•Photocrosslinkable biomimetic chitosan derivative PCCs-GMA was synthesized.•Biomimetic PCCs-GMA hydrogels showed tunable mechanical and swelling properties.•PCCs-GMA hydrogels showed better blood compatibility than Cs-GMA hydrogels.•PCCs-GMA hydrogels showed low protein adsorption comparable with PEG-DA hydrogels.Photocrosslinkable biomimetic chitosan derivative, glycidyl methacrylate-phosphorylcholine-chitosan (PCCs-GMA) was synthesized through the combination of Atherton-Todd reaction for coupling phosphorylcholine and ring opening reaction of epoxides for attaching GMA, and confirmed by 1H and 31P NMR and Fourier transform infrared (FTIR) spectroscopy. The photo-crosslinking reaction of PCCs-GMA with different degree of substitution (DS) of GMA allowed the formation of biomimetic hydrogels with tunable mechanical and swelling properties. Cold crystallization behaviors ascribed to their restrained freezing bound water were investigated using differential scanning calorimetry (DSC). The rheological and swelling behaviors, hemolysis as well as protein sorption of PCCs-GMA hydrogels were investigated in terms of the DS of GMA, using fibrinogen, bovine serum albumin and lysozyme as model proteins. Low irreversible protein sorption and non hemolytic results indicated that photo-crosslinked PCCs-GMA hydrogels may offer a promising candidate material with resistance to protein fouling in biomedical applications.

Bioinspired double-positively charged phosphodicholine (PdC)-chitosan conjugate was synthesized via Atherton-Todd reaction, which can hydrolyze to zwitterionic phosphorylcholine (PC)-chitosan in basic solutions, confirmed by 1H and 31P NMR spectra. Thermal analysis revealed that there existed the freezing bound water due to the introduction of PdC and PC groups for both PdC-chitosan and PC-chitosan, implying that double-positively charged PdC-chitosan may exhibit excellent biocompatibility as zwitterionic PC-chitosan. Cytotoxicity, hemolysis and antibacterial activity evidenced that PdC-chitosan displayed high antibacterial activity against Escherichia coli and Staphylococcus aureus under physiological conditions, and very low cytotoxicity and hemolytic activity, owing to its highly selective lysis of bacterial membranes over mammalian cell membranes mainly resulting from the competition of electrostatic interactions and shielding effect of the restrained water of PdC, while biocompatible PC-chitosan showed no antibacterial activity due to its non-fouling property. The results indicated that biocompatible double-positively charged PdC-containing bioinspired polymers may provide a promising approach for developing safe and effective antibacterial agents.

•pH responsive biomimetic chitosan derivative NAcHis-PCCs was synthesized.•Self-assembled NAcHis-PCCs nanoparticles showed acid-induced size increase.•NAcHis-PCCs nanoparticles with PC shell could avoid adverse biological response.•QUE/NAcHis-PCCs nanoparticles exhibited an acid triggered drug release behavior.Novel pH-responsive biodegradable biomimetic nanocarriers were prepared by the self-assembly of N-acetyl-l-histidine-phosphorylcholine-chitosan conjugate (NAcHis-PCCs), which was synthesized via Atherton-Todd reaction to couple biomembrane-like phosphorylcholine (PC) groups, and N,N′-carbonyldiimidazole (CDI) coupling reaction to link pH-responsive N-acetyl-l-histidine (NAcHis) moieties to chitosan. In vitro biological assay revealed that NAcHis-PCCs nanoparticles had excellent biocompatibility to avoid adverse biological response mainly owing to their biomimetic PC shell, and DLS results confirmed their pH-responsive behavior in acidic aqueous solution (pH ≤ 6.0). Quercetin (QUE), an anti-inflammatory, antioxidant and potential anti-tumor hydrophobic drug, was effectively loaded in NAcHis-PCCs nanocarriers and showed a pH-triggered release behavior with the enhanced QUE release at acidic pH 5.5 compared to neutral pH 7.4. The results indicated that pH-responsive biomimetic NAcHis-PCCs nanocarriers might have great potential for site-specific delivery to pathological acidic microenvironment avoiding unfavorable biological response.

•Novel amphiphilic biomimetic chitosan derivative DCA–PCCs was synthesized.•BSA and DCA–PCCs can self-assemble to form spherical nanocomplexes.•BSA/DCA–PCCs nanocomplexes show excellent cytocompatibility and hemocompatibility.•BSA/DCA–PCCs nanocomplexes exhibited a sustained drug release behavior.A bio-inspired nanocarrier was developed for protein delivery based on biodegradable amphiphilic chitosan derivative (DCA–PCCs) with hydrophilic cell membrane mimic phosphorylcholine (PC) and hydrophobic deoxycholic acid (DCA) moieties, which was synthesized via the combination of Atherton–Todd reaction and carbodiimide coupling reaction. Using bovine serum albumin (BSA) as model protein, it was found that DCA–PCCs with suitable degree of substitution of PC and DCA moieties can load proteins by forming nanocomplexes via a solvent evaporation method. The physicochemical characteristics of BSA/DCA–PCCs nanocomplexes were investigated by Zetasizer, atomic force microscopy (AFM) and Fourier-transform infrared (FT-IR) spectroscopy. In vitro biological evaluation revealed BSA/DCA–PCCs nanocomplexes as blank DCA–PCCs nanoparticles had excellent cytocompatibility and hemocompatibility mainly due to the presence of cell membrane mimic phosphorylcholine. BSA release results suggested BSA/DCA–PCCs nanocomplexes showed a sustained release behavior following first order exponential decay kinetics. The results indicated DCA–PCCs provided a promising approach for effectively delivering therapeutic proteins.

•DCA–PCCs with phosphorylcholine and deoxycholic acid was synthesized.•DCA–PCCs can self-assemble to form spherical micelles in aqueous system.•DCA–PCCs micelles had excellent cytocompatibility and hemocompatibility.•DCA–PCCs micelles loaded with quercetin exhibited a sustained drug release behavior.Novel biomimetic amphiphilic chitosan derivative, deoxycholic acid–phosphorylcholine–chitosan conjugate (DCA–PCCs) was synthesized based on the combination of Atherton–Todd reaction for coupling phosphorylcholine (PC) and carbodiimide coupling reaction for linking deoxycholic acid (DCA) to chitosan. The chemical structure of DCA–PCCs was characterized by 1H and 31P nuclear magnetic resonance (NMR). The self-assembly of DCA–PCCs in water was analyzed by fluorescence measurements, dynamic laser light-scattering (DLS), zeta potential and transmission electron microscopy (TEM) technologies. The results confirmed that the amphiphilic DCA–PCCs can self-assemble to form nanosized spherical micelles with biomimetic PC shell. In vitro biological evaluation revealed that DCA–PCCs micelles had low toxicity against NIH/3T3 mouse embryonic fibroblasts as well as good hemocompatibility. Using quercetin as a hydrophobic model drug, drug loading and release study suggested that biomimetic DCA–PCCs micelles could be used as a promising nanocarrier avoiding unfavorable biological response for hydrophobic drug delivery applications.

A novel approach to construct biomimetic nanocarriers with suppression of the protein-nanocarrier interactions was developed. Firstly, biomimetic N-phosphorylcholine-chitosan derivative (N-PCCs) with biomembrane-like phosphorylcholine (PC) group was successfully synthesized through Atherton-Todd reaction and subsequently hydrolysis, and structurally characterized. Using bovine serum albumin (BSA) as a model protein, UV adsorption spectra and fluorescence spectra revealed that the interactions between N-PCCs and BSA were effectively suppressed and the conformation of BSA was almost unchanged with the addition of N-PCCs. Moreover, N-PCCs nanoparticles can be easily formed by ionic crosslinking with lower particle size and zeta potential value compared with Cs nanoparticles. The results suggested that biomimetic N-PCCs nanoparticles may be used as a promising nanocarrier avoiding unfavorable biological response for effectively delivering therapeutic and/or diagnostic agents.A novel biomimetic nanocarrier with suppression of the protein-nanocarrier interactions was successfully constructed by crosslinking biomimetic N-phosphorylcholine-chitosan derivative with TPP, which can be used for effectively delivering therapeutic and/or diagnostic agents, avoiding unfavorable biological response.Highlights► We synthetize a novel biomimetic N-phosphorylcholine-chitosan derivative (N-PCCs). ► The interactions between N-PCCs and BSA are effectively suppressed. ► N-PCCs can easily form nanoparticles through crosslinking with TPP.

A novel approach to improve the antiviral efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) and reduce their side effects was developed by constructing a nanosized NRTI monophosphate-polymer conjugate using d4T as a model NRTI. Firstly, a novel chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate with a phosphoramidate linkage was efficiently synthesized through Atherton–Todd reaction under mild conditions. The anti-HIV activity and cytotoxicity of the polymeric conjugate were evaluated in MT4 cell line. Then the conjugate nanoparticles were prepared by the process of ionotropic gelation between TPP and chitosan-d4T conjugate to improve their delivery to viral reservoirs, and their physicochemical properties were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) techniques and X-ray diffraction (XRD). In vitro drug release studies in pH 1.1 and pH 7.4 suggested that both chitosan-d4T conjugate and its nanoparticles prefer to release d4T 5′-(O-isopropyl) monophosphate than free d4T for prolonged periods, which resulted in the enhancement of anti-HIV selectivity of the polymeric conjugate relative to free d4T due to bypassing the metabolic bottleneck of monophosphorylation. Additionally, the crosslinked conjugate nanoparticles can prevent the coupled drug from leaking out of the nanoparticles before entering the target viral reservoirs and provide a mild sustained release of d4T 5′-(O-isopropyl) monophosphate without the burst release. The results suggested that this kind of chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate nano-prodrugs may be used as a targeting and sustained polymeric prodrugs for improving therapy efficacy and reducing side effects in antiretroviral treatment.