Inspired by sweet or sugar-coated bullets that are used for medications in clinics and the structure and function of biological melanin, a novel kind of sweet polydopamine nanoparticles and their anticancer drug doxorubicin loaded counterparts are prepared, which integrate an active targeting function, photothermal therapy, and chemotherapy into one polymeric nanocarrier. The oxidative polymerization of lactosylated dopamine and/or with dopamine are performed under mild conditions and the resulting sweet nanoparticles are thoroughly characterized. When exposed to an 808 nm continuous-wave diode laser, the magnitude of temperature elevation not only increases with the concentration of nanoparticles, but can also be tuned by the laser power density. The nanoparticles possess strong near infrared light absorption, high photothermal conversion efficiency, and good photostability. The nanoparticles present tunable binding with RCA₁₂₀ lectin and a targeting effect to HepG2 cells, confirmed by dynamic light scattering, turbidity analysis, MTT assay, and flow cytometry. Importantly, the sweet nanoparticles give the lowest IC₅₀ value of 11.67 μg mL⁻¹ for chemo-photothermal therapy compared with 43.19 μg mL⁻¹ for single chemotherapy and 67.38 μg mL⁻¹ for photothermal therapy alone, demonstrating a good synergistic effect for the combination therapy.

Disulfide-centered star-shaped poly(ε-benzyloxycarbonyl-l-lysine)-b-poly(ethylene oxide) block copolymers (i.e., A₂B₄ type Cy-PZlys-b-PEO) were synthesized by the combination of ring-opening polymerization and thiol-yne chemistry. Their molecular structures and physical properties were characterized in detail by FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, wide-angle X-ray diffraction, and polarized optical microscope. Despite mainly exhibiting an α-helix conformation, the inner PZlys blocks within copolymers greatly prohibited the crystallinity of the outer PEO blocks and presented a liquid crystal phase transition behavior in solid state. These block copolymers Cy-PZlys-b-PEO self-assembled into nearly spherical micelles in aqueous solution, which had a hydrophobic disulfide-centered PZlys core surrounded by a hydrophilic PEO corona. As monitored by means of DLS and TEM, these micelles were progressively reduced to smaller micelles in 10 mM 1,4-dithiothreitol at 37 °C and finally became ones with a half size, demonstrating a reduction-sensitivity. Despite a good drug-loading property, the DOX-loaded micelles of Cy-PZlys-b-PEO exhibited a reduction-triggered drug release profile with an improved burst-release behavior compared with the linear counterpart. Importantly, this work provides a versatile strategy for the synthesis of the disulfide-centered star-shaped polypeptide block copolymers potential for intracellular glutathione-triggered drug delivery systems. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2000–2010

Thermosensitive diethylene glycol-derived poly(L-glutamate) homopolypeptides (i.e., poly-L-EG₂-Glu) with different molecular weights (MW) (M_n,GPC = 5380–32520) were synthesized via the ring-opening polymerization (ROP) of EG₂-L-glutamate N-carboxyanhydride (EG₂-Glu-NCA) in N,N-dimethylformamide solution at 50 °C. Their molecular structure, conformation transition, liquid crystal (LC) phase behavior, lower critical solution temperature (LCST) transition, and morphology evolution were thoroughly characterized by means of FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, wide angle X-ray diffraction, polarized optical microscope, transmission electron microscope, and dynamic light scattering. In solid state, the homopolypeptide poly-L-EG₂-Glu presented a conformation transition from α-helix to β-sheet with increasing their MW at room temperature, while it mainly assumed an α-helix of 80–86% in aqueous solution. Poly-L-EG₂-Glu showed a thermotropic LC phase with a transition temperature of about 100 °C in solid state, while it gave a reversible LCST transition of 34–36 °C in aqueous solution. The amphiphilic homopolypeptide poly-L-EG₂-Glu self-assembled into nanostructures in aqueous solution, and their critical aggregation concentrations decreased with increasing MW. Interestingly, their morphology changed from spherical micelles to worm-like micelles, then to fiber micelles with increasing MW. This work provides a simple method for the generation of different nanostructures from a thermosensitive biodegradable homopolypeptide. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Dendron-like poly(ε-benzyloxycarbonyl-L-lysine)/linear poly(ethylene oxide) block copolymers (i.e., Dm-PZLys-b-PEO, m = 0 and 3; Dm are the propargyl focal point poly(amido amine) dendrons having 2^m primary amine groups) were for the first time synthesized by combining ring-opening polymerization (ROP) of ε-benzyloxycarbonyl-L-lysine N-carboxyanhydride (Z-Lys-NCA) and click chemistry, where Dm-PZLys homopolypeptides were click conjugated with azide-terminated PEO. Their molecular structures and physical properties were characterized in detail by FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, polarized optical microscopy, and wide angle X-ray diffraction. Both homopolypeptides and copolymers presented a liquid crystalline phase transition for PZLys block, and the transition was irreversible. Moreover, the degree of crystallinity of PEO block within linear copolymers decreased from 96.2% to 20.4% with increasing PZLys composition, whereas that within dendritic copolymers decreased to zero. The secondary conformation of PZLys progressively changed from β-sheet to α-helix with increasing the chain length. These copolymers self-assembled into spherical nanoparticles in aqueous solution, and the anticancer drug doxorubicin-loaded nanoparticles gave a similar morphology compared with their blank counterparts. The drug-loaded nanoparticles showed a triphasic drug-release profile at aqueous pH 7.4 or 5.5 and 37 °C and sustained a longer drug-release period for about 2 months. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Bioreducible and core-crosslinked hybrid micelles were for the first time fabricated from biodegradable and biocompatible trimethoxysilyl-terminated and disulfide-bond-linked block copolymers poly(ε-caprolactone)-S-S-poly(ethylene oxide), which were prepared by combining thiol-ene coupling reaction and ring-opening polymerization. The molecular structures, physicochemical, self-assembly, and bioreducible properties of these copolymers were thoroughly characterized by means of FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, wide-angle X-ray diffraction, dynamic light scattering (DLS), and transmission electron microscopy. The core-crosslinking sol-gel reaction was confirmed by ¹H NMR, and the core-crosslinked hybrid micelles contained about 3 wt % of silica. The bioreducible property of both uncrosslinked and core-crosslinked micelles in 10 mM 1,4-dithiothreitol (DTT) solution was monitored by DLS, which demonstrated that the PEO corona gradually shedded from the PCL core. The anticancer doxorubicin drug-loaded micelles showed nearly spherical morphology compared with blank micelles, presenting a DTT reduction-triggered drug-release profile at 37 °C. Notably, the core-crosslinked hybrid micelles showed about twofold drug loading capacities and a half drug-release rate compared with the uncross-liked counterparts. This work provides a useful platform for the fabrication of bioreducible and core-crosslinked hybrid micelles potential for anticancer drug delivery system. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Dendron-like/dendron-like poly(ε-caprolactone)-b-poly(γ-benzyl-L-glutamate) block copolymers with asymmetrical topology (PCL-b-PBLGⁿ, both the subscript and the superscript denote the degree of polymerization and the branch number, respectively; n = 1, 2, and 4) were synthesized by combining ring-opening polymerization (ROP) and click chemistry. The dendron-like propargyl focal point PCL precursor with eight branches was synthesized from the controlled ROP of ε-caprolactone, and then click conjugated with azido focal point poly(amido amine) dendrons to generate the PCL-dendrons with multiple primary amine groups. The PCL-dendrons were further used as macroinitiators for the ROP of γ-benzyl-L-glutamate N-carboxyanhydride to produce the targeted asymmetrical block copolymers. Their molecular structures and physicochemical properties were thoroughly characterized by means of FT-IR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, and wide angle X-ray diffraction. Both the maximal melting temperature and the degree of crystallinity of PCL block within copolymers decreased with increasing the PBLG branches and/or the chain length, demonstrating that the crystallinity of PCL block was progressively suppressed by PBLG block. Meanwhile, the PBLG block within copolymers progressively transformed from β-sheet to α-helical conformation with increasing the PBLG chain length. Consequently, this provides a versatile strategy for the synthesis of biodegradable and biomimetic block copolymers with asymmetrical dendritic topology. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011

Versatile strategies are currently being discovered for the fabrication of synthetic polypeptide-based hybrid hydrogels, which have potential applications in polymer therapeutics and regenerative medicine. Herein, a new concept—the reverse micellar hydrogel—is introduced, and a versatile strategy is provided for fabricating supramolecular polypeptide-based normal micellar hydrogel and reverse micellar hydrogels from the same polypeptide-based copolymer via the cooperation of host–guest chemistry and hydrogen-bonding interactions. The supramolecular hydrogels are thoroughly characterized, and a mechanism for their self-assembly is proposed. These hydrogels can respond to dual stimuli—temperature and pH—and their mechanical and controlled drug-release properties can be tuned by the copolymer topology and the polypeptide composition. The reverse micellar hydrogel can load 10% of the anticancer drug doxorubicin hydrochloride (DOX) and sustain DOX release for 45 days, indicating that it could be useful as an injectable drug delivery system.

Dendron-like poly(γ-benzyl-L-glutamate)/linear poly(ε-caprolactone)/dendron-like poly(γ-benzyl-L-glutamate) triblock copolymers having 2^{m + 1} PBLG branches (denoted as PBLG-Dm-PCL-Dm-PBLG, m = 0, 1, 2, and 3) were for the first time synthesized by utilizing ring-opening polymerization (ROP) and click chemistry. The bifunctional azide-terminated PCL (N₃-PCL-N₃) was click conjugated with propargyl focal point PAMAM-typed dendrons Dm to generate Dm-PCL-Dm, which was then used as macroinitiator for the ROP of BLG-NCA monomer to produce the targeted PBLG-Dm-PCL-Dm-PBLG triblock copolymers. Their molecular structures and physical properties were characterized in detail by FTIR, NMR, gel permeation chromatography, differential scanning calorimetry, and wide angle X-ray diffraction (WAXD). The crystallinity of the central PCL segment within these copolymers is increasingly suppressed by the flanking PBLG wedges, whereas the PBLG segments gradually changed from a β-sheet conformation to an α-helix conformation with the increasing PBLG branches. These triblock copolymers formed thermoreversible organogels in toluene, and the dendritic topology of PBLG wedges controlled their critical gelation concentrations. The self-assembled structure of organogels was further characterized by means of transmission electron microscopy, WAXD, and small-angle X-ray scattering. The fibers with flat ribbon morphology were clearly shown, and the gelation occurred through a self-assembled nanoribbon mechanism. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 709–718, 2010

Biocompatible and biodegradable ABC and ABCBA triblock and pentablock copolymers composed of poly(ε-caprolactone) (PCL), poly(L-lactide) (PLA), and poly(ethylene glycol) (PEO) with controlled molecular weights and low polydispersities were synthesized by a click conjugation between alkyne-terminated PCL-b-PLA and azide-terminated PEO. Their molecular structures, physicochemical and self-assembly properties were thoroughly characterized by means of FT-IR, ¹H-NMR, gel permeation chromatography, differential scanning calorimetry, wide-angle X-ray diffraction, dynamic light scattering, and transmission electron microscopy. These copolymers formed microphase-separated crystalline materials in solid state, where the crystallization of PCL block was greatly restricted by both PEO and PLA blocks. These copolymers self-assembled into starlike and flowerlike micelles with a spherical morphology, and the micelles were stable over 27 days in aqueous solution at 37 °C. The doxorubicin (DOX) drug-loaded nanoparticles showed a bigger size with a similar spherical morphology compared to blank nanoparticles, demonstrating a biphasic drug-release profile in buffer solution and at 37 °C. Moreover, the DOX-loaded nanoparticles fabricated from the pentablock copolymer sustained a longer drug-release period (25 days) at pH 7.4 than those of the triblock copolymer. The blank nanoparticles showed good cell viability, whereas the DOX-loaded nanoparticles killed fewer cells than free DOX, suggesting a controlled drug-release effect. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010

Biodegradable and amphiphilic poly(L-lactide)-b-poly(ethylene oxide) copolymers with different arms (PLLA-b-PEO having one, two, four, and six arms) were successfully synthesized via a two-step synthetic strategy. The hydrophilicity–hydrophobicity balance of these copolymers was mainly controlled by both the arm number of copolymers (i.e., macromolecular architecture) and the poly(ethylene oxide) (PEO) composition. Biodegradable nanoparticles could be generated by direct injection of these PLLA-b-PEO copolymers solutions into distilled water, and their critical micelles concentrations decreased with the increasing arm number of copolymers. Moreover, both the hydrophilic PEO composition and the arm number of copolymers controlled the average size of PLLA-b-PEO nanoparticles, and the nanoparticles with adjustable sizes (20–85 nm) completely meet the size prerequisite (less than 100 nm) for targeted drug delivery. In vitro degradation of PLLA-b-PEO nanoparticles showed that the PLLA composition gradually increased over the degradation time, and the degree of crystallinity of PLLA block within copolymers increased simultaneously. Furthermore, the nimodipine drug loading efficiency of the PLLA-b-PEO copolymers was apparently higher than that of PLLA homopolymers. The drug-release experiments demonstrated that these biodegradable nanoparticles might be used for a short-time controlled release system. Consequently, this will provide a facile method not only to design new PLLA-based biomaterials from both the macromolecular architecture and the hydrophilicity–hydrophobicity balance, but also to fabricate biodegradable nanoparticles with adjustable sizes for drug delivery. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009

Star-shaped polypeptide/glycopolymer biohybrids composed of poly(γ- benzyl L-glutamate) and poly(D-gluconamidoethyl methacrylate), exhibiting controlled molecular weights and low polydispersities, were synthesized by the combination of ring-opening polymerization of γ-benzyl-L-glutamate N-carboxyanhydride and the direct atom transfer radical polymerization of unprotected D-gluconamidoethyl methacrylate glycomonomer. These biohybrids were characterized in detail by means of FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, and wide angle X-ray diffraction. Independent of weight fraction of hydrophilic glycopolymer segment, the biohybrids self-assembled into large spherical micelles in aqueous solution, which had a helical polypeptide core surrounded by a multivalent glycopolymer shell. The deprotected poly(L-glutamate)/glycopolymer hybrid exhibited a pH-sensitive self-assembly behavior, and the average size of the nanoparticles decreased gradually over the aqueous pH value. Moreover, whatever these biohybrids existed in unimolecular level or glycopolymer-surfaced nanoparticles, they had specific biomolecular recognition with Concanavalin A compared with bovine serum albumin. Furthermore, star-shaped biohybrids showed a higher doxorubicin loading efficiency and longer drug-release time than linear analogues. This potentially provides a platform for fabricating targeted anticancer drug delivery system and studying glycoprotein functions in vitro. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2009–2023, 2009

Biomimetic star-shaped poly(ε-caprolactone)-b-poly(gluconamidoethyl methacrylate) block copolymers (SPCL-PGAMA) were synthesized from the atom transfer radical polymerization (ATRP) of unprotected GAMA glycomonomer using a tetra(2-bromo-2-methylpropionyl)-terminated star-shaped poly(ε-caprolactone) (SPCL-Br) as a macroinitiator in NMP solution at room temperature. The block length of PGAMA glycopolymer within as-synthesized SPCL-PGAMA copolymers could be adjusted linearly by controlling the molar ratio of GAMA glycomonomer to SPCL-Br macroinitiator, and the molecular weight distribution was reasonably narrow. The degree of crystallization of PCL block within copolymers decreased with the increasing block length ratio of outer PGAMA to inner PCL. Moreover, the self-assembly properties of the SPCL-PGAMA copolymers were investigated by NMR, UV-vis, DLS, and TEM, respectively. The self-assembled glucose-installed aggregates changed from spherical micelles to worm-like aggregates, then to vesicles with the decreasing weight fraction of hydrophilic PGAMA block. Furthermore, the biomolecular binding of SPCL-PGAMA with Concanavalin A (Con A) was studied by means of UV-vis, fluorescence spectroscopy, and DLS, which demonstrated that these SPCL-PGAMA copolymers had specific recognition with Con A. Consequently, this will not only provide biomimetic star-shaped SPCL-PGAMA block copolymers for targeted drug delivery, but also improve the compatibility and drug release properties of PCL-based biomaterials for hydrophilic peptide drugs. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 817–829, 2008