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Versatile Polydopamine Platforms: Synthesis and Promising Applications for Surface Modification and Advanced Nanomedicine Wei Cheng, Xiaowei Zeng, Hongzhong Chen, Zimu Li, Wenfeng Zeng, Lin Mei, and Yanli Zhao ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.9b04436 • Publication Date (Web): 01 Aug 2019 Downloaded from pubs.acs.org on August 1, 2019
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Versatile Polydopamine Platforms: Synthesis and Promising Applications for Surface Modification and Advanced Nanomedicine Wei Cheng,†,∥ Xiaowei Zeng,*,†,‡,∥ Hongzhong Chen,‡ Zimu Li,† Wenfeng Zeng,† Lin Mei,† and Yanli Zhao*,‡,§ †Institute
of Pharmaceutics, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen
University, Guangzhou 510275, 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, 50
Nanyang Avenue, Singapore 639798, Singapore ABSTRACT: As a mussel inspired material, polydopamine (PDA) possesses many properties, such as simple preparation process, good biocompatibility, strong adhesive property, easy functionalization, outstanding photothermal conversion efficiency and strong quenching effect. PDA has attracted increasingly considerable attention because it provides a simple and versatile approach to functionalize material surfaces for obtaining a variety of multifunctional nanomaterials. In this review, recent significant research developments of PDA including its synthesis and polymerization mechanism, physicochemical properties, different nano/micro-structures and diverse applications are summarized and discussed. For the sections of its applications in surface modification and biomedicine, we mainly highlight the achievements in the past few years (2016-2019). The remaining challenges and future perspectives of PDA based nanoplatforms are discussed rationally at the end. This timely and overall review should be desirable for a wide range of scientists and facilitate further development of surface coating methods and the production of PDA based materials. KEYWORDS: biomedicine, disease treatment, dopamine, hybrid materials, nanostructures, polydopamine, polymerization mechanism, surface modification
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Surface modification could affect material properties such as chemical inertness, susceptibility,
stability,
adhesion,
biocompatibility,
degradability,
hydrophilicity/hydrophobicity, and secondary functionalization.1,2 Inspired by the natural world, some approaches have been designed to modify the surfaces of substrate materials. In the past few years, adhesives have been widely utilized for the surface modification of substrates. As a kind of bivalve molluscs, mussel can immobilize strongly to the surfaces of almost all types of substrates, even if the surface is wet.3,4 High adhesive capacity should be ascribed to the interface between the mussel adhesive proteins (MAPs) and substrate surface.5 The Luoyang Bridge was completed in 1059 at the mouth of Luoyang River in Quanzhou, China. As the first stone bay bridge in China, it enjoys the reputation of "one of the four ancient bridges of China".6 To solidify the base in the river, the ancient Chinese cultivated considerable oysters under the bridge, and allowed firm adhesion between the bridge base and pier due to high adhesive capacity of oysters. The oysters covering the stone pier formed a protective layer on the surface, not only preventing direct flood impact, but also mitigating water pollution-induced pier erosion.7 Mussel can anchor itself onto the surfaces of substrates through Mytilus edulis foot proteins (Mefps). A large number of catecholic amino acids, such as 3,4-dihydroxy-Lphenylalanine (DOPA), are preferentially distributed in Mefps, especially in Mefp-3, Mefp-5 and Mefp-6.8,9 MAPs are rich in various catecholic amino acids, including dopamine (DA) and its derivatives, benefiting the bonding or crosslinking of marine adhesives (Figure 1).10,11 Various substrates, such as ceramics, noble metals, metal oxides, semiconductors, silica, mica, and even some synthetic polymers, could be surface-functionalized with polydopamine (PDA). Until now, vast multifunctional substrates with specific properties have been constructed. A thin adherent copolymer film was spontaneously deposited by immersing substrates into a dilute aqueous DA solution (10 mM Tris-HCl, pH 8.5). As a crucial catecholamine neurotransmitter and hormone, DA is the metabolite of DOPA, which plays significant physiological roles in mammalian central hormonal, nervous, renal and cardiovascular systems.12,13 DA and other catechols can be converted into the quinone form through oxidation reactions under weakly alkaline conditions. Then, the quinone form reacts with other catechols and quinones to afford PDA. More importantly, this process provides an active platform for secondary modifications via Schiff base reaction or Michael addition, and ligands containing nucleophilic functional groups (amine and thiol) can also react with PDA.14-16 Since the pioneering study by Messersmith and coworkers in 2007, researchers have fabricated a lot of surface-modified materials based on PDA.17 For instance, Ye et al. 2
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reviewed bioinspired catechols and their derivatives for surface modification, as well as the design, synthesis, adsorption mechanism, stability and applications of PDA in 2011.11 In 2014, Liu et al. discussed the preparation of PDA and derivatives together with their application prospects in environmental, energy and biomedical fields.2 Städler and Wei as well as their coworkers successively summarized biomedical applications on the basis of surface modification by PDA coating.18 In 2017, Batul et al. reviewed the research progress about the application of PDA in the biomedical field, and discussed the polymerization mechanisms.19 Since the PDA research involves many different fields and has been developing rapidly, these reviews either did not provide comprehensive aspects of PDA or are out of date to cover the latest work. Thereby, the aim of this timely and comprehensive review is to link this gap and summarize recent significant advancements of PDA research (Scheme 1). First, we describe the preparation and polymerization mechanism of PDA systems. After that, outstanding properties of PDA as well as PDA produced in different forms are introduced. Following this section, the surface modification of various organic and inorganic nanomaterials including metals, metal oxides, carbons and polymers by PDA are compiled. Finally, we elaborate related biomedical applications. This review is expected to evidently promote the applications of PDA-based surface modification to biomedicine, and facilitate PDA-based interdisciplinary research from biology, medicine, pharmaceutics, biomedical engineering, chemistry, and materials. Preparation and Polymerization Mechanism of PDA PDA
is
mainly
obtained
by
three
commonly
used
methods,
including
electropolymerization, enzymatic oxidation and solution oxidation.2 Among these methods, due to simple polymerization process without using complicated instruments, solution oxidation has become the most widely used approach to prepare PDA. In this section, we discuss some of the key factors in the solution oxidation process such as solvent, pH, oxidants, monomer concentration and external stimuli, which can significantly affect PDA morphology, film thickness and reaction rate. Then, we describe some other methods of PDA synthesis and its polymerization mechanisms. Buffer and Solvent. The buffer chemical composition could sever as a possible way to control PDA particle formation, and thus choices of solvents are critical in the PDA preparation process. Vecchia et al. reported the effects of different buffers (Tris, phosphate and bicarbonate buffer) on the PDA buildup, particle morphology and paramagnetic properties.20 They found that the average size of PDA particles in tris buffer is much smaller 3
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than that in phosphate and bicarbonate buffer. This observation is because dopamine-quinine, as an intermediate product, is a crucial control point in the pathway, which could be targeted by the nucleophiles in Tris buffer, thus hindering the particle growth. Therefore, owing to slow and moderate reaction rate, tris buffer (pH 8.5) can be used to efficiently modulate PDA growth and other properties. In addition to the polymerization into nanoparticles, PDA is also widely used to modify diverse substrates including some hydrophobic materials such as polyethylene membranes.21 In this case, the organic solvents (e.g. methanol and ethanol) with low surface tension instead of aqueous solvent are used. Furthermore, the use of organic solvents can prevent the degradation of hydrolysable materials and enhance the drying rate of substrates. Yan and coworkers used water and ethanol mixed solvent for the synthesis of PDA nanoparticles.22 The size of the PDA nanoparticles could be simply modulated by varying the volume ratio of water to alcohol together with the DA concentration. pH and Temperature. The kinetic study on the DA oxidation indicates that the ratedetermining step is the abstraction of a hydrogen atom from the deprotonated hydroxyl group by oxygen. The following ring closing reaction of semiquinone to form dopaminochrome is relatively quick. Consequently, the rate constant for the DA oxidation is mainly affected by temperature, pH, and the concentration of oxygen and DA. The latter two factors will be discussed in the following sections. Lee et al. synthesized PDA nanoparticles, and controlled the size and shape through DA oxidative self-polymerization in an aqueous NaOH solution without using particulate templates.23 The size of synthetic PDA nanoparticles was controlled from less than 100 nm to hundreds of nanometers, dependent on pH value, temperature and DA concentration. Upon increasing the NaOH amount, the PDA nanoparticles became smaller until the NaOH/DA hydrochloride molar ratio reached unity. When the NaOH amount exceeded that of DA, a black amorphous polymeric material instead of particles was obtained. Additionally, it was found that the particle size deceased with raising the reaction temperature. Although a weakly alkaline condition (pH > 8) is generally required for oxidative selfpolymerization of DA, Zheng et al. studied the formation of PDA in an acidic condition.24 The PDA polymerization could still be carried out even at pH~1 via a hydrothermal method. The PDA generated by this method exhibited similar chemical properties with that produced in a basic condition. However, the hydrothermal process requires high temperature and pressure. For example, in a strong acidic condition (pH 1), the temperature should be increased to 160 °C in order to obtain PDA nanoparticles. Moreover, the effects of temperature, reaction time and mechanical stirring on PDA preparation could be found from some other studies.25 4
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Oxidants. Oxidants are essential for the PD polymerization. The frequently used oxidant for traditional PDA formation in alkaline condition is the dissolved oxygen in solvents. Bernsmann and coworkers used Cu2+ instead of oxygen as the oxidant and studied the deposition kinetics of PDA.26 It was found that, in the presence of Cu2+, the thickness of PDA film could extend to more than 70 nm, while the film growth stopped at about 45 nm when using O2. More interestingly, with Cu2+ as the oxidant, the film deposition was still observed even at acidic pH (pH 4.5), whereas no PDA deposition happened any longer when pH decreased to 7.0 in the presence of O2. In another study, the effect of three different oxidants ((NH4)2S2O8, NaIO4, and CuSO4) on PDA oxidation at pH 5.0 was investigated.14 A quick formation of a homogeneous and thick PDA film with superhydrophilicity and superoleophobicity was prepared in the presence of NaIO4 at 20 mM. This PDA film exhibited a eumelanin-like character, which was close to the PDA coating produced by autoxidation at an alkaline condition. By contrast, when using (NH4)2S2O8 and CuSO4 as oxidants, the products mainly consisted of uncyclized amine-containing units. This result may be attributed to the fact that the oxidative degradation process by NaIO4 could form a high proportion of carboxylate groups, leading to hydrophilic coating. Some other inorganic oxidants such as potassium permanganate (KMnO4) and Fe3+ were also used in the DA oxidation process.27 Dopamine Concentration and Substrates. The DA concentration plays an important role in controlling the deposition kinetics, film thickness, surface roughness, and morphology. Ball et al. tested the changes of PDA film thickness along with DA solution concentration on silicon substrates.28 Surprisingly, the maximal film thickness kept increasing with the increase of DA concentration from 0.1 to 5.0 g L-1. They also found that the roughness of PDA films produced in high DA concentration was generally higher as compared with that in low DA concentration. This observation is because high concentration of DA could increase the formation of some small PDA particles through the self-polymerization in solution, and these small particles then deposited on the PDA external surface, leading to increased roughness of PDA coating. This fact was also proven by Liu et al. using Au nanoparticles as the inner cores.29 Therefore, the film thickness and surface roughness can be controlled by adjusting the DA concentration. Mondin et al. studied the DA polymerization processes on two different substrates (Al2O3 and WC) with similar sizes, as well as on the same substrate with different sizes (micro- and nanoparticles of WC). The PDA coating thickness on particles and thickness growth were dependent on the material type and particle size.30 TEM images of PDA-coated 5
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WC nanoparticles polymerized under different times showed that, throughout the polymerization, the thickness increased almost linearly to (33 ± 6) nm at the speed of approximately 1.4 nm h-1. After the polymerization for 24 h, the thickness of PDA coating on Al2O3 microparticles was (65 ± 10) nm, and those of coating on WC microparticles and nanoparticles were (18 ± 4) and (33 ± 6) nm, respectively. Particularly, the PDA coating thickness on Al2O3 microparticles was quite similar to that of the model reported by Lee et al.,17 whereas the coating on WC microparticles was thinner, suggesting that the DA deposition was affected by the substrate materials. Since the thickness of coating on WC nanoparticles was almost twice higher than that on WC microparticles, the substrate size also showed effects. External Stimuli. One major drawback of the PDA preparation is its slow kinetics. The generation of radical species by applying external energy such as microwave irradiation could facilitate the PDA formation as studied recently by Lee and coworkers.31 When the DA solution was exposed to microwave irradiation (1000 W), the PDA coating on gold substrate increased to ~18 nm in only about 15 min, whereas the same coating thickness required more than 6 h by using conventional alkaline coating method. It was claimed that the coating thickness depended on the microwave power. The mechanism of the fast coating kinetics was that the microwave energy could generate a large amount of catechol radicals that accelerated PDA surface coating. On the other hand, the increased temperature of the solution caused by the microwave irradiation could lead to thermal acceleration of O2-involved oxidation at the early polymerization stage and the radical-involved oxidation during the whole coating process. They concluded that microwave irradiation could significantly speed up the PDAcoating kinetics without extra addition of oxidants, which could avoid the surface contamination by those chemical agents. Ultraviolet (UV) light irradiation is another method to accelerate PDA coating formation. Du and coworkers reported a method to control both the onset and termination of DA polymerization using vitamin C (VC) and UV.32 The inhibition of DA polymerization was realized by adding only a tiny amount of VC, because VC could reduce reactive DA-quinine into catechols. In contrast, the UV light could not only significantly promote the oxidative consumption rate of VC, but also accelerate the DA oxidation, thus triggering the DA coating formation. Therefore, a light-induced control of DA polymerization without changing the common medium (oxidant and base) could be achieved by this method. Other Methods for PDA Synthesis. In addition to oxidative self-polymerization, PDA was also prepared by other strategies. For instance, electropolymerization was employed to 6
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generate PDA from DA monomers and to directly deposit it on electrodes.33,34 This method has higher DA utilization and deposition rates than that of self-polymerization. Additionally, the electropolymerized PDA thickness could be controlled precisely. On the other hand, a drawback of this method is that electrically conductive materials are required to carry out the electropolymerization. DA was also polymerized using enzymes, especially environmentally friendly ones.35-37 The reaction by using enzymes was based on the biosynthesis of eumelanin and pheomelanin. The properties of the PDA product obtained by this method were similar to those of naturally occurring melanin. Polymerization Mechanisms of PDA. Although PDA can be obtained through polymerization under facile and mild conditions, the related mechanisms remain elusive hitherto, because complicated redox reactions are involved and a series of intermediates are produced. Initially, the mechanism for PDA formation was considered analogous to the synthetic pathway of melanin (eumelanin) in living organisms, i.e. covalent polymerization. The melanin biosynthesis pathway transforms DA into 5,6-dihydroxyindole (DHI), which is an oxidative reaction, followed by further covalent polymerization.38-41 Accordingly, the chemical structure of PDA could be effectively clarified based on the similarity to melanin. Under weakly alkaline conditions with dissolved oxygen, DA is oxidized into dopaminequinone (Figure 2). When the amine group is deprotonated, the obtained molecule undergoes Michael addition reaction. Dopaminequinone is subjected to intramolecular cyclization and reversible oxidation to form dopaminochrome, and then intramolecular rearrangement to generate DHI (steps A and B in Figure 2).42,43 The reverse dismutation reaction between o-quinone and catechol of DHI causes crosslinking and yields PDA finally.44,45 The PDA formation by following the DHI chemistry is similar to the biosynthesis of melanin, so that the brownish black color originates from a copolymer with covalent bonding. Lee et al. reported that both noncovalent self-assembly and covalent polymerization occurred during the PDA formation.16 They reported that the covalent bond-forming DA oxidative polymerization was attributed to a physical self-assembly pathway. By using highperformance liquid chromatography-mass spectrometry (HPLC-MS), they observed that considerable unpolymerized DA could form self-assembled complexes with its oxidative product DHI. (Figure 2). HPLC-MS further proved that DA was encapsulated stably, with only a little release from the matrix. Meanwhile, the covalent bond-forming DA oxidative polymerization took place. The resulting (DA)2/DHI complex was entrapped tightly in the product, yielding a brownish black PDA precipitate, possibly because of intermolecular 7
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interactions including quadrupole-quadrupole, T-shape, π-π stacking, hydrogen bonding, and cation-π interactions. The possible mechanisms of DA polymerization into PDA have been tentatively elucidated by several popular models. The first presumption is covalent bonding polymerization, i.e., DA is oxidized into dopaminequinone at aerobic and alkaline conditions, and thereafter into DHI, followed by the deprotonation and intermolecular Michael addition to afford cross-linked PDA. The resulting PDA is abundant in active functional groups, providing a versatile platform for further reactions.17,41,46 The second model combines covalent polymerization with noncovalent self-assembly, and the latter involves ionic, charge transfer, T-shape, hydrogen bonding, and 𝜋-𝜋 stacking interactions.16,47 Regarding whether PDA is a covalent polymer or a noncovalent aggregate of some species with low molecular weight, Delparastan and coworkers studied the characterization of PDA films using single-molecule force spectroscopy (SMFS) (Figure 3).48 They found that PDA films had high-molecular-weight polymer chains composed of covalently connected subunits. Intramolecular interactions among these PDA chains were weak and reversible noncovalent interactions. They also observed that the formation of PDA films probably began with the adsorption of small oligomeric species at the solid-liquid interface, followed by the polymerization to form higher-molecular-weight PDA chains. While the research showed direct evidence about the presence of polymers in PDA, they could not rule out the existence of other small molecules and oligomer components in PDA by these experiments. Properties of PDA As a mussel-inspired polymer, PDA exhibits many important properties that are closely related to its chemical structure and composition, providing important applications in diverse research fields. These properties include high adhesion capability, high reactivity, photothermal effect and quenching effect. In this section, we discuss some of these important physicochemical properties. Adhesion Capability and Chemical Reactivity. The chemical composition of PDA has two key features: high primary and secondary amine content and high catechol(3,4dihydroxybenzene) content. The coexistence of these two types of functional groups is considered to contribute to strong interfacial adhesion of PDA. This strong adhesive property allows PDA films to attach to almost all type of organic and inorganic material surface, including noble metals, semiconductors, metal oxides and polymers, regardless of their size and shape. More importantly, PDA coating can serve as a “bridge” to further react with other 8
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compounds through secondary reactions. The properties and composition of the secondary coating are highly tailorable. Molecules with nucleophilic functional groups, such as thiol and amine, could be incorporated onto the PDA surface through Schiff base reaction or Michael addition. Owing to the versatility and simplicity, this principle has been extensively exploited to immobilize different functional species (e.g., biomacromolecules and long-chain molecules) onto diverse types of substrates.15,49 Additionally, PDA could bind to nearly all kinds of transition metals and radioisotopes.50 Therefore, some useful metal ions and radioisotopes could be fixed on PDA films by chelating between metal ions and oxygen or nitrogen atoms of PDA, endowing these materials with contrast properties for imaging or capabilities for the application in radioisotope therapy of cancer. This feature of PDA could also be used for the removal of heavy metals (Pb2+, Hg2+, Cu2+, and Cr6+) toward water purification.51 Last but not least, drug molecules, such as doxorubicin (DOX), could be attached onto the PDA surface by π-π stacking or hydrogen bonding interactions, thus affording drug delivery systems. Photothermal Conversion Capability. For clinically relevant applications in photothermal therapy (PTT), materials with absorption in near infrared (NIR) region (650– 900 nm) are more attractive, because this feature enables deeper penetration of light and relatively low scattering/absorption of biological tissues.52 As one of the NIR light responsive materials, PDA can effectively absorb and transfer NIR optical energy into heat, enabling it to be a desirable photothermal therapeutic agent for tumor treatment and bacteria killing. PDA possesses an excellent photothermal conversion efficiency of ~40%, which is much higher than that of some reported PTT species, such as carbon-based nanomaterials, Cu-based nanoparticles, Au-based metal nanoparticles, and organic polymers. For example, Lu et al. investigated the photothermal effect of PDA nanoparticles (~160 nm) for cancer therapy.53 They evaluated the molar extinction coefficient of PDA to determine its NIR absorption capability. Although the value of PDA (7.3×108 M-1 cm-1) was a bit lower than that of porphysomes (~109 M-1 cm-1), it was still higher in comparison to other PTT systems (Table 1).54-58 Upon the NIR light irradiation for 500 s (808 nm, 2 W cm-2), the temperature of PDA aqueous solution (200 μg ml-1) increased by 33.6 °C, whereas the temperature increase for pure water group was only 3.2 °C. Then, the photothermal therapeutic potential of PDA was assessed both in vitro and in vivo. It was reported that these nanoparticles could efficiently kill cancer cells and inhibit tumor proliferation without damaging healthy tissues. On account of strong NIR absorption capacity and high photothermal conversion efficiency as well as easy surface decoration with other functional components, PDA could facilitate the design and
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fabrication of multifunctional platforms for synergistic therapy by combining PTT with other types of treatments. Quenching Effect. The development of various fluorescent sensors for detecting different biomolecules has attracted widespread attention. Owing to the inherent advantages of fluorescent sensors, such as operational convenience, high sensitivity, and in situ imaging properties, they hold a great potential for the applications in drug discovery, clinical diagnostics, environmental monitoring, and food safety.59 This type of sensors is usually based on Förster resonance energy transfer (FRET), consisting of a quencher and a fluorophore. The quenching effect is due to the energy/electron transfer between excited fluorophore as energy/electron donor and quencher as energy/electron acceptor. The strong fluorescence quenching ability of PDA was reported by Xu and coworkers.59 They labeled DNAs with four kinds of different fluorophores, i.e., 6-carboxytetramethylrhodamine (TAMRA), 6-carboxyfluorescein (FAM), aminomethylcoumarin acetate (AMCA), and Cy5. As shown in Figure 4A-E, in the absence of PDA nanospheres, these fluorophore-labeled DNAs showed strong fluorescence emission. After the introduction of PDA, however, the DNA probe would bind to the PDA surface and thus result in strong fluorescent quenching effect of the fluorophores. Up to 97% quenching efficiency was obtained for all four fluorophores. The quinone residues on the PDA surface could capture most of excited electrons from the fluorescent dyes upon laser irradiation, leading to the fluorescence quenching.60 Thus, the fluorescence quenching is distance-dependent, which means that the farther the fluorophores from the PDA surface are, the weaker the quenching effect of PDA for these fluorophores is. Recently, Cho and coworkers conducted a research to inhibit innate fluorescence quenching property of PDA.61 Silica layers with different thickness were coated on the surface of PDA nanospheres. Then, these nanoparticles were labeled with fluorescent molecules on the outer layer. They found that, as the thickness of silica coating increased, significantly enhanced fluorescent intensity could be achieved. Biocompatibility and Endosomal Escape. PDA is a naturally occurring substance in organism, which has a wide distribution in human bodies and other living systems. It is a promising candidate for the applications in the biomedical field. The biocompatibility of PDA is of cardinal significance. Ji et al. studied the in vitro and in vivo biocompatibility and stability of PDA shell coated on gold nanoparticles (GNP@PDA).29 3-(4,5-Dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay exhibited that GNP@PDA (with a concentration of Au up to 20 mg L-1) did not have obvious cytotoxicity on HepG2 cells. Next, 10
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they studied the biocompatibility of GNP@PDA in vivo. Haemotoxylin and eosin (H&E) stained images of major organs (liver, spleen, and kidney) revealed that no notable organ damages were found for GNP@PDA-treated mice after 42 days. As shown in Figure 4F-M, the thickness of the PDA shell on gold nanoparticles was not significantly changed in the liver cells after the injection up to 42 days. These results revealed that the PDA coating is biocompatible and stable in vivo. It is worth noticing that GNPs@PDA could be observed not only in lysosome (Figure 4G,I,M), but also in cytosol (Figure 4H,K), indicating that GNPs@PDA could partially escape from lysosomes/endosomes. This phenomenon might be attributed to relatively high amount of amino groups on the PDA shell, which could result in endosomal escape on account of the proton sponge effect. The endosomal escape ability of PDA was also proven by Ding and coworkers.62 This great feature makes PDA a promising delivery platform, which can help transport a broad range of cargos, such as anticancer drugs and siRNA, into cytoplasm. In addition to gold nanoparticles, Lee et al. used graphene quantum dots as the core and studied the cytotoxicity of PDA-coated dots in vivo.63 It was observed that the PDA coating could reduce the inflammation and blood toxicity caused by uncoated graphene quantum dots. Tan et al. studied the biosafety of hollow PDA nanocapsules.64 They loaded ionic liquids (ILs) into the cavity of hollow PDA and evaluated the cytotoxicity of this IL/PDA composite on HepG2 cells. The viability of cells was still about 80% when the concentration of IL/PDA reached 200 μg mL-1, suggesting that IL/PDA had no obvious cytotoxicity. Nano/Microstructures of PDA Owing to its robust properties, PDA can be produced in different nanostructures. To date, diverse types of PDA-derived nanocomposites have been reported. In this section, we mainly discuss the nanostructures of PDA itself, and the core@shell nanocomposites based on PDA surface modification will be discussed in Section five. PDA Nanoparticles. PDA nanoparticles could be prepared simply by the polymerization of DA under basic conditions. A variety of methods have been adopted for the generation of PDA nanoparticles depending on the requirements of size or specific applications. As abovementioned, physicochemical properties of PDA nanoparticles could be affected by reaction conditions, such as solvent, pH, reaction time and DA concentrations. PDA nanoparticles ranging from 50 nm to 400 nm could be produced by adjusting these factors.22,23,53 However, the fabrication of relatively small PDA nanoparticles (
