Self-Assembled Hybrid Nanostructures: Versatile Multifunctional

Review Cite This: Chem. Mater. 2018, 30, 25−53

pubs.acs.org/cm

Self-Assembled Hybrid Nanostructures: Versatile Multifunctional Nanoplatforms for Cancer Diagnosis and Therapy Menghuan Li,†,‡ Zhong Luo,*,† and Yanli Zhao*,‡,§ †

School of Life Science, Chongqing University, Shapingba District, Chongqing 401331, People’s Republic of China Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore § School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore ‡

ABSTRACT: Self-assembled organic−inorganic hybrids are a class of promising nanomaterials possessing interesting physiochemical and biological characteristics, making them highly attractive in cancer-related biomedical applications. By using self-assembly as a synthetic tool and various organic/inorganic species as the building blocks, scientists are able to create a myriad of hybrid nanosystems. These promising nanosystems show favorable nano-bio interfacial properties, while still retaining their physical/chemical functionalities. The present Review aims to provide a systematical overview of the selfassembled hybrid nanostructures and highlight their implementations in cancer diagnosis and treatment by highlighting notable recent examples. In addition, the existing challenges in the bench-to-bedside translation of these nanotherapeutics as well as the potential technological breakthroughs in the future studies were also discussed in detail. Overall, this Review presents how clinical oncology could benefit from the convergence of self-assembly paradigm and nanotechnology.

1. INTRODUCTION The expansion of nanotechnology has provided new avenues for the prevention,1,2 diagnosis3,4 and treatment5 of a variety of cancers, as the performance of conventional pharmaceuticals are severely limited by their intrinsic physio-chemical properties.6,7 Thanks to their small sizes (from 10 nm to a few hundred nanometers) and tunable characteristics, pharmaceutical nanoagents hold great promise in addressing the health problems associated with cancer.6 Pharmaceutical nanostructures could be synthesized from a variety of raw materials, such as lipids,8,9 polymers,10 nucleic acids,11 proteins12 and many other inorganic materials.13 Additionally, the biological activities of these nanostructures could be tailored and improved by surface engineering,14,15 which may further expand their potential use in pharmaceutical applications. These intriguing properties have inspired numerous concepts and designs for advanced biomedical nanosystems. In particular, those nanostructured biomaterials fabricated through the self-assembly of organic/inorganic hybrid building blocks have demonstrated a myriad of powerful advantages in laboratory and preclinical studies, which may lead to promising applications for cancer-related diagnosis and treatment. Self-assembly is usually described as an energy minimization process that generates a large well-defined structure by the spontaneous repetition of smaller ones, which is determined by the size, amount/geometry of the structural unit and the strength of interactions among the units. Different from the covalent conjugation strategies, the self-assembly approach relies on those relatively weaker noncovalent forces such as © 2017 American Chemical Society

hydrogen bonding interaction, electrostatic association, van der Waals interactions, and hydrophobic interaction to organize the building blocks into well-defined spatial configurations.16 Within this perspective, using the self-assembly for the construction of organic/inorganic hybrid nanobiomaterials could not only combine the intrinsic properties of the heterogeneous building blocks, but also potentially attain new physical, chemical and biological functions through the supramolecular interaction among them. Based on our own research as well as other critical studies, we review the scientific progress in organic/inorganic hybrid nanomaterials that are either formed by self-assembly or require self-assembly events to achieve certain functions (Scheme 1), as well as the balancing between their functional novelty and clinical relevance. This Review starts with a brief discussion on the cancer-related applications of self-assembly nanotechnologies and inorganic preparations to justify the interest in the development of self-assembled hybrid nanobiomaterials. Subsequently, we provide a comprehensive compilation of recent representative studies in this field, which is organized depending on the proposed clinical applications and then the inorganic components involved. We focus on the integration of self-assembly technology for the development of hybrid nanobiomaterials, which should possess the desired nano-bio interface properties similar to those self-assembled organic Received: September 16, 2017 Revised: November 15, 2017 Published: November 17, 2017 25

DOI: 10.1021/acs.chemmater.7b03924 Chem. Mater. 2018, 30, 25−53

Review

Chemistry of Materials Scheme 1. Schematic Illustration of the Review Content

nanocarriers have to be tailored to prolong their blood circulation time. Typically, nanoparticles with a size less than 5 nm are rapidly removed from the blood through extravasation and renal clearance, while those sized around several hundred nanometers tend to accumulate in liver, spleen and bone marrow. Consequently, the nanocarriers should be larger than the renal filtration threshold, but small enough to avoid the nondiscriminating uptake by liver and spleen. Moreover, nanocarriers without appropriate surface modification could quickly bind to the serum proteins and are subsequently removed by the macrophage phagocytic system (MPS). A common approach to solve this issue is to conjugate hydrophilic polymers (exemplified by poly(ethylene glycol), i.e., PEG) onto the surface of the nanocarriers, which could form a hydrated barrier to reduce opsonin adsorption. Tumor Specificity: EPR Effect and Active Targeting. There are two basic approaches to enhance the selectivity and specificity of the drug delivery, which are realized through passive accumulation (passive targeting) and tumor-targeting vectors (active targeting). For the passive targeting approach, it is well-known that tumor blood vessels are usually highly abnormal, and the vessel walls are more “leaky” than normal vessels. As a result of the fenestrated tumor vasculature and damaged lymphatic drainage combined, nanoscale substances could leak from the tumor microvessels and accumulate in the tumor parenchyma. This phenomenon is formally named as the enhanced retention and permeability (EPR) effect. The actual efficiency of EPR-dependent drug delivery could be affected by

nanoplatforms, while retaining the unique functionality of the inorganic components. At the end of this Review, we highlight their potential clinical advantages and existing challenges, with the objective to increase the scientific and technological investment in this field.

2. GENERAL CONSIDERATIONS ON NANOTECHNOLOGY-ENABLED CANCER DIAGNOSIS AND THERAPY In the past few decades, there has been a surge of using nanotechnology for oncological applications. However, only a small number of theranostic nanosystems reached commercialization stage. Nevertheless, both the successes and failures of these trials may provide insights into the preparation and utilization of nanomaterials from a more balanced perspective, which could be indicative for the future development of nanomaterials in the cancer diagnosis and therapy. Although there are still no internationally accepted regulations currently available for the development and administration of nanosystems in oncology, a number of criteria have been proposed and commonly used by material scientists and clinicians, which may facilitate the bench-to-bed translations of nanosystems for cancer diagnosis and treatment. 2.1. Design Rationales of Nanosystems for Cancer Therapy. Long Circulation Half-Life. When administered intravenously, the drug-loaded nanocarriers have to avoid various clearance mechanisms in order for the drug to reach the tumor tissues. Therefore, some design features of the 26


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Chemistry of Materials

Additionally, as properties of nanomaterials may vary significantly even within the same class, their efficacy and safety are required to be evaluated on a case-by-case basis. 2.2. Design Rationales of Nanosystems for Cancer Diagnosis. The introduction of nanotechnology has offered a new promise for early and accurate detection of cancer, which is of equal importance to medical treatment. It is well-known that certain materials may provide unique chemical and physical properties when their size is reduced to the nanoscale, which could be potentially used as diagnostic agents with better performance. The technical and regulatory considerations associated with these diagnostic nanosystems are briefly summarized below. Improving the Signal-to-Background Ratio. To detect the evidence of malignancy in a sample, the signal generated by contrast mechanisms at the tumor must be stronger than the background noise. Therefore, to enhance the clinical efficiency of a diagnostic probe, one may choose to enhance the signal that corresponds to the tumor or lower the background, or both at the same time. For instance, Mi et al. reported a pHactivatable Mn2+-doped calcium phosphate nanoparticle capable of amplifying magnetic resonance signals in the acidic tumor environment, which could be used to detect invisible millimeter-sized metastatic tumors in the liver.22 Tumor Sensitivity, Resolution and Specificity. Early diagnosis is particularly important for patients with many cancer indications, and its realization essentially requires new diagnostic modalities with higher sensitivity and better resolution. Enhancing the resolution and sensitivity of cancer diagnosis may facilitate clinicians to detect even smaller cancers and more accurately predict the therapeutic responses, which is crucial to improve survival rates. Moreover, it was reported that the nanoprobes could also be with tumor-targeting ligands to achieve highly specific imaging of the tumor site,23 which may facilitate the molecular characterization of the tumor tissue. Functionality and Safety. From an overall perspective, the safety criteria of diagnostic nanosystems for in vivo applications are similar to those of the drug nanocarriers, such as the requirement of clearance ability, nontoxicity and immunocompatibility. Nevertheless, some properties like effective size and surface functionalization may vary depending on the diagnostic modalities and specific functions. For instance, some nanoparticle imaging probes were designed to be long circulating, which potentiate the repetitive imaging of the tumor area without the need of additional administration of imaging probes. In some circumstances, however, the probes should be able to be rapidly eliminated to avoid unspecific retention, which may result in increasing background noise and long-term health risks.24 These issues highlight the importance of balance between functions and safety for diagnostic nanoprobes, which again suggest the necessity that the safety and performance of these nanosystems should be analyzed and optimized on an individual basis.

a number of factors, including size, charge and surface chemistry. For instance, previous reports indicate that nanoparticles should be in the size range of 50−150 nm so as to extravasate from the neovasculature, while the surface modification of hydrophilic polymers like PEG could significantly prolong the blood-circulation half-life of nanomaterials and thus improve their accumulation at the tumor site.17 Active targeting is another approach that may potentially enhance the nanoparticle accumulation at the tumors while minimizing the collateral damage, which improves the EPRenabled targeting effect through the conjugation of tumorspecific ligands. These ligands are designed to bind to their target receptors that are overexpressed in tumor cells. In an ideal circumstance, the ligand−receptor interaction could trigger efficient and specific internalization of the nanoparticles. Currently, some of the most exploited tumor-specific targets are folic acid receptors, transferrin receptors and integrin receptors. As our understanding of the tumor biology deepens, a variety of new targeting ligands are already underway, which may present unique advantages for the treatment of various tumor indications.10,18 Barrier Penetration and Drug Release Control. The complexity of tumor tissues has created a series of biological barriers that impede the therapeutic action of drug-loaded nanocarriers, which include cancer associated fibroblasts, acidic pH, hypoxia, high interestitial pressure, etc. These obstacles are sufficient to confer resistance to existing treatment modalities. Therefore, nanocarriers should also be able to overcome these barriers to enhance the efficacy against the targeted tumors. For instance, Zhou et al. conjugated recombinant human hyaluronidase PH20 onto the surface of nanocarriers to enhance the drug penetration in tumors, which could degrade the tumor extracellular matrix to facilitate interstitial diffusion.19 Alternatively, scientists have proposed and evaluated a number of strategies that may potentially overcome the aforementioned mechanisms of treatment resistance, such as nanocarriers that may undergo a size reduction20 or charge reversal21 process in response to certain triggers in the tumor microenvironment. Nevertheless, it should also be mentioned that complex tumor microenvironment may also create opportunities for tumor therapy with nanomaterials. By taking advantage of the difference between tumor and normal tissues, nanocarriers could also be fabricated in such a way that the drug release could be initiated in the tumor microenvironment by a certain triggering mechanism. These stimuli could be endogenous (pH, redox potential, reactive oxygen species level, etc.) or exogenous (light, hyperthermia, magnetic field, ultrasound, etc.). Compared with those nonresponsive nanosystems from which the encapsulated drugs are released through uncontrollable random diffusion, these stimuli-responsive nanocarriers allow the tailoring of the release profiles to adapt specific needs of patients. Safety. Safety has always been the major factor of consideration for the development of nanomedicine. Materials with dimensions at the nanoscale could provide many desirable attributes for biomedical applications, yet they are also inevitably associated with some other adverse biological activities that may present hazards to the patients. Therefore, nanomedicine must be made from compounds of biological origin, or at least bioinert substances, therefore ensuring their nontoxicity and immunocompatibility. Moreover, the nanocarriers should be able to self-degrade in vivo or be cleared from the body to minimize the risk of long-term health problems.

3. SELF-ASSEMBLED ORGANIC NANOSYSTEMS FOR CANCER-RELATED APPLICATIONS Currently, a series of self-assembly-based organic imaging and/ or therapeutic agents for cancer diagnosis and treatment have been successfully commercialized or entered clinical trial stage.25,26 For instance, liposomes, which are essentially spherical vesicles consisting of fluid enclosed by one or more self-assembled bilayers of natural or synthetic phospholipids, are one of the most successful self-assembled biomedical 27


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Chemistry of Materials Table 1. Some Self-Assembled Organic Nanosystems That Are Currently Used in Clinical Practice Platform type

Trade name

Formulation

Indication

Clinical benefit

ref.

DaunoXome

Liposomal daunorubicin

Breast cancer, advanced HIV-associated Kaposi sarcoma, acute nonlymphocytic leukemia, ovarian cancer, multiple myeloma

33

Liposomal doxorubicin PEGylated liposomal doxorubicin Liposomal vincristine

Used together with cyclophosphamide for the first-line treatment of metastatic breast cancer in adult women HIV-associated kaposi sarcoma, ovarian cancer, breast cancer, multiple myeloma

Enhanced drug deposition in tumor, decreased side effects, also capable of escaping multidrug resistance Decreased cardiotoxicity and enhanced in vivo retention Increased circulation stability and reduced cardiotoxicity

Myocet

36

Liposomal mifamurtide Liposomal eribulin mesylate

Osteosarcoma

Long circulation half-life, enhanced tumor accumulation, sustained drug release and reduced neurotoxicity Longer plasma half-life

Breast cancer, liposarcoma

Relatively wide therapeutic window and favorable pharmacokinetics

38

Breast cancer, small cell lung cancer

Permitting much higher doses to be used and enhanced tumor distribution

39

Breast cancer, pancreatic cancer, nonsmall-cell lung cancer

Reduced toxicity, increased circulation time

40

Liposomes

Doxil/Caelyx

Marqibo

Mepact Halaven

Leukemia, Hodgkin disease, non-Hodgkin lymphomas, Wilms’ tumor, rhabdomyosarcoma, neuroblastoma

34 35

37

Micelles Genexol-PM

PEGylated micellar paclitaxel Supramolecular protein-drug formulation Abraxane Albumin-bound paclitaxel

its excellent biodegradability and biocompatibility and extensively studied as drug delivery vehicles.60−63 Overall, the synthetic organic building blocks could be an important instrument in a broad array of cancer-related applications including drug delivery and bioimaging. With the rapid advances in tumor pathology and our understanding of the interaction at molecular and nanoscale level, some natural biomacromolecules are increasingly being used for the fabrication of self-assembly based nanoscale constructs, which may bring potential benefit to cancer patients. Notably, these emerging natural or naturally derived organic building blocks include and not limited to proteins,64−66 peptides/polypeptides,67−70 DNA,71−74 polysaccharides.75,76 Several new preparation methods have also been developed for the nanofabrication by the self-assembly of these substrates. For instances, one of the major breakthroughs in DNA bioengineering technology is the DNA origami, which uses multiple short complementary oligonucleotides to fold a long strand of DNA into a predetermined shape.77 The programmable flexibility of DNA origami enables the preparation of well-defined multidimensional biofunctional materials.78,79 More importantly, recent insights have demonstrated that biomolecules and nanoparticle species could also be incorporated into DNA origami structures, which further expand their application potential.80 Another example is the self-assembly of polyelectrolytes,81,82 which could be used to produce supramolecular nanomaterials with tailorable structures and versatile functions using charged or chargeable biomacromolecules including polypeptides, glycosaminoglycans and DNA.83,84 Compared with their synthetic counterparts, these natural or naturally derived organic building blocks may provide unique advantages for many cancer-related pharmaceutical applications, as many of them are intrinsically bioactive. However, it is also worth noting that despite their biological origin, extensive testing and characterization are still needed to thoroughly evaluate their in vivo efficacy and safety.

nanoplatforms since the emergence of nanomedicine. They have been found broad application in cosmetic, pharmacy, food and agriculture industry and approved for cancer therapy in 1995. It has so far demonstrated great application potential.27,28 In the study by Spring et al., they developed a photoresponsive multi-inhibitor liposome that is capable of synchronous lightinduced chemotherapy and inhibition of treatment resistance, which offers novel prospects for the realization of spatiotemporally controlled drug release and reduced ill effects.29 Compared with those conventional administration approaches, these delivery systems could provide many pharmacologically favorable properties such as the entrapment of water-insoluble drugs, manipulation of pharmacokinetic parameters, alleviation of side effects and enhanced resistance to physiological degradation of bioactive agents, thus significantly improving the pharmacological efficacy while minimally impacting healthy tissues and organs. The manufacturing approaches and clinical advantages of these self-assembly-based nanosystems have been thoroughly and excellently discussed in several recent reviews.30−32 Tables 1 and 2 list some representative selfassembled organic nanosystems for cancer diagnosis and treatment in clinical practice and clinical trials.33−54 As demonstrated in these tables, both synthetic and natural organic species (including their functional derivatives) could be used for the fabrication of self-assembled nanomedicine. The major advantage of synthetic organic building blocks is that they could be prepared with high cost effectiveness and purity while exhibiting tailor-made biological properties. For example, PEG, polylactide (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(glycolic acid) (PGA), poly(caprolactone) (PCL), poly(butylene succinate) (PBS) and poly(p-dioxanone) (PPDO) are frequently used synthetic constituents for the fabrication of self-assembled nanobiomaterials, all of which have been approved by FDA for certain in vivo biomedical applications.55 Specifically, due to the minimal immunogenicity/antigenicity/ toxicity and high hydrophilicity, PEG has been widely employed in various self-assembled nanosystems to impart antifouling properties and prolong the in vivo circulation time.56−59 Another good example of clinically approved synthetic polymers is PLGA, which is widely recognized for 28


Celsion

Lipomedix Pharmaceuticals

Celator Pharmaceuticals

Genprex

CSPC ZhongQi Pharmaceutical Technology Juvaris Bio-Therapeutics Inc. SignPath Pharma, Inc.

LiPlasome Pharma

AstraZeneca, Pfizer

Crystal Therapeutics

Nippon Kayaku Co., Ltd. NanoCarrier Co., Ltd.

Cerulean Pharma Inc.

Thermodox

Promitil

Vyxeos/CPX-351

Oncoprex

Mitoxantrone hydrochloride liposome JVRS-100

LiPlaCis

AZD2811

CriPec

NK105 NC-4016

CRLX101

Lipocurc

Merrimack

Sponsor

MM-302

Name

29

Paclitaxel-incorporating micelles Diaminocyclohexane platinum entrapped in micelles via polymer−metal complexation Camptothecin complexed to a linear, cyclodextrin-based polymer

Cisplatium incorporated in liposomes, can be degraded by secretory phospholipase A2 (sPLA2) Aurora kinase inhibitor incorporated in polymeric micelles via ion pairing Docetaxel entrapped in micelles

Inducing significant innate immunity

Better in vivo tolerance and superior antitumor activity Enhanced delivery efficiency (25-fold) and triggered drug release Significantly improved toxicity profile than free mitomycin-C Superior response rate and no increase in serious toxicity Improved antitumoral efficacy with minimal side effects Improved safety profile and efficacy

Advantage

Solid tumors

Enhanced delivery efficiency and reduced side effects Metastatic breast cancer Selective uptake of formulated drug at the tumor site Solid tumors Enhanced therapeutic index and preclinical efficacy Solid tumors Controlled drug release at the tumor site, improved efficacy and tolerability Breast cancer Superior activity and tolerability of paclitaxel Advanced solid tumors, lymphoma Increased cell permeability and enhanced retention Advanced solid tumors Long circulation half-life and sustained drug release

Acute myelogenous leukemia

Plasmid DNA complexed with cationic liposomes Curcumin encapsulated in liposomes

Malignant lymphoma

Nonsmall cell lung cancer

HER2-positive advanced/ metastatic breast cancer Primary liver cancer/recurrent chest wall breast cancer Solid tumor and metastatic colorectal cancer Leukemias

Indication

Mitoxantrone HCL (Novantrone) entrapped in liposomes

Cytarabine and daunorubicin (molar ratio 5:1) encapsulated in liposomes TUSC2 gene encapsulated in cationic liposomes

Mitomycin-C encapsulated in PEGylated liposomes

Doxorubicin encapsulated in thermosensitive liposomes

HER2-targeted antibody−liposomal doxorubicin conjugate

Composition

Table 2. Some Self-Assembled Organic Nanosystems Currently in Clinical Trials

II

III I

I

I

III

54

52 53

51

50

49

48 I

46 I

47

45

II

I

44

III

43

42 I

41

(Stopped) III

ref.

II

Clinical trial phase

Chemistry of Materials Review


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Table 3. Representative Nanosystems with FDA-Approval or under Clinical Trials That Contain Inorganic Components Marketed nanosystems comprising biofunctional inorganic components Trade name

Company

Nanotherm Feridex/Endorem GastroMARK/umirem

MagForce AMAG pharmaceuticals AMAG pharmaceuticals

Name

Sponsor

Composition

Indication

Iron oxide nanoparticles Hyperthermia ablation of glioblastoma Dextran coated SPION In vivo imaging Silicone coated SPION In vivo imaging Inorganic nanosystems currently under clinical trials Composition

Year approved

ref.

2010 FDA (1996) Discontinued (2008) 2009

97 98 99

ClinicalTrials.gov identifier (phase)

Advantage

Indication Thermal ablation of solid primary and/or metastatic lung tumors Locally advanced squamous cell carcinoma

AuroLase

Nanospectra Biosciences

PEGylated silica-gold nanoshells

Can be irritated by near-infrared light for thermal ablation

NBTXR3/ PEP503

Nanobiotix

Hafnium oxide nanoparticles

Cornell Dots

Hybrid Silica Technologies

Magnablate

University College London

Silica nanoparticles with an NIR fluorophore, PEG coating, and a 124I radioable-led cRGDY targeting peptide Iron nanoparticles

Can enhance tumor cell death via electron production under external radiation Brighter fluoresce than existing dyes

Sienna+/SentiMag

Endomagnetics

Iron oxide particles coated with carboxydextran

TNF-Bound Colloidal Gold

National Institutes of Health Clinical Center

Colloidal gold-bound tumor necrosis factor

Circumvent the long-term risks of surgical prostate removal High accuracy and reliability

Lowered cost with comparable efficiency

Imaging of malignant brain tumors and melanoma Thermal ablation for prostate cancer Mark and locate cancerous lymph nodes prior to surgery Stimulate the immune system and stop tumor cells from growing

ref.

NCT01679470 (Not provided)

100

NCT01946867 (I)

101


102

NCT02033447 (0)

103

NCT01790399; NCT02249208

104


105

porous silica.96 Overall, these methods are well-proven modification strategies, which may significantly improve the bioavailability and biocompatibility of the inorganic components. Nevertheless, it usually requires a series of complex chemical reactions to achieve high-affinity binding of the bioactive moieties, which may have potential negative impact on their biofunctionality. As technologies advance, alternative preparation methods for organic−inorganic hybrid materials are urgently needed, which should be safe, fast, simple and versatile. Table 3 presents some representative inorganic nanosystems that have been approved or under clinical trials.97−105

4. INORGANIC NANOMATERIALS FOR CANCER DIAGNOSTICS AND THERAPY In the earliest times, a lot of scientific effort for pharmaceutical nanotechnology has been devoted to the development of “soft” nanoplatforms based on organic constructions units, which possess excellent biocompatibility and versatile surface chemistry. However, with the improved understanding of inorganic chemistry and molecular biology, inorganic nanomaterials with irreplaceable physio-chemical properties have also attracted increasing interest for biomedical applications. Compared with their organic counterparts, inorganic nanoparticles have many unique and interesting functionalities, such as the high luminescence of quantum dots (QDs),85 superparamagnetic behavior of iron oxide nanoparticles86,87 and localized surface plasmon resonance of gold nanorods.88 These physicochemical functionalities are highly desired for biomedical applications like high-resolution in vivo imaging or photothermal ablation, but are rarely found on those organic materials currently available. However, the clinical translation of these inorganic nanoparticles has been initially impeded by many intrinsic and persistent issues. It has been consistently revealed in many reports that using unmodified inorganic nanoparticles for clinical applications could raise potential health risks due to their problematic bioaccumulation, biodegradability, difficult body clearance, etc. Additionally, much of the physiological detail regarding the pharmacokinetic characteristics and biological impacts of these inorganicnanoparticle-based nanomedicine, such as their body distribution, circulation time, disease-targeting efficiency and immune response, still remains to be elucidated, which may further hamper their clinical translation.89−95 After years of development, there are already many approaches for the biofunctionalization of inorganic substrates. Some of the most frequently used methods are (1) conjugating biomacromolecules onto inorganic nanoparticles with covalent linkage or (2) coating the particle surface with biocompatible synthetic materials such as functional polymers and meso-

5. SELF-ASSEMBLED ORGANIC−INORGANIC HYBRIDIZED NANOBIOMATERIALS: PRINCIPLES AND SUPRAMOLECULAR ASSEMBLY STRATEGIES Self-assembly techniques are emerging as an important approach for the nanoengineering of organic/inorganic hybrid nanosystems. Compared with those previously mentioned conventional functionalization strategies, the self-assembly approach excels with their excellent generality, simple preparation, low cost and versatile combination of functional components. With rationally designed components and aggregation mechanisms, the self-assembly technologies could not only effectively improve the biocompatibility of inorganic nanoparticles, but also facilitate the engineering of specialized types of hybrid materials that are tailored to specific clinical needs. Particularly, the self-assembly approach could retain and improve the unique properties of inorganic nanoparticles, as well as to endow them with new powers through modification and supramolecular interaction. For instance, it is now widely acknowledged by the biomedical scientific community that due to their unfavorable size, charge and chemical composition, most inorganic nanoparticles have difficulties to be efficiently removed from the body as intact nanoparticles or degraded into biologically benign compounds, thus greatly amplifying their potential long-term toxicity.106−108 In this regard, the selfassembly approach provides alternative avenues for the 30


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the current self-assembly approaches, which is highly favorable for nanomanufacturing.

engineering of inorganic nanoparticles and incorporation of chemotherapeutics, which are functionally balanced between long blood circulation/sustained treatment and rapid clearance of the depleted nanocarriers from the body. In summary, such advantages are critical for the development of advanced inorganic nanoparticle based pharmaceutical nanosystems, and may further promote their clinical translation. A plethora of techniques have been developed to integrate heterogeneous components into biofunctional nanostructures via self-assembly, most of which belong to the so-called “bottom-up” approach. Though some factors or parameters may vary depending on situations, these preparation methods all rely on the utilization of supramolecular chemistry and noncovalent physiochemical forces to achieve the spontaneous formation of the proposed nanostructures. Based on how the building blocks were organized and controlled, as well as considering the popularity in biomedical research and the impact on industrial production, the existing self-assembly strategies could be roughly divided into coassembly, hierarchical self-assembly and directed self-assembly, which will be introduced briefly below.109 Coassembly. The coassembly technique refers to the simultaneously self-assembly of multiple different building blocks into a synergic nanosystem. The basic concepts have been excellently demonstrated in the study by Guo et al., in which they reported a facile coassembly method to prepare various heterogeneous superstructures using polyphenol as the functional ligand to mediate the interlocking process. Moreover, the functionalization and assembly of the components are simple and modular, which could be used for the rapid production of assemblies over a wide range of length scale.110 Hierarchical Self-Assembly. The defining feature of hierarchical self-assembly is that the self-assembly process could be temporally divided into multiple stages. Typically, the basic molecular building blocks will first organize into a “firstorder” assembly, which would be used as the building block to afford a “second-order” assembly. Such process could be repeated for many times, eventually leading to a supramolecular nanostructure of increasing size and complexity.111−113 Using this strategy, scientists were able to create various biofunctional superstructures out of simple structural units. For instance, Mout et al. fabricated highly sophisticated multilayered hybrid nanostructure with recombinant proteins and engineered gold nanoparticles, in which the individual protein molecules and nanoparticles first coassembled into discrete colloids (size: ∼10 nm) and then aggregate into a granule-like structure (size:

Self-Assembled Hybrid Nanostructures: Versatile Multifunctional

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