Recent Advances and Progress on Melanin-like Materials and Their

Review Cite This: Biomacromolecules XXXX, XXX, XXX−XXX

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Recent Advances and Progress on Melanin-like Materials and Their Biomedical Applications Long Huang,†,# Meiying Liu,†,# Hongye Huang,† Yuanqing Wen,† Xiaoyong Zhang,*,† and Yen Wei*,‡,§ †

Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031, China Department of Chemistry and the Tsinghua Center for Frontier Polymer Research, Tsinghua University, Beijing 100084, P.R. China § Department of Chemistry and Center for Nanotechnology, Chung-Yuan Christian University, Chung-Li 32023, Taiwan ‡

ABSTRACT: Melanins are well-known biopolymers that are ubiquitous in nature, distributed widely in microorganisms, plants, and animals, and play significant physiological roles. They are mostly biopolymers formed from phenolic compounds by polymerization via quinones. Poly(dopamine) (PDA), a melanin-like material, is similar in structure and properties to eumelanin and has attracted considerable interest for various types of biological applications. This review outlines the recent advances in the structure and synthesis of PDA and discusses applications of PDA in many biological fields, such as biological imaging, photothermal therapy, and drug delivery systems. The purpose of this review is to give a brief overview of the synthesized procedures, structure, biomedical applications, and prospects of melanin-like materials.

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INTRODUCTION Melanins are well-known biopolymers that are ubiquitous in nature, distributed widely in microorganisms, plants, and animals, and play significant physiological roles.1 Melanins have a diverse number of functions in the biosystem, such as photoprotection, antioxidation, thermoregulation, metal chelation, and some involvement in nerve systems and so forth.2−7 In general, melanins in organisms play a defensive role. In man and other vertebrates, melanin functions as a sunscreen or camouflage.8 Melanins protect fungi against environmental stresses: high insolation, low temperature, low water content, starvation, elevated ROS, and increased radioactivity.9−11 In the plant kingdom, the intensity of melanin formation is often correlated with resistance to microbial and viral infections.12 Structurally, melanins have been continuously explored in many ways in recent years.13−15 However, to date, the structures of melanins are still not completely clear, and there is no unified definition as melanins are so diverse in origin, color, size, and function. Currently, the widespread and simple definition of melanin is “Melanins are mostly biopolymers formed from phenolic compounds by polymerization via quinones”. For better comprehending the melanin concept and structure, melanins have been classified into three main types on the basis of their precursor molecule: brown-black eumelanins, yellow-red pheomelanins, and a heterogeneous group of allomelanins. As shown in Scheme 1, the eumelanins (eu = good) and the pheomelanins (pheo = cloudy or dusky) are derived from tyrosine. Eumelanins are dark brown to black pigments with 6−9% nitrogen and 0−1% sulfur. Tyrosinase catalyzes the formation of 3,4-dihydroxyphenylalanine (DOPA) from tyrosin. Then, the DOPA oxidation step is manifested in © XXXX American Chemical Society

dopaquinone formation followed by the cyclization and build up 5,6-dihydroxyindole (DHI) or 5,6-dihydroxyindole-2carboxylic acid (DHICA) with their following oxidation to indole-5,6-quinone or indole-5,6-quinonecarboxylic acid. Finally, the brown and black pigment eumelanins are fabricated by polymerization of oxidationto indole-5,6-quinone or indole5,6-quinonecarboxylic acid.16−18 Unlike eumelanins, pheomelanins are yellowish or reddish pigments with 8−11% nitrogen and 9−12% sulfur, and they can be dissolved in alkali media. Pheomelanins are found in relatively large quantities in red hair, freckles, and feathers of fowls and other birds. 19−22 Pheomelanins originate from tyrosine/DOPA just like eumelanins. After dopaquinone formation, the synthesis pathway involves sulfur compounds (cysteine). In presence of cysteins, dopaquinones connect with cysteins to form 5-Scysteinyldopa and 2-S-cysteinyldopa, which give benzothiazine intermediates resulting in the formation of pheomelanins (Scheme 1).20,23−27 In general, allomelanins derived from 1,3,6,8-tetrahydroxynaphthalene (1,3,6,8-THN) are very common in fungi and typically do not contain nitrogen, such as Aspergillus nidulans, A. niger, Alternaria alternata, Cladosporium carionii, Exophiala jeanselmei, Fonsecaea compacta, F. pedrosoi, Hendersonula toruloidii, Phaeoannellomyces wernickii, Phialophora richardsiae, P. verrucosa, Wangiella dermatitidis, and Xylohypha bantiana.28−30 In this type of allomelanin derived from 1,3,6,8Special Issue: Biomacromolecules Asian Special Issue Received: March 13, 2018 Revised: April 27, 2018

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DOI: 10.1021/acs.biomac.8b00437 Biomacromolecules XXXX, XXX, XXX−XXX

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Biomacromolecules Scheme 1. Common Biosynthetic Pathways for Melanins

THN, the first detectable intermediate 1,3,6,8-THN is reduced by a specific reductase enzyme to scytalone.28,31 Scytalone is dehydrated enzymatically to 1,3,8-trihydoxynaphthalene (1,3,8THN), which is in turn reduced, possibly by a second reductase, to vermelone. Next, a further dehydration step is performed to produce intermediate 1,8-DHN. Subsequently, a dimerization of the 1,8-DHN and polymerization are performed, possibly catalyzed by laccases, phenol oxidases, peroxidases, and catalases.32−34 This is a general model for allomelanin biosynthesis. However, in fact, the synthetic routes of allomelanins are varied according to the different precursors such as metabolites of homogentisic or p-hydroxyphenylpyruvic acid (piomelanins), γ-glutamyl-4-hydroxybenzene, and catechols.35−40 The synthetic routes of allomelanin pigments are various and beyond the scope of this review. Most reported melanins are synthesized via the biosynthetic pathways described above. Interestingly, some fungi have more

than one biosynthetic pathway of melanins. For example, in Talaromyces marnef fei (Basionym: Penicillium marnef fei), both allomelanins and eumelanins can be synthesized depending on growth conditions and supply of precursors.41 Thus, the complexities of the natural melanin put us in a bit of a spot for their extraction and purification, which greatly limits the applications of melanin. Many natural melanins have been obtained by separation and purification of the pigment from their biological environment.42−45 However, the inherent properties of the natural melanins cannot be detected accurately because there is no accepted set of standardized procedures that has been proven not to alter their inherent physicochemical properties.7 Therefore, standardized detection and extraction technologies need to be defined to obtain the unmodified characteristics of natural melanins. From another perspective, it is entirely natural that synthetic melanins have significant vogue. PolyB


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Figure 1. Preparation of PDA FONs by oxidation of PDA and subsequent utilization of the PDA FONs for cell imaging (a). TEM image of PDA FONs; scale bar = 100 nm (b). Normalized PL emission spectra (with gradually increased excitation wavelengths from 360 to 500 nm) of the PDA FON dispersion in water (c). Cellular toxicity and cellular imaging of PDA FONs (d). CLSM images of cells imaged under bright field (e) 405 and (f) 458 nm excitations. Reproduced from ref 73, with permission from The Royal Society of Chemistry.

structures of PDA have been studied by many means.62,65−67 In 2013, Beck et al. soberly investigated the structure of PDA by several analytical methods, including 13C CPPI MAS NMR spectroscopy, 1H MAS NMR spectroscopy, and high-resolution ES(+)-MS. On the basis of these analysis data, they developed a structural model of PDA consisting of mixtures of different oligomers wherein indole units with different degrees of (un)saturation and open-chain dopamine units occur. This gave fresh inpetus to elucidate and understand the structure of PDA.68 PDA, as a melanin-like material, is produced by the oxidative polymerization of dopamine, but the producing environments are very different. The solution oxidation method is the most widely used protocol for the production of PDA.69−73 Its monomer, dopamine, can be oxidized and spontaneously selfpolymerize under alkaline conditions (pH >7.5) with oxygen under ambient conditions without any complicated instrumentation or harsh reaction conditions. When dopamine monomers are added to an alkaline solution, the polymerization of dopamine monomers occurs immediately coupled with a color change from colorless to pale brown and finally turning to a deep brown over time. For a PDA film on substrates to be achieved, the concentration of dopamine monomer must be higher than 2 mg/mL.74 The biosynthesis of melanins in an organism is inseparable from the participation of enzymes. This provides a new method for synthesizing PDA by means of an enzymatic oxidation process. In fact, a number of studies in the enzymatic polymerization of phenol derivatives, phenolic compounds, and aromatic amines have been reported.75,76 Tan et al. use laccase-catalyzed polymerization to fabricate a biomacromolecule immobilization platform for eletrochemical biosensing and biofuel cell applications.76 As compared with the traditional synthesis method, the enzyme-catalyzed method is relatively complicated but has higher efficiency and does not produce any waste. That is in accordance with green chemistry concepts. Research suggests electropolymerization of dopamine is less reported, but it can also be used as a backup method for

(dopamine) (PDA), synthesized using L-DOPA or DHI as precursors, gives place to a synthetic melanin similar to natural eumelanin. It can be applied in many fields, such as energy, environmental, and biomedical, and it has potentially broad application prospects.46,47 As PDA and eumelanins have the same precursors and similar oxidative and synthesis steps, PDA is used as a model melanin for biophysical studies and other applications of eumelanins.20,48,49 In recent years, PDA, a melanin-like material, has rapidly expanded to include surface modification, interfacing with cells, biosensing, light-harvesting systems for energy applications, nanomedicine, and so on.50−57 The aim of this review is to outline the recent progress and developments in the use of the synthetic melanin-like PDA as a coating material in the field of biology applications. In the first section of this review, we will briefly summarize recent advances in the structure and synthesis of PDA. We will outline the latest research on the structure of PDA, and then three synthetic methods of PDA will be discussed and compared to help us to have a general understanding of PDA. In the second section of this review, we will focus on the application of PDA in many biological fields such as biological imaging, photothermal therapy, and drug delivery systems. Some further developments and directions regarding the biomedical applications of PDA will also be discussed. We trust this review will attract significant research interest from scientists in the biological, chemistry, materials, and medicine fields.

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STRUCTURE AND SYNTHESIZED PROCEDURES In the Introduction, we briefly learned about the biosynthesis route of melanins distributed in animals, plants, and microbes. Despite several decades of work on melanins, in fact their complete structures are still not clear.58−60 In 2007, Messersmith and co-workers reported that PDA was produced by the oxidative polymerization of dopamine (DA) at pH 8.5 in the presence of oxygen.61 Since then, research on PDA is being paid increasing attention in the academic world.46,56,62−65 The C


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Figure 2. Schematic showing the preparation of PEI-PDA FONs through self-polymerization using polyetheniemine (PEI) and dopamine (DA) as the precursors and cell imaging applications of PEI-PDA FONs (a). PL spectra of PEI-PDA FONs (in water). The emission peak of PEI-PDA FONs is located at 526 nm, and the excitation peak is located at 380 nm. When PEI-PDA FONs were excited at various wavelengths, the fluorescence intensity of PEI-PDA FONs was correspondingly changed (b). Cell viability of PEI-PDA FONs with A549 cells (the concentrations of PEI-PDA FONs ranged from 10 to 120 mg/mL) (c). CLSM images of A549 cells incubated with 10 mg/mL of PEI-PDA FONs for 3 h. Bright field (d), excited with 405 nm laser (e), merged image (f). Scale bar = 20 m. Reproduced from ref 87, with permission from The Royal Society of Chemistry.

the preparation of FONs through simple procedures are of great research interest. Among them, the melanin-like materials based on DOPA, as fluorescent probes for cell fluorescence imaging, have been reported in recent years.73,86,87 For example, Zhang et al. first reported the novel polydopaminebased FONs (PDA FONs), which could be obtained directly by the oxidation of PDA nanoparticles using hydrogen peroxide (H2O2) (Figure 1).73 According to the TEM picture of PDA FONs, the diameter and length of synthesized wormlike nanomaterials in Figure 1b are approximately 150 and 600 nm, respectively. The normalized photoluminescence (PL) emission spectra of PDA FONs in water exhibit a unique phenomenon: the peaks of the emission spectra move to higher wavelength positions with the progressively increased excitation wavelengths from 360 to 500 nm (Figure 1c). This was consistent with the results of subsequent cell imaging. In vitro cell imaging of PDA FONs and the cell-internalized PDA FONs emitted green and green-yellow fluorescence with the irradiation of lasers at 405 and 458 nm, respectively (Figure 1e and f). Moreover, the authors evaluated the cytotoxicity of PDA

PDA synthesis. The data make clear that molecularly imprinted polymers can be synthesized on a gold electrode in one step by electrochemical copolymerization of o-phenylenediamine and PDA.77 Despite the simplicity and effectiveness, PDA only can cover the surface of electrically conductive materials, which restricts the electropolymerization of PDA applications.

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APPLICATIONS Biological Imaging. Biological optical imaging is often used to analyze the characteristics and morphology in specific regions of cells or organisms, and it can be divided into fluorescence imaging, bioluminescence imaging, photoacoustic imaging, optical tomography, and so on owing to the different detection methods.78−81 Previously, a number of fluorescent organic nanoparticles (FONs) based on conventional organic dyes or aggregation-induced emission (AIE) active dyes and natural carbohydrate polymers have been reported for fluorescence imaging.82−85 However, many of these FONs based on organic dyes require complex procedures for the synthesis of organic dyes and fabrication of FONs. Therefore, D


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Figure 3. (a) Preparation of the liposome−BSM. The left legs of normal nude mice (n = 12) were injected subcutaneously with liposome−BSM (BSM = 10 mg/mL, 100 μL for each mouse) (b). Reprinted from ref 99; copyright 2016, with permission from Elsevier.

procedure for fabrication of PDA-based fluorescent probes and also expanded its applicability. However, the fluorescence properties of these PDA-based probes could not be adjusted well through self-polymerization of DA-containing polymers and PEI. Further studies for the preparation of PDA-based fluorescent materials that could adjust their fluorescence properties well would be of great research interest. Photothermal Therapy (PTT). There is evidence that cancer has reached epidemic proportions globally with more than 2.8 million people dying in 2015, and the number of deaths is more than 7500 per day according to the World Cancer Report. At present, clinical therapies are limited to surgical, chemotherapy, and physiotherapy. Unfortunately, these approaches treat cancer while also destroying the immune system of patients, causing strong side effects. Owing to the high efficiency and low side effects of PTT for cancer treatment, PTT has attracted increasing attention and has been extensively investigated by scientists. In cancer treatment, PTT agents (PTAs) that possess high efficiency of light−heat conversion are injected into humans, and then using target recognition technology, they are gathered in the region of tumor tissues to kill cancer cells by converting light energy to heat energy under the irradiation of a localized near-infrared (NIR) laser. So far, numerous PTAs based on various melanins have been subjected to increasing research for PTT.95−98 A variety of PTAs, such as black sesame melanin (BSM) and red blood cell (RBC) membrane-camouflaged melanin (Melanin@ RBC) have previously been examined for PTT applications.95,96 For example, Chu et al. extracted a natural BSM from black sesame seeds that shows exciting potential for sentinel lymph node (SLN) mapping and laser-driven cancer hyperthermia (Figure 3).95 First, the BSM was extracted from black sesame seed skin. Then, liposome-BSM, with excellent biocompatibility, can be built up by self-assembly of BSM and lipid (Figure 3a). SLN mapping of liposome-BSM indicated that liposomeBSM nanocomposites could passively target and explicitly denote the SLNs (Figure 3b). After PBS-dispersed liposome− BSM nanocomposites (BSM = 5 mg/mL, 70 mL) were injected into mice and then irradiated by an NIR laser (808 nm) for 20 min per day, the size in the mice was close to zero. Experimental results demonstrated the new melanin-like PTA (liposome−BSM) achieved the expected effects.

FONs through a counting kit-8 (CCK-8) assay (Figure 1d). No obvious cytotoxicity is observed with the increase in the concentration of PDA FONs. Experimental results showed that the water-soluble and biocompatible melanin-like nanocomposites are suitable agents for cell imaging. Thereafter, a number of fluorescent nanoparticles based on melanin-like materials have been fabricated and considered for cell imaging.88,89 For example, Caruso et al. fabricated the fluorescent PDA-based capsules using sacrificial templates and subsquent oxidation.90 In their report, the core−shell nanocomposites with PDA coatings were formed through the selfpolymerization of dopamine in an alkaline solution. After removal of the templates, fluorescently labeled PDA (F-PDA) capsules were fabricated via the polymerization of dopamine (DA) in the presence of H2O2. The biological assays suggested that these F-PDA capsules exihibited negative effects toward HeLa cells and could be internalized into cells through endocytosis. As compared with the previous report by Zhang et al., this novel method could well-control the size and morphology of fluorescent PDA-based materials. Moreover, these fluorescent capsules could also provide a large space for loading biologically active agents for drug delivery.91 Apart from the oxidation procedure, some simple methods have also been reported for fabricating fluorescent PDA-based fluorescent probes. For example, Liu et al. designed a facile strategy for preparing melanin-like nanoparticles (PEI-PDA) through selfpolymerization of DA in the presence of polyethylenimine (PEI) (Figure 2).87 The whole synthesis step is convenient, effective, green, and scalable (Figure 2A). The synthesized PEIPDA possessed a number of excellent properties, such as high water dispersibility, excellent biocompatibility, and multifunctional capability. Moreover, because of the strong fluorescence of PEI-PDA, even if the concentration of PEI-PDA was as low as 10 mg/mL, the cell uptake of PEI-PDA can still be clearly observed. More recently, some other reports have also demonstrated that the fluorescent polymeric nanoparticles could be fabricated through the reaction of PEI- and DAcontaining polymers, which can be synthesized through controlled living polymerization and conjugation reactions.92−94 Therefore, the chemical compositions and physicochemical properties as well as functions of these PDA-based fluorescent probes could also be adjusted well based on the DA-containing polymers. These studies further simplified the E


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Figure 4. Schematic illustration of red blood cell membrane-camouflaged melanin nanoparticles for enhanced photothermal therapy (a). Tumor volume curves of A549 tumor-bearing mice with different treatments (for laser, melanin + 2 W/cm2 laser and Melanin@RBC + 2 W/cm2 laser groups, tumors were irradiated by an 808 nm laser (2 W/cm2) for 5 min; for Melanin@RBC + 1 W/cm2 laser group, tumors were irradiated by an 808 nm laser (1 W/cm2) for 10 min). Tumor models without any treatment were used as a negative control (b). Body weight curves of mice of each group (c). Photos of tumors dissected from each group on the 13th day after photothermal treatment and comparison of tumor weights of each group (**p < 0.01, ***p < 0.001, and n.s., no significance; data are means ± SD with n = 5) (d and e, respectively). Plots of in vitro PA signal versus various concentrations of melanin and Melanin@RBC nanoparticles; inset is the PA images of Melanin@RBC nanoparticles with various concentrations of 0, 5, 12.5, 25, 50, 100, and 200 μg/mL (f). Quantitative analysis of in vivo PA signal at the tumor region before (Pre) and after intravenous injection of 100 μL of Melanin@RBC and melanin nanoparticles (1 mg/mL) in A549 tumor-bearing mice; the PA intensity from Pre image is defined as 0 (*p < 0.05 and **p < 0.01 compared with melanin nanoparticles; data are means ± SD with n = 3) (g). Reprinted from ref 96; copyright 2017, with permission from Elsevier.

melanin-like materials could be self-detected by photoacoustic imaging apart from their use for PTT. Moreover, other imaging agents such as fluorescent dyes, radioactive elements, and magnetic materials could also be facilely introduced into these melanin-like materials.100,101 Thus, multifunctional composites based on melanin-like materials could be fabricated. Drug Delivery Systems. Drug delivery systems (DDS) are technical systems that can regulate the distribution of drugs in space, time, and dose in organisms. The goal of DDS is to deliver the right amount of medicine to the right place at the right time to increase the efficiency of drugs used, improve the curative effects, and reduce cost and side effects. Transport vehicles, which serve the DDS, mainly include inorganic materials, polymeric materials, organic materials, and so forth. Melanin, a natural nontoxic organic material, has been used as a transport vehicle for DDS, and it has been explored with great interest. For example, Araujo et al. extracted sepia melanin from

Aside from the PTAs based on melanin of plants, PTAs extracted from animals have also been produced for PTT by Jiang et al.96 In this work, the melanin extracted from living cuttlefish, which could effectively eliminate the side-effects as well as default metabolism in biological systems, was coated by an erythrocyte membrane to form red blood cell (RBC) membrane-camouflaged melanin (Melanin@RBC) nanoparticles as novel PTAs (Figure 4a). The Melanin@RBC nanoparticles were injected into A549 tumor-bearing mice. Thirteen days later, tumors were almost completely eliminated with irradiation by an 808 nm laser (2 W/cm2) for 5 min per day. More importantly, there was no recrudescence after treatment. Furthermore, the in vivo photoacoustic (PA) imaging studies demonstrated well that Melanin@RBC nanoparticles were capable of photoacoustic imaging and 4 h after nanoparticle injection shall be considered as a priority option for tumor PTT therapy. These results indicate that these F


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Figure 5. SEM images of melanin extracted from cuttlefish (a) neat and (b) impregnated with MZ. XRD of MZ, MZ-impregnated melanin, pure melanin, and a physical mixture of MZ and melanin (c). MZ release profile from melanin nanoparticles at pH 7.4 and pH 2.2 (d). Reprinted from ref 102; copyright 2014, with permission from Elsevier.

and a layer of PDA capable of absorbing near-infrared light, showing good performance in the combined chemo- and photothermal therapy (CT-PTT) of liver cancer.103 Zhang et al. developed melanin nanoparticles (MNPs) as transport vehicles for delivering sorafenib (SRF) to treat cancer with integration of photoacoustic imaging (PAI) and positron emission tomography (PET) (Figure 6).104 SRF, a drug that has recently been approved as a multikinase inhibitor for treating unresectable hepatocellular carcinoma, was successfully integrated with MNPs through π−π interactions to form a water-soluble nanocomplex (SRF-MNPs) for tumor therapy in living mice by tail-vein injection (Figure 6a). SRF-MNPs showed a similar release curve at different pHs that is highly in accordance with the nature of the π−π interactions (Figure 6b). The slow release of SRF-MNPs can help the SRF transport and gradually release at the tumor to enhance the therapeutic effect. Moreover, SRF delivery was easily monitored by PET and PET +CT through direct blending of SRF-MNPs with 64Cu2+ (Figure 6c). The result showed there was little 64Cu2+-chelated SRF-MNPs existing in other major organs, and the SRF-MNPs were cleared mainly through the hepatobiliary system. Futhermore, in vivo PAI was further utilized to investigate the distribution of MNPs as drug carriers in the tumor over time; at 4 h postinjection, the PA signal by SRF-MNPs reaches maximum intensity (Figure 6d). The efficacies of oral SRF and tail vein-injected SRF-MNPs were compared (Figure 6e). After 20 d treatment, all volumes of HepG2 tumors treated with oral SRF and tail vein-injection increased from approximately 100 to 679 and 1105 mm3, respectively, indicating that the MNP drugloaded system greatly enhanced the efficacy and security for tumor treatment.

Sepia officinalis ink sacs and then evaluated pH-targeting property of the melanin-like nanoparticles as biocompatible transport vehicles and metronidazole (MZ) as a model drug (Figure 5).102 MZ was loaded into nanosized melanin-like particles using supercritical CO2 technology and then released at physiologic pH (7.4) and acidic pH (2.2). The drug release quantification was evaluated by building calibration curves considering λ= 319 nm, which corresponds to the maximum absorbance of MZ in phosphate and glycine-HCl buffers. By comparing the drug release quantification at different pH levels, it was shown that the Sepia melanin was sensitive to pH and had potential as a transport vehicle for DDS. On the other hand, fluorescent melanin-like capsules were fabricated via selfpolymerization of DA on templates, which were removed to form PDA capsules.91 The fluorescent dye AF488 was incorporated into these PDA capsules to make them fluorescent. At the same time, the negative carboxyl group could be introduced into these fluoroscent PDA capsules through thiol-catechol reaction. Further investigation demonstrated that the antitumor agent (DOX) could be loaded on these PDA capsules and released it from these melanin-like capsules with pH responsiveness. More importantly, the melanin-like materials could also further modify other functional polymers to endow them with diverse properties and functions. This is very useful for their biomedical applications. Melanin-like materials can be applied in many fields owing to their structural characteristics. The integration of multifunctional applications of melanin-like materials is a development trend for the future. Some important literature has also been reported recently.103 Mrowczynski and co-workers recently synthesized nanomaterials bearing a chemotherapeutic drug G


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Figure 6. Schematic illustration of the process of imaging-guided therapy of HepG2 tumors in vivo by SRF-MNPs (a). SRF release from SRF-MNP over time at pH 7.2 and 5.0 (b). Representative decay-corrected coronal (top) and transaxial (bottom) small-animal PET images (upper layer) and overlaid CT (gray) and PET (color) images (bottom layer) of HepG2 tumors (region enveloped by white dotted line) acquired at 2, 4, and 24 h after tail vein injection of 64Cu-radiolabled (70.0 ± 5.0 μCi) SRF-MNPs (c). PA images, ultrasound (US) images, and overlaid PA (green) and US images (gray) of HepG2 tumors (region enveloped by yellow dotted line) before and after tail vein injection of 200 μL of SRF-MNP (SRF, 10 mg/ kg; MNP, 40 mg/kg) in living mice (excitation wavelength = 680 nm for PAI) (d). Representative photos of HepG2 tumor-bearing mice before and day 20 after tail vein-injected treatment with 200 μL of PBS, PEG-MNP (MNP, 16 mg/kg) and SRF-MNP (SRF, 4 mg/kg; and MNP, 16 mg/kg) and oral treatment with SRF (20 mg/kg); the white arrows refer to the tumor position (e). Tumor growth curves of HepG2 tumor-bearing mice after various treatments (n = 6 per group) (f). Reprinted with permission from ref 104. Copyright 2015, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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CONCLUSIONS AND FUTURE PERSPECTIVES Melanin is widely distributed in nature and has abundant sources. This review first gives an overview over the current state of research on melanin structures. Melanins have been classified into three main types on the basis of their precursor molecule: eumelanins, pheomelanins, and allomelanins. As PDA and eumelanins have the same precursors and similar oxidative and synthesis steps, PDA is used as a melaninlike material for biophysical studies and other applications. Melanin-like materials (including PDA) have been widely applied in many fields because of their excellent biocompatibility and biodegradability. This review summarizes research progress on the structure and synthesis of PDA and focuses on recent progress regarding the applications of PDA in biological imaging, photothermal therapy, and drug delivery systems. The full value of melanin-like materials in these areas has been explored, as even the integration of multifunctional applications of melanin has also been studied. Despite great advances, there are many challenges that have to be overcome. First, natural melanins have a variety of sources and complex structures; at present there is no standard procedure of extraction and purification. Its applications have been limited to tedious extraction procedures and immature synthetic means. Moreover, although PDA had shown great potential in the fields of biological imaging, photothermal therapy, and drug delivery

systems, more data on their pharmacokinetics, long-term toxicity, and degradation properties should be obtained before their potential clinical applications are investigated. Further, the present melanin and melanin-like materials are basically hydrophobic organic compounds that must be modified before they are formally applied, which undoubtedly adds to the complexity of applications. On the basis of problems described herein, more research should focus on the following aspects: (1) establishing a standard procedure for separating and purifying natural melanin and synthesizing artificial watersoluble melanin-like materials, (2) further exploring the structures of melanin and PDA, (3) further studying potential applications of melanin-like materials, which is still in its infancy, as developing new application fields of melanin-like materials is a future direction, and (4) carefully examining future data about the toxicity of melanin-based materials before wide applications, because even though many reports have demonstrated that melanin and melanin-based materials such as PDA are of excellent biocompatibility, it has also been reported by Liebscher et al. that PDA can induce unwanted side effects and affect their important applications, especially in biomedicine.105

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Biomacromolecules ORCID

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Xiaoyong Zhang: 0000-0003-4116-3773 Author Contributions #

L.H. and M.L. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the National Natural Science Foundation of China (Nos. 51363016, 21474057, 21564006, 21561022, 21644014, 51673107, 21788102) and Natural Science Foundation of Jiangxi Province in China (Nos. 20161BAB203072, 20161BAB213066).

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