A photoresponsive S-(o-nitrobenzyl)-l-cysteine N-carboxyanhydride (NBC-NCA) monomer was for the first time designed, and the related poly(S-(o-nitrobenzyl)-l-cysteine)-b-poly(ethylene glycol) (PNBC-b-PEO) block copolymers were synthesized from the ring-opening polymerization (ROP) of NBC-NCA in DMF solution at 25 °C. Their molecular structures, physical properties, photoresponsive self-assembly, and drug release of PNBC-b-PEO were thoroughly investigated. The β-sheet conformational PNBC block within copolymers presented a thermotropic liquid crystal phase behavior, and the crystallinity of PEO block was progressively suppressed over the PNBC composition. The characteristic absorption peaks of these copolymers at about 310 and 350 nm increased over UV irradiation time and then leveled off, indicating that the o-nitrobenzyl groups were gradually photocleaved from copolymers until the completion of photocleavage. The PNBC-b-PEO copolymers self-assembled into spherical nanoparticles in aqueous solution, presenting a photoresponsive self-assembly behavior, together with a size reduction of nanoparticles after irradiation. The anticancer drug doxorubicin can be released in a controlled manner by changing the light irradiation time, which was induced by gradually photocleaving the PNBC core of nanoparticles. This work provides a facile strategy not only for the synthesis of photoresponsive polypeptide-based block copolymers but also for the fabrication of photoresponsive nanomedicine potential for anticancer therapy.

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.

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Despite clinical applications of the first‐generation tissue adhesives and hemostats, the correlation among microstructure and hemostasis of hydrogels with wound healing is less understood and it is elusive to design high‐performance hydrogels to meet worldwide growing demands in wound closure, hemostasis, and healing. Inspired by the microstructure of extracellular matrix and mussel‐mimetic chemistry, two kinds of coordinated and covalent glycopolypeptide hydrogels are fabricated, which present tunable tissue adhesion strength (14.6–83.9 kPa) and microporous structure (8–18 µm), and lower hemolysis <1.5%. Remarkably, the microporous size mainly controls the hemostasis, and those hydrogels with larger pores of 16–18 µm achieve the fastest hemostasis of ≈14 s and the lowest blood loss of ≈6% than fibrin glue and others. Moreover, both biocompatibility and hemostasis affect wound healing performance, as assessed by hemolysis, cytotoxicity, subcutaneous implantation, and hemostasis and healing assays. Importantly, the glycopolypeptide hydrogel‐treated rat‐skin defect model achieves full wound closure and regenerates thick dermis and epidermis with some hair follicles on day 14. Consequently, this work not only establishes a versatile method for constructing glycopolypeptide hydrogels with tunable adhesion and microporous structure, fast hemostasis, and superior healing functions, but also discloses a useful rationale for designing high‐performance hemostatic and healing hydrogels.

A new class of linear-dendron-like poly(ε-caprolactone)-b-poly(ethylene oxide) (PCL-b-PEO) copolymers with unsymmetrical topology was synthesized via controlled ring-opening polymerization (ROP) of ε-caprolactone (CL) followed by a click conjugation with azide-terminated PEO (PEO-N 3 ). The dendron-like PCL terminated with a clickable alkyne group (Dm-PCL, m ) 0, 1, 2, and 3) was for the first time synthesized from the ROP of CL monomer using a propargyl focal point dendrons Dm with primary amine groups as the initiators and stannous octoate as catalyst in bulk at 130 °C. Then, the linear-dendron-like Dm-PCL-b-PEO copolymers were obtained by the click conjugation of Dm-PCL with PEO-N 3 using PMDETA/CuBr as catalyst in DMF solution at 35 °C. Their molecular structures and physical properties were in detail characterized by FT-IR, NMR, MALLS-GPC, DSC, and WAXD. Both DLS and TEM analyses demonstrated that the biodegradable micelles and vesicles with different sizes (less than 100 nm) self-assembled from these Dm-PCL-b-PEO copolymers in aqueous solution, and both the PEO composition and the linear-dendron-like architecture of copolymers controlled the morphology and the average size of nanoparticles. To the best of our knowledge, this is the first report that describes the synthesis of linear-dendron-like PCL-b-PEO block copolymers via the combination of ROP and click chemistry. Consequently, this provides a versatile strategy not only for the synthesis of biodegradable and amphiphilic block copolymers with linear-dendron-like architecture but also for fabricating biocompatible nanoparticles with suitable size for controlled drug release.

Two types of three-arm or four-arm star-shaped hydroxy-terminated poly( -caprolactone) (PCL) were successfully synthesized via the ring-opening polymerization of -caprolactone (CL) with multifunctional initiator, such as trimethylolpropane (TMP) or pentaerythritol (PTOL), and stannous octoate (SnOct 2) catalyst in bulk at 110 °C. The number-average molecular weight of PCL is proportional to the molar ratio of monomer to initiator. 1 H NMR spectroscopy of the resulting PCL indicates that it contains a primary hydroxy end group in each arm. The star-shaped PCL with hydroxy end groups can be used as a macroinitiator for block copolymerization with DL-3-methylglycolide (MG) using SnOct2 catalyst in bulk at 115 °C. 1 H NMR spectra of the resulting block copolymers show that the molecular weights and the unit compositions of the block copolymers were controlled by the molar ratios of MG monomer to hydroxy groups of PCL and MG to CL in feed, respectively. Moreover, the molecular weights of the resulting block copolymers linearly increased with the increase of the molar ratios of MG to CL in feed. The molecular weight distributions of the block copolymers were rather narrow (M w/Mn ) 1.09-1.26). 13 C NMR spectra of the resulting block copolymers clearly show their diblock structures, that is, PCL as the first block and poly(DL-lactic acid-alt-glycolic acid) (DL-PLGA50) with alternating structures of lactyl and glycolyl units as the second block. Therefore, two types of three-arm or four-arm star-shaped diblock copolyesters comprising the first block PCL and the second block DL-PLGA50 were successfully synthesized via the sequential ring-opening polymerization of CL with multifunctional initiator and SnOct2 catalyst and then followed by copolymerization with MG.

Dendron-like/linear/dendron-like poly(epsilon-caprolactone)-b-poly(ethylene glycol)-b-poly(epsilon-caprolactone) triblock copolymers with controlled molecular weights (M(n) = 9550-30 460) and low polydispersities were synthesized by a click conjugation between dendron-like poly(epsilon-caprolactone) and bifunctional azide-terminated poly(ethylene glycol) (copolymer yield = 56-89%). Their molecular structures and physicochemical and self-assembly properties were thoroughly characterized by means of FT-IR, (1)H NMR, multiangle laser light scattering coupled with gel permeation chromatography, differential scanning calorimetry, wide-angle X-ray diffraction, dynamic light scattering, and transmission electron microscopy. Using a nanoprecipitation method, these triblock copolymers self-assembled into spherical flower-like micelles with an average diameter of less than 50 nm in aqueous solution, and both the copolymer composition and the dendritic topology of the hydrophobic core had no apparent influence on the morphology of nanoparticles. The critical aggregation concentrations of these copolymers ranged from 0.034 to 0.048 mg/mL. However, the anticancer doxorubicin-loaded nanoparticles showed worm-like micelles similar to blank nanoparticles fabricated by a dialysis method, and the loaded doxorubicin drug hardly affected the final morphology of nanoparticles. Moreover, the doxorubicin-loaded nanoparticles fabricated from the dumbbell copolymer showed a higher drug loading efficiency of 18% and a longer drug-release time of 45 days than the linear counterpart. Consequently, this provides a versatile strategy not only for the synthesis of biodegradable and biocompatible dendron-like/linear/dendron-like triblock copolymers with dumbbell topology by using click chemistry but also for fabricating worm-like doxorubicin-loaded nanoparticles for anticancer drug release.

Multidrug resistance (MDR) of cancers that results from overexpression of a P-glycoprotein (P-gp) transporter mainly causes chemotherapy (CT) failure and hinders clinical transitions of current polypeptide nanomedicines. Herein, a novel polypeptide nanocomposite PNOC-PDA that integrates heat-sensitive NO gas delivery and photothermal conversion attributes can overcome MDR and maximize CT; meanwhile the optimized CT and intracellular high-concentration NO gas can assist a mild photothermal therapy (PTT) to eradicate cancer cells. The triple therapies produced a superior and synergistic effect on MDR-reversal and killing MCF-7/ADR in vitro, and the P-gp expression level was downregulated to 46%, as confirmed by means of MTT, Western blot, flow cytometry, and confocal laser scanning microscopy. Significantly, by using one intravenous injection of PNOC-PDA/DOX and a single near-infrared irradiation, the triple therapies of mild PTT, NO gas therapy, and CT achieved complete MCF-7/ADR tumor ablation without skin damage, scarring, and tumor recurrence within 30 days. This work provides a versatile method for the fabrication of NIR-responsive polypeptide nanocomposite with intrinsic photothermal conversion and NO-releasing attributes, opening up a new avenue for reversing MDR in tumors.