDA, which could be further modified with a designed polyethylenimine-folic acid (PEI-FA) polymer in order to introduce a targeting function on nanoparticles.62 This material showed very good photothermal properties under low power laser operation as 0.33 W and low nanostructure concertation, which allowed efficient thermal ablation of cancer cells to be performed. It is important to highlight that promising results in PTT therapy using this nanocomposite were obtained because of co-introduction of ICG and PDA on the surface of gold nanostars, due to the dual nature of ICG, which can be used in the PTT and PDTimproving thermal properties of the material. An exceptional outcome of anticancer treatment


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was observed when a targeting ligand was attached to nanoparticles and was reflected in in vitro and in vivo experiments. In a similar strategy reported by Li et al.69, GNSs were first mixed with PEI modified with SH groups to some extent in order to stabilize the GNS. The gold nanostructures obtained were submitted to a reaction with dopamine under basic conditions, resulting in a PDA rim. However, this caused particles to increase in size from 90 to 125 nm. The GNS@PDA obtained exhibited high contrast properties in CT (computer tomography) and additionally exhibited a much higher hyperthermic effect under NIR irradiation in comparison to bare GNS. Synthesized nanoparticles had considerably greater biocompatibility than naked GNS due to the PDA shell. In this study, the use of PDA was crucial to obtaining an efficient multimodal nanoplatform for PTT and CT. Biological tests showed that synthesized nanocomposites had an outstanding capability to remove cancer cells and work better in CT than iodine-based contrast agents Omnipaque. Not only a single PDA-coated gold nanostructure can be exploited in nanomedicine. For instance, it was demonstrated by Wang et al. that a PDA interlayer allow graphene oxide (GO) and GNS to be glued.70 This triple combination of materials exhibited higher photothermal properties than those determined for respective components and ensured the colloidal stability of the composite. The NIR absorption and heat emission of GO were particularly heightened, thus the potential application of such a platform in nanomedicine is more possible than free GO. Moreover, DOXO could be deposited on this advanced carrier via a π-π interaction and released in a pH-responsive manner. The DOXO release could be enhanced by NIR irradiation. The synergistic effect of PTT and CT was shown in vitro and in vivo. It is important to mention that in contrast to mere PDA or PDA-covered photothermal agents, here a 655 nm laser was used rather than the routinely applied 808 nm. In recent research, PDA was merged with a spherical gold NP (AuNP) followed by



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surface modification with BSA-dextran.71 Such a modification had a great influence on in vivo PTT, due to the fact that the group of animals fed with these nanoparticles revealed full removal of tumor and no regrowth was observed even after 100 days, while in the other control groups fed with AuNP@PDA without BSA-dextran tumors recurred. The authors explained this phenomena by the fact that dextran brushes prolonged circulation of nanocomposites in the blood and enhanced the uptake of nanoparticles by cancer cells via the EPR effect, leading to their increased concentration and, in consequence, more efficient PTT. Furthermore, the nanoparticles obtained showed very good contrast properties in computer tomography and low toxicity. MFNPs based on AuNP@PDA were synthesized by Zeng et al. to serve as a contrast agent in T1weight NMR imaging and computer tomography.72

First, DOTA, a chelator entity for

gadolinium ions, and lactobionic acid were modified with phospholipids and then linked with AuNP@PDA, resulting in a lipid shell around particles. (See Figure 14) Moreover, before linking lactobionic acid and DOTA to the surface of AuNP@DPDA ICG was deposited. Active targeting of hepatocellular carcinoma cells was assured by lactobionic acid-bearing galactose, as it was demonstrated that HepG2 cells equipped with ASGP receptors were able to selectively bind such functionalized nanomaterial, in contrast to cells without a receptor. Overall, combinations of components provided nano-sized material for dual imaging modes with high photothermal properties and high selectivity towards cancer cells.


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Figure 14 Schematic illustration of synthetic rout towards multifunctional gold with photothermal properties nanoparticles bearing targeting ligand and contrast agent. a) MRI properties of multifunctional nanoparticles b) contrast properties in computer tomography. Reprinted with permission from references 72. Copyright 2014 ACS

An interesting strategy towards the preparation of gold petals on an AuNP@PDA core was reported by Kumar et al., who used PDA's ability to reduce gold salts in a controlled manner.73 The resulting nanomaterials were found to be efficient agents for linked PTT-PDT anticancer therapy which simultaneously could be exploited in monitoring DNA changes in post threated cells therapy using surface-enhanced Raman scattering (SERS). (See Figure 15)



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Figure 15 a) Schematic illustration of oxidative nanopeeling chemistry of polydopamine on AuNP b) TEM image of AuNP@PDA with ∼5 nm PDA layer. c) TEM image of AuNP@PDA after adding HAuCl4. d) TEM image of petals on AuNP@PDA after 1 min of the reaction. e) SEM image of AuNP@PDA with petals. f) TEM image of AuNP@PDA with petals and a magnified petal image (g) TEM images of AuNP@PDA with petals synthesized by increasing amounts of HAuCl4 from left to right. Reprinted with permission from references 73. Copyright 2014 ACS

Recently Tian et al. reported the preparation of gold hollow clusters with improved photothermal properties based on the assembly of AuNP@PDA. In their research AuNP@PDA was mixed with PEI and methoxy-polyethylen(glycol) amine (PEG-amine) under appropriate conditions. The formation of regular cluster was fragile and depended on the pH reaction and the ratio between PEI and PEG amines. It was found that pH 6 was crucial to obtain the most stable dispersion of these structures, while the best ratio between PEI and PEG-amine was 5:5, resulting in the most uniform and regular shape of particles. Such nanostructures could be further applied in anticancer PTT with high efficiency, as proved in vitro and in vivo. It is important to mention


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that the resulting nanostructures had almost the same PTC efficiency as pure PDA particles, although they exhibited much higher therapeutic efficiency in killing cancer cells under NIR irradiation.74 In the literature one can also find other reports on PDA on gold nanoparticles, although their theranostic potential was not exploited, even though they show promising properties. For example, Yo et al. reported ultra-small AuNP@PDA with improved contrasting properties for computer tomography, which could cover the “diagnostic” part of the theranostic approach. However, no investigation regarding an anticancer approach was described.75 5. Carbon nanomaterials The family of carbon nanomaterials consists of fullerene, carbon nanotubes, graphene, carbon dots, nanodaimonds and a carbon sphere. The latest excellent review deals with the preparation of carbon multifunction nanoplatforms for nanomedicine and their further use in this area, so the reader is encouraged to refer to this publication.76 The most popular carbon nanotubes (mostly multiwall carbon nanotubes (MWCNT)), in particular, are the focus of a lot of attention in biomedical application77 , because they can be engineered by controlling various reaction parameters, which subsequently influence their physical and biological properties.78 In addition, single wall carbon nanotubes (SWCNT) exhibited photothermal properties under NIR irradiation, which makes them more attractive for further application.79 The big issue is the cytotoxicity of carbon nanomaterials, especially carbon nanotubes, while they might show similarity to asbestos fibers.80 Functionalization strategies for overcoming the drawbacks of carbon nanotubes for improving their biocompatibility and biodegradation were exhaustively reviewed by Marchesan et al. and research in this field still remains a hot topic.81 In this paragraph, merging PDA with carbon nanomaterials will be presented, as well as strategies towards preparation of multifunctional nanostructures for cancer therapy.



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An important issue in the chemistry of pristine carbon nanomaterials is their poor dispersibility in water, which is crucial for their application in nanomedicine. An interesting strategy was presented by Xu et al., who first covered carbon nanotubes with PDA, followed by the addition of poly(PEGMA-co-NAPAM) polymer to PDA sell via a Michael reaction.82 The PDA coating improved the dispersion of carbon nanotubes to some extent, but better results were obtained after the polymer was grafted to the surface. Significantly, CNT@PDA@poly(PEGMA-coNAPAM) showed good biocompatibility toward skin cells. What is also important is that the drug loading efficiency of DOXO was found to be near 37 %. The plateau of release was observed after around 20 h and remained stable in the next 60 h, reaching 66 %. These materials seem to have great potential as NDDS, thus more biological experiments, including bioimaging, would provide more information necessary for comprehensive description of these nanocarriers. Unfortunately, the author did not investigate the photothermal properties of the composite that was prepared. Zhao et al. proposed multimodal nanomaterials built from PDA@SWCNT modified with radisotope 131I and Mn2+ ions.83 Such materials showed T1 and T2-weight contrast properties and gave rise to a synergistic therapeutic outcome when photothermal therapy and radioisotope cancer therapy were simultaneously applied. The resulting MFNPs were investigated both in vitro and in vivo. (See Figure 16) In another study PDA was used to prevent any leakage of gadolinium ions loaded into MWCNT.84 After grafting PEG moiety to MWCNT@Gd@PDA, a nanostructure was applied in vivo in a radical photothermal ablation dissection of regional lymph nodes of pancreatic cancer and tracking of nanomaterials by means of MRI using T1-weight contrast properties. This strategy was found to give better results than in a previously applied nanostructure made from graphene and magnetic nanomaterials.


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Figure 16 Schematic illustration of synthesis of multifunctional polydopamine coated SWCNT. Reprinted with permission from references 83. Copyright 2016 Ivyspring International Publisher

PDA was employed by Hu et al. to fabricate graphen-fulleren C60 composites for simultaneous PTT and PD therapy.85 Polydopamine was used as a linker between these two carbon nanostructures, allowing mild reaction conditions in synthesis of a nanohybrid structure. This material was also modified with folic acid moiety, and this provided active targeting towards cancer cells. In this way both the photothermal properties of graphene and PDA were linked with ROS (reactive oxygen species) generation provided by C60. As expected, irradiation of nanohybrid with light led to an additive effect in anticancer therapy, since a significant decrease in HeLa cell viability was observed. Graphene oxide was used as a core to build a multimodal platform for PTT and PAI by Hu et al. who covered GO with PDA under routinely used polymerization conditions followed by deposition of ICG.86 The photothermal properties of this nanomaterial were significantly elevated by ICG, due to the promoted NIR absorption, which resulted in enhanced properties in PAI. Studies carried out in vitro and in vivo proved that PTT using these composites led to complete



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suppression of cancer growth at a low nanomaterial concentration. Moreover, prepared composites exhibit low toxicity and as shown in cytotoxicity tests. PDA was used to coat graphene oxide followed by dual functionalization with mesoporous silica layer and hyaluronic acid. In this way Shao et al. obtained a multi-layer structure which exhibited strong photothermal properties and could be loaded with DOXO. (See Figure 17) As in previous studies, the PTT effect here also increased with an increasing composite concentration and higher laser power. Moreover, the active targeting was assured because of hyaluronic acid (HA), therefore these materials showed improved internalization inside cancer cells.87 They did not influence cell viability, while loading with DOXO and linkage with NIR irradiation caused a drastic drop in cell viability due to the synergistic therapeutic effect of CT and PTT. The results obtained in vitro were further verified in vivo.

Figure 17 Schematic illustration of preparation multilayer structure based on graphene@PDA and mesoporous silica for linked anticancer therapy. Images from confocal microscope showing the delivery of doxorubicin to cancer cells. Reprinted with permission from references 87. Copyright 2017 ACS


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It is important to stressed that dopamine and others catecholamines e.g. norepinephrine have influence on graphene oxide since they can reduce it to graphene after coating.88-90 Mechanism of this process was proved by carrying out polymerization reaction of norepinephrine on graphene oxide in acid conditions.88 The obtained data suggested that neither the surface modification by norepinephrine nor the reduction of the graphene oxide occurred. Thus, the reduction of graphene oxide was likely due to the released electrons when norepinephrine was oxidized under basic conditions, suggesting direct coupling of oxidation and reduction in the reaction. Another type of carbon nanomaterial, namely Carbon spheres (CS), was covered with PDA followed by the addition of folic acid to the PDA layer via EDC protocol.91(See Figure 18) In the next step, ICG was linked to CS@PDA@FA surface via a π-π interaction of dye with the PDA shell. These materials could be applied in simultaneous PTT and PDT treatment of Hela cells and served as a contrast agent. The nanohybrid was stable in water and other relevant biological media. Its performance in anticancer therapy was checked in vitro on an HeLa cell line.

Figure 18 Schematic illustration of the preparation of PDA carbon spheres bearing folic acid and ICG and their application on combined PTT-PDT therapy. Reprinted with permission from reference 91. Copyright 2016 ACS



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6. Rare earth nanoparticles Rare earth metals, predominantly lanthanide, are used in the synthesis of an emerging class of upconverting nanoparticles, which seems to be versatile cores for multifunction theranostic nanoparticles. These particles have the advantage over commonly used dyes, because they do not suffer from high photobleaching and show very low background autofluorescence. Moreover, they emit light from the UV or visible range after irradiation with NIR. The application of upconverting nanoparticles in the biomedical field was reviewed in recent articles which are available elsewhere and will not be discussed here in detail.92-93 However, fusion of upconverting nanoparticles with PDA is a brand new approach towards novel multimodal probes for nanomedicine and this field is still in its infancy. So far, the potential of these composites has been exploited by 3 groups. Liu et al. developed βNaGdF4:Ye3+,Er3+@ β-NaGdF4 nanoparticles, which were further coated with a thin PDA layer and stabilized with a PEG chain.94 Afterwards DOXO was loaded, resulting in a theranostic tool for combined PTT-CT and multimodal imaging using computed tomography (CT), MRI and fluorescence imaging. Merging chemotherapy and PTT provided a superior therapeutic outcome as presented in in vitro and in vivo studies and a dual approach was necessary for the complete death of cancer cells. Similar particles were proposed by Liu et al., who synthesized NaF4:Ye3+,Er3+@ NaF4@PDA with ICG for linked PTT-PDT.95 (See Figure 19) Optical imaging of that probe inside cancer cells was also performed on 2D cell lines, as well as in vivo. ICG attached to NaF4:Ye3+,Er3+@ NaF4@PDA nanoparticles improved their photothermal properties, while photostability of ICG deposited on nanoparticles was higher than in the case of free dye. Biological tests carried out on a HeLa cell line revealed that such materials do not show


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significant cytotoxicity and can be gradually extracted from the organism. Nevertheless, synthesized materials could be employed in killing cancer cells under NIR irradiation, as demonstrated in vitro and in vivo.

Figure 19 Schematic illustration of preparation multifunctional rare earth nanoparticles with PDA shell and their application in combined PTT-PDT cancer therapy. Reprinted with permission from reference 95. Copyright 2016 The Royal Society of Chemistry

Recently, Liu et al. focused on the preparation of a multimodal probe for MRI imaging that could be used in T1-weight and T2-weight modes and which after being coated with a layer showed excellent photothermal properties.96 The activity of the nanoparticles obtained was assessed in an in vivo test that also proved the multimodal character of these nanoparticles. Experiments with NIR irradiation of tumors in vivo showed that these materials performed well in photothermal anticancer therapy. The upconverting nature of nanoparticles allowed probes to be visualized using a luminescent microscope merged with a 980 nm laser. Neither of the composites described above used a targeting ligand and their internalization in vivo took place via the EPR effect.



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7. Micelles and liposomes Micelles are self-assembly structures made from block-copolymers resulting in a hydrophilic head and hydrophobic core with a diameter of less than 100 nm.97 They exhibit a narrow size distribution and enhance the solubility of hydrophobic, poorly water-soluble drugs, which makes them as an alternative to other nanocarriers e.g. metallic nanoparticles. Recently, micelle-based nanostructures fulfilling the requirements of modern theranostic nanomaterials have been reported.98 Nevertheless, application of theranostic micelles is still challenging and requires further exploration and development. Liposomes are bilayer structures with a hydrophilic core which are exploited as vesicles for various drugs or other nanoparticles as well. They can be obtained in various sizes, even up to 400 nm. Moreover, liposomes can be functionalized with a targeting ligand or PEG chains to prevent opsonization, which increases their blood circulation time and delivery efficiency. Liposomes are characterized by low cytotoxicity and low immunogenicity. The main drawbacks of liposomes are their low drug loading efficacy and complex preparation, thus they differ from batch to batch. Nevertheless, they have found application in the synthesis of drug delivery stems and, like micelles, liposomes are extensively researched for their use in theranostics.99 Scientists have taken advantage of micelles and liposomes and merged them with PDA to produce smart nanomaterials for bioapplication. For example, Zhang et al. reported micelles rimmed with PDA shell that were around 20 nm and carried BZT and DOXO simultaneously.100 (See Figure 20) This material could be delivered to breast cancer cells during drug release occurring under NIR irradiation. Their NIR absorption properties were tailored by changing the PDA thickness on the micelles through varying the concentration of dopamine in the polymerization reaction. However,


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NIR irradiation not only destroyed nanocarriers to release drugs, but also significantly increased dual chemotherapy. In other words, co-delivery of chemotherapeutics was combined with PPT treatment, which is quite sophisticated and evidently can be a successful approach towards linked anticancer therapy.

Figure 20 Schematic view of the preparation of smart micelles bearing DOXO and BZT and their use in linked PTTCT therapy. Reprinted with permission from reference 100. Copyright 2015 The Royal Society of Chemistry

In another strategy micelles were obtained from poly(ethylene glycol)45-b-poly(L-cysteine)20 with incorporated DOXO.101 These micelles were found to effectively kill HeLa cancer cells in combined PTT-CT therapy as found in vitro studies. However, they had a size above 100 nm and a relatively high PDI, which suggested their polydispersity. As in the aforementioned report NIR irradiation also improved drug release from the carrier, therefore enhanced results in anticancer therapy were observed. Any targeting ligands or contrast agents were attached to the structure described in both reports. Therefore their internalization relied solely on the EPR effect and they lacked imaging properties. Thus exploitation of PDA chemistry in order to link targeting ligands or contrast agents could help to develop advanced and efficient nanoplatform for anticancer therapy and convert them to theranostic tools. Liposome

vesicles

made

from

1-Hexadecanoyl-2–(9Z-octadecenoyl)-sn-glycero-3-

phosphocholine (POPC) covered with PDA were shown to deliver 5 fluorouracil (5-FU) to



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kidney cancer cells successfully.102 It is worth highlighting that in this report dissolution of PDA under acid conditions was used to perform drug release in a pH responsive manner, so PDA served as a protecting layer which kept the payload inside the liposome and prevented its uncontrolled release, rather than active PTT agent or linking point for other molecules. SEM studies revealed that the structures obtained significantly exceed 100 nm. 8. Miscellaneous Besides commonly used metallic nanoparticles like gold and iron oxides, other metallic nanosized cores were also merged with PDA in order to obtain multifunctional nanoplatforms for cancer therapy. Tungsten trioxide particles covered with PDA and hyaluronic acid were reported by Sharker et al.103 They used the adhesive properties of dopamine in order to deposit the hyaluronic modified with dopamine moieties on the surface of WO3 followed by incubation in basic pH. As a result, they obtained a layer of PDA analogue 10 nm thick. Unfortunately, particle size exceeded the limit for nanomaterials significantly, since they were more than 170 nm. Nevertheless, due to the PDA-derived coating, they showed outstanding biocompatibility of up to 1 mg/ml. The photothermal conversion efficacy was found to be 11.78%, which is much lower than in the case of mere PDA, but close to frequently used gold nanostructures, thus particles can be considered for further studies. This phenomenon was attributed to the hyaluronic acid shell around particles, which diminished the photothermal properties, but at the same time served as a biocompatible protecting layer for particles and targeting ligand binding to CD 44 receptor present in malignant cells. Particle selectivity was checked in vivo. It was shown that in contrast to mere WO3 modified particles bearing hyaluronic acid moiety were more efficient photothermal agent and exhibited sufficient selectivity towards cancer cells. In vivo tests showed that synthesized structure have great potential in the removal of cancer cells.


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In another example Mn3O4 nanoparticles were covered with PDA, followed by PEG addition and DOXO loading.104 (See Figure 21) This multifunctional nanostructure exhibited high T1-weight MRI contrast properties and could carry the drug to cancer cells, allowing a combination of chemotherapy with photothermal therapy. It is important to highlight that these nanoparticles were well coated with a continuous shell of PDA and did not show aggregation. Moreover, their contrast properties were 3 times higher than those of the commercially available contrast agent Magnevist. Their potential was also explored in vivo. Tests revealed that all “functions” are accessible in a living organism and successful combined CT-PTT therapy can be carried out using this sophisticated multifunctional nanocarrier.

Figure 21 Schematic view of the synthesis of multimodal Mn3O4 nanoparticles with PDA rim and their use in linked PTT-CT cancer therapy. Reprinted with permission from reference 104. Copyright 2016 The Royal Society of Chemistry

Not only spherical nanomaterials can be used in synthesis of multimodal nanostructures. The latest report of Li and Wang stated that 2D semiconductors also have potential in this field. In the first report Bi2Se3 two-layer nanoplates rimmed with PDA were changed to multifunctional composites, since its cytotoxicity was diminished, and improved photothermal properties were



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also demonstrated.105 (See Figure 22) In addition, the material obtained could serve as a contrast agent in computer tomography due to the contrast properties of the core. Interestingly, human serum albumin was used here to assure the colloidal stability of the nanostructure and to protect the drug against rapid degradation. That unique material was tested in vitro. As expected, a synergistic therapeutic effect between CT and PTT was observed in combined therapy, since 93 % of cancer cell inhibition was observed, while only 24% and 74 % was found for CT and PTT, respectively. Moreover, the anticancer properties of these nanoparticles were assessed in vivo and showed efficient performance in anticancer therapy.

Figure 22 Schematic illustration of the preparation of smart 2D Bi2Se3 structure and its further application and attributes. Reprinted with permission from reference 105. Copyright 2016 ACS

Wang et al. exploited a MoSe2 sheet to synthesize multimodal platforms. First, MoSe2 structures were covered with PDA, according to the routine method using a TRIS buffer and air followed by DOXO loading.106 The resulting nanocomposites MoSe2@PDA measured more than 300 nm, as shown in the DLS test and exhibited very good photothermal properties, as well as low cytotoxicity. Therefore, the authors applied it in dual anticancer CT-PTT therapy, both in vitro and in vivo. A test carried out on mice revealed that a combined approach to anticancer therapy gave better results and the tumor volume was more than 10 times smaller than in the case when


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free DOXO was applied. Moreover, in this group no recurrence of tumor was observed, even after 15 days. In a recent paper, Yang et el. presented metal-organic nanoparticles belonging to the family of Metal Organic Framework (MOF) made from IR825, a dye with properties of photothermal agent and manganese ions.107 (See Figure 23) The resulting structure was shelled with PDA followed by PRG addition via a Michel reaction. Such a structure had a diameter of approximately 70 nm, and showed stable photothermal properties. It did not cause any toxic effect on several cell lines, as checked in vitro using a MTT test, even at a high concentration of nanoparticles. Due to the presence of Mn2+ materials could serve as a contrast agent in T1-weight MRI, and the presence of PDA and dye allow PTT of cancer cell to be performed both in vitro and in vivo. The authors of this report also showed detailed in vivo investigations on particles' kinetic excretion. They found that the material obtained was removed from the mouse's body in the first 12 h through urine and feces, but around 8% of injected dose per gram tissue was still served in the place of interest. These results were supported by ICP-AES and MRI. Synthesized material exhibited high efficacy in killing cancer cells when PTT was applied. Additionally, an in vivo test showed that mice treated with PTT and CT using this nanostructure did not suffer from tumor recurrence and their lifespan was 60 days, while in other control groups they survived only 24 days.



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Figure 23 Schematic view of the synthesis of metal-organic nanoparticles for linked PTT-CT cancer therapy. LIVE/DEAD assay performed for cells incubated with nanomaterial and irradiated with different laser powers. Green – live cells, Red-dead cells. Reprinted with permission from reference 107. Copyright 2016 ACS

Polymeric particles are a frequently used class of particles in nanomedicine. They have been covered with PDA to prepare new drug delivery nanoplatforms. However, theranostic potential of this hybrid materials have not been fully exploited so far. In one of the earliest reports, Amoozgar et al. found that particles made from poly(lactic-coglycolic acid) modified with a PDA shell and a variety of diamines can bind paclitaxel (PTX).108 It was demonstrated in vivo that therapy utilizing these particles led to a higher survival percentage of infected mice, even though they did not bear the targeting ligand. Xiong et al. prepared particles coated with PDA made from block copolymer of methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) with loaded PTX.109 These materials were used to deliver the drug to melanoma cancer cells. It was found that this structure works better in chemotherapy than free drug, which was proved in vitro and in vivo. It is important to highlight here that the PDA shell on polymeric particles prevents an undesired excessive drug release and assured long-lasting drug release properties. Unfortunately, in both aforementioned examples the photothermal properties of PDA were not recognized at that time, so combined therapy was not performed and structures lack targeting, which could have improved their therapeutic effect.


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In another example, Zhu et al. presented D-α-tocopherol polyethylenglycol succinatepoly(lactide) particles with incorporated docetaxel (DTX), which were additionally rimmed with a PDA shell and modified with galactosoamine.110 The functionalization with sugar moiety gave rise to improved uptake of particles by tumor cells and prevented their excessive accumulation in other organs. In consequence, these particles assured a superior therapeutic effect compared to materials without targeting moiety, as proved in vivo. A similar structure was presented by Xu et al., who loaded DTX on polymer particles, followed by PDA and aptamer conjugation. Linkage of aptamer assured active targeting at cervical cancer cells and resulted in more efficient chemotherapy, as presented in vitro and in vivo.111 A unique approach towards multiple breast cancer therapy was presented by Ding et al.112 Instead of the most common combination of CT with PTT, they merged dual CT with PTT and gene therapy. In order to implement this strategy, they used an amphiphilic co-polymer P (MEO2MAco-OEGMA-co-DMAEMA)-b-PLGA (PMODP) with encapsulated DOXO and PXT followed by linkage of siRNA against survivin. Furthermore, this platform of approximately 126 nm was covered with a shell of PDA. In detailed studies it was shown that the diameter of the prepared particles increased, while the dopamine concentration

increased. Taking into consideration

covering capacity and photothermal properties, the authors determined the best ratio of particles to dopamine as 1 to 1.5. Thus, further work was carried out on material obtained under these conditions. It is important to highlight that the PDA shell protected drugs from burst releases from particles. However, carrier degradation occurred under NIR irradiation, which gave rise to the desired slow and long-lasting drug release. The maximum cumulative release of 93 % was observed after 2 weeks.



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Further biological analysis revealed that a composite with DOXO and PXT has similar anticancer properties as free drugs, but after coating with PDA its toxicity was even lower. This was due to the PDA shell preventing drugs from an extensive release and vast negative charge to particles, which could have hampered their uptake. However, a significant drop in cell viability was observed when cells incubated with particle-bearing drugs and siRNA were irradiated with NIR. The authors carried out a control test, which proved that increased mortality of cancer cells was the result of synergistic interaction of CT, PTT and gene therapy. What the authors found in vitro was further demonstrated and confirmed in vivo, where they observed that triple therapy was more effective than dual or mono therapies (CT or PTT or gene therapy) applied separately. 9. Conclusions and Remarks In this short review, the latest advances in the synthesis of novel multifunctional nanocarriers based on polydopamine for cancer therapy were compiled and described. One can notice that these structures employ commonly used nanomaterials as a core, but coating with a polydopamine changed them into multifunctional composites by vesting them with photothermal properties. In consequence, they can be applied in linked therapies like simultaneous chemo and photothermal therapy or photothermal with photodynamic therapy. Such strategies towards killing cancer cells were shown to be superior to a conventional approach dealing solely with chemotherapeutics. Additionally, a PDA shell on nano-sized cores allows straightforward functionalization with PEG ligands improving their colloidal stability, the attachment of drugs or metal ions that might subsequently serve as a contrast agent. What is essential to note is that in the majority of studies reviewed multifunctional nanostructures were found to exhibit very good anticancer properties in vivo, thus part of pre-clinical studies seems to be performed and one can expect that some of the reported nanomaterials can go to clinical trial at some point. However,


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what is also noticeable is that the majority of nanomaterials lack active targeting. This needs to be taken into consideration, while further composites need to be engineered if one is to think about the further application and the need to prevent the uncontrolled spread of nanoparticles in the body. Obviously, mere PDA (nano)structures are gaining more and more attention, since they can easily be provided with strong photothermal properties and allowed to avoid the metallic core. Moreover, multifunctional nanostructures made from rare earth metals and micelles remain unexplored territory and it is likely that they will be investigated in the near future. Finally, a PDA-coated nanostructure can be obtained relatively cheaply, since the polymerization reaction does not require sophisticated or expensive reagents and occurs at room temperature. Important issue in synthesis of PDA based multifunctional nanomaterials is their interaction with hydrophobic drugs that need to later on deliver to cancer cell. In majority of described examples DOXO was used as model chemotherapeutic drugs linked to PDA coated structures. Generally, it is assumed that DOXO is attached to PDA via weak π-π interaction and hydrogen bonds what allow to release DOXO in pH dependent manner since such bonds can be destroyed in lower pH. Therefore, one can expect that PDA coated nanomaterials loaded with DOXO should have similar drug release profile and efficiency. (Amount of loaded drug can differ from structure to structure due to the available active surface). Surprisingly, in described examples cumulative release of DOXO for different materials vary from ~10% to ~85%. Thus, one can hypothesize that other mechanisms can be involved in the interaction of DOXO with PDA too. Since PDA is quinones-rich it can undergo reaction with amines, therefore it cannot be ruled out that DOXO fixed covalently to PDA by amino group present in its structure as was recently suggested.51 Thus, it seems that nature of interaction between DOXO and other hydrophobic drugs with PDA still remains open question and requires further studies.



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Nevertheless, there are some drawbacks in studies on PDA multifunctional nanostructures. For instance, PTT with mere PDA structures or PDA-coated nanostructures differ in terms of material concentration, due to the different PDA masses deposited on the core. Furthermore, PTT experiments are often performed under different irradiation times and laser powers, so it is hard to compare their efficiency. Stability studies in relevant biological fluids are not always described in detail and performed under different conditions, so there is a lack of standardization. Therefore if PDA-based multifunctional nanostructures are going to exceed other groups of nanomaterials, work needs to be done in this area to construct common standards. Taking the above into consideration, it can be concluded that PDA-based multimodal nanomaterials are a promising candidate for further clinical use, and fascinating new nanomaterials will appear in this emerging field. It is impressive to see such a huge development in this particular area in a relatively short period of time, therefore it is obvious that PDA coated nanomaterials have attracted significant attention from many research groups and will continue to do so with upcoming applications. Acknowledgments Dedicated to prof. Jürgen Liebscher on the occasion of his 72th birthday This work was supported by the National Science Center in Poland under research grant number UMO-2014/13/D/ST5/02793. Also support provided by the National Center for Research and Development under research programme LIDER/11/0055/L-7/15/NCBiR/2016 is gratefully acknowledged. Bibliography 1. Hanahan, D.; Weinberg, R. A., The Hallmarks of Cancer. Cell 100 (1), 57-70. 2. Yuan, Y.; Cai, T.; Xia, X.; Zhang, R.; Chiba, P.; Cai, Y., Nanoparticle Delivery of Anticancer Drugs Overcomes Multidrug Resistance in Breast Cancer. Drug Delivery. 2016, 23 (9), 3350-3357. 3. Dong, X.; Mumper, R. J., Nanomedicinal Strategies to Treat Multidrug-Resistant Tumors: Current Progress. Nanomedicine (London, U. K.) 2010, 5 (4), 597-615.


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Table 1. Various classes of PDA based nanomaterials and their application in cancer therapy. In column Therapy CT-chemotherapy, In column Imaging CT-computer tomography, FA-folic acid, PTT-photothermal therapy, PDTphotodynamic therapy, MRI – magnetic resonance imaging, PAI-photoacoustic imaging, Y-Yes, N-No refers only to in vivo tests Core Active Targeting Therapy Imaging Cell line/In vivo Ref molecule Ligand Mere PDA structures 28 PDA --------PTT MRI 4T1 and HeLa/Y 29 PDA CPT --CT ---HeLa and A549/N 31 PDA ----PTT MRI SW620/Y



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

PDA PDA@PEG

PAI

ICG/MRI PAI/MRI MRI -------

---

PTT-CT PTT PTT-CT PTT-CT PDT and PTT RIT and CT

HeLa/Y MCF-7 and PC-9/Y 4T1/Y 4T1/Y HeLa/Y CT26/N HepG2/Y

CT

4T1/Y

PDT and RT MWTT MWTT-CT

---PTT ----

PDA@SiO2

---

---

PTT

PDANP@PEG PDA PDA@PEI

--DOX DOXO

----

T1-MRI/ fluorescence MRI

A549/Y HepG2/Y HeLa andHepG2/Y PC-3/Y

41

DOXO

---------

HeLa/Y HeLa/N HeLa/N

45

Fe3O4@PDA Fe3O4@PDA Fe3O4@PDA Fe3O4@PDA Fe3O4@PDA Fe3O4@PDA Fe3O4@PDA Fe3O4@PDA

DOXO 5-FU DOXO ------mRNA ICG ---

51

Fe3O4@PDA

BTZ

HeLa/N MAMAC/Y N/Y HeLa/Y A549/Y MC-7/N NIH 3T3/Y HeLa and Hep2G/N ---

GNR@PDA

---

PDA@PEG PDP@PEG PDA/IL PDA/IL

GNR@PDA

RGDC

DOXO and ISOTOPS C6 and CUR

33

PTT-CT PTT-CT

PDA@PEG PDA PDA@MOF PDA PDA

DOXO DOXO/ SN38 DOXO ----DOXO BTZ C6

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--------------

PTT CT FA CT Magnetic Nanoparticles --CT --CT --CT --PTT --PTT --PTT --PTT --PTT

----Gold Nanostructures Anti-EGFR PTT

DOXO or MB

---

GNR@PDA GNS@PDA

Pt ICG

RGD FA

CTPTT/PTTPDT CT/PTT PTT/PDT

GNS@PDA GO@PDA@GNS AuNP@PDA AuNP@PDA AuNP@PDA@A u petals AuNP@PDA hollow structure AuNP@PDA

--DOXO Dextran ICG ---

------LA ---

---

CNT@PDA SWCNT@PDA

---------MRI MRI MRI/PAI MRI MRI --Optical tomography Optical imaging

MCF-7,OSCC15 and MDA –MB231/N HeLa/Y

34 35 36 37 38 39

40

42 43

44

46 47

52 53 58 57 54 56 55 59

63

67

H1299/Y MCF-7/Y

68

PTT PTT PTT PTT PTT-PDT

SPECT/CT NIR fluorescence CT --CT T1-MRI/CT ---

HeLa/Y 4T1/Y KB/Y HepG2/N HeLa/N

69

---

PTT

---

MCF-7/Y

---

---

---

CT

HeLa,PC-3,IMR90/Y

DOXO 131 I

-----

--MRI T1-T2

A431/N 4T1/Y

Carbon materials CT PTT-RIT


62

70 71 72 73

74

75

82 83

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CNT@PDA@Gd GR@PDA@C60 GO@PDA GO@PDA@SiO2 CS@PDA

----ICG DOXO ICG

βNaGdF4:Ye3+,Er3 + @ βNaGdF4@PDA NaF4:Ye3+,Er3+@ NaF4@PDA NaDyF4:Yb@Na LuF4:Yb,Er@PD A@Mn2+

DOXO

Micelle@PDA Micelle@PDA Liposome@PDA

DOXO/BZT DOXO 5-FU

WO3@PDA-HA

---

Mn3O4@PDA Bi2Se3@PDA MoSe2@PDA Mn-IR825@PDA

DOXO DOXO/HSA DOXO ---

FA -------

CT-PTT CT-PTT CT-PTT PTT

MRI T1 CT --T1-MRI

PLGA@PDA

PTX

---

CT

---

MPEG-bPCL@PDA TPGSPLA@PDA M-PLGATPGS@PDA PMODP@PDA

--FA --HA FA

PTT PTT-PDT PTT CT-PTT PTT-PDT Rare earth metals -----PTT-CT

MRI-T1 ---------

BxPC-3/Y HeLa/N 4T1/Y HeLa/Y HeLa/N

CT/MRI/ confocal

SW620/Y

84 85 86 87 91

94

ICG

---

PTT-PDT

NIR imaging

HeLa/Y

---

---

PTT

MRI T1-T2

U87MG/Y

95

96

Micelles and Liposomes --PTT-CT --PTT-CT --CT Miscellaneous HA PTT

-------

MCF-7/Y HeLa/N SK-RC-2/N

---

100 101 102

PTX

---

CT

---

MDAMB231,MDCK,A549 /Y MCF-7/Y HeLa/Y HeLa/Y 293T/HeLa/A549/ Y BR5FVB1Akt,SKOV3 Calu6, Y A875/Y

DTX

Galactosamine

CT

---

HepG2

110

DTX

Aptamer

CT

---

HeLa/Y

111

DOX/ PTX/siRNA

---

CT-PTT/ gene therapy

---

MDA-MB-231/Y

112


103

104 105 106 107

108

109


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TOC


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