Bingqiang Li

A pH- and thermo-responsive poly(amino acid)-based drug delivery system

A pH- and thermo-responsive poly(amino acid)-based amphiphilic copolymer was developed, functioning as a tumour targeting drug delivery system with good biocompatibility and biodegradability. To provide multi-stimuli sensitivity characteristics to the poly(amino acid)s, the polyaspartamide scaffold has been functionalized with N,N-diisopropylamide groups via aminolysis reaction of polysuccinimide. PEG chains have also been chemically grafted to the poly(amino acid) backbone through acid-labile hydrazone linkages, providing a removable shield for the poly(amino acid) based nanoparticles. Furthermore, doxorubicin was chemically linked to the copolymer chain via hydrazone bonds, acting as the hydrophobic moiety to drive the polymeric self-assembly. Free doxorubicin molecules could be encapsulated into the self-assembled nanoparticles via hydrophobic interactions and molecular π-π stacking. The results obtained show that the drug release can be triggered by the temperature with a significantly increased release being observed under acidic conditions. The cytotoxicity behaviour of the copolymers and drug-loaded nanoparticles was investigated in vitro at varying pH values and different temperatures. In doing so, superior characteristics concerning compatibility and anti-cancer activity could be observed.

A pH and redox dual stimuli-responsive poly(amino acid) derivative for controlled drug release

A pH and redox dual stimuli-responsive poly(aspartic acid) derivative for controlled drug release was successfully developed through progressive ring-opening reactions of polysuccinimide (PSI). Polyethylene glycol (PEG) chains were grafted onto the polyaspartamide backbone via redox-responsive disulfide linkages, providing a sheddable shell for the polymeric micelles in a reductive environment. Phenyl groups were introduced into the polyaspartamide backbone via the aminolysis reaction of PSI to serve as the hydrophobic segment of micelles. The polyaspartamide scaffold was also functionalized with N-(3-aminopropyl)-imidazole to obtain the pH-responsiveness manifesting as a swelling of the core of micelles at a low pH. The polymeric micelles with a core-shell nanostructure forming in neutral media exhibited both pH and redox responsive characteristics. Doxorubicin (DOX) as a model drug was encapsulated into the core of micelles through both hydrophobic and π-π interactions between aromatic rings and the DOX-loaded polymeric micelles exhibited accelerated drug release behaviors in an acidic and reductive environment due to the swelling of hydrophobic cores and the shedding of PEG shells. Furthermore, the cytocompability of the polymer and the cytotoxicity of DOX-loaded micelles towards Hela cells under corresponding conditions were evaluated, and the endocytosis of DOX-loaded polymeric micelles and the intracellular drug release from micelles were observed. All obtained data indicated that the micelle was a promising candidate for controlled drug release.

A hydrazone crosslinked zwitterionic polypeptide nanogel as a platform for controlled drug delivery

A pH-responsive polypeptide nanogel was prepared via hydrazone self-crosslinking under mild conditions. Zwitterionic sulfobetaine was introduced to the polypeptide by aminolysis reaction of polysuccinimide with N,N-dimethylaminopropylamine, and the subsequent ring-opening reaction between tertiary amine and 1,3-propanesultone. The hydrazine and aldehyde modified poly(α,β-L-aspartic acid) precursors, poly(aspartamide sulfobetaine-co-aspartylhydrazide) and poly(aspartamide sulfobetaine-co-2-oxoethyl aspartamide) were prepared by the successive aminolysis reaction of polysuccinimide. The obtained zwitterionic poly(aspartamide) nanogel exhibited excellent anti-protein adsorption ability and stability in protein solutions. An anticancer drug, doxorubicin (DOX), was entrapped into the nanogel, and showed accelerated release under acidic conditions. Additionally, the nanogel entrapped DOX could be successfully released into the cancer cells and showed high cytotoxicity. This easily prepared nanogel, with features of biocompatibility, anti-protein adsorption ability, and pH-responsiveness, is a promising controlled drug delivery system.

A pH, glucose, and dopamine triple-responsive, self-healable adhesive hydrogel formed by phenylborate–catechol complexation

An injectable polyethylene glycol (PEG) hydrogel was successfully prepared via borate–catechol complexation using dopamine functionalized 4-armed PEG (4-arm-PEG-DA) and phenylboronic acid modified 4-armed PEG (4-arm-PEG-PBA). The hydrogel was formed within 10 s by mixing 15 wt% 4-arm-PEG-DA with 15 wt% 4-arm-PEG-PBA buffer solutions at pH 9.0. The hydrogel was characterized by Fourier transform infrared (FT-IR) spectroscopy, rheological measurements, scanning electron microscopy (SEM) and lap shear strength tests. Furthermore, pH, glucose and dopamine responsiveness of the hydrogel based on phenylborate–catechol complexation was demonstrated by degradation experiments and drug release tests. The lap shear strength tests indicated that the hydrogel possessed the ability of self-healing which was bestowed by the phenylborate–catechol dynamic covalent bond. Moreover, the hydrogel could serve as a decent bio-adhesive due to its adhesion properties on different substrates especially the porcine skin. In vitro cytotoxicity tests demonstrated the excellent cytocompatibility of the hydrogel. The results of all the experiments indicate that our newly developed multi-functionalized hydrogel can have potential applications in biomedical fields such as drug delivery, tissue engineering, and bio-adhesives.

Injectable dopamine-modified poly(α,β-aspartic acid) nanocomposite hydrogel as bioadhesive drug delivery system

Hydrogel systems based on cross-linked polymeric materials with adhesive properties in wet environments have been considered as promising candidates for tissue adhesives. The 3,4-dihydroxyphenylalanine (DOPA) is believed to be responsible for the water-resistant adhesive characteristics of mussel adhesive proteins. Under the inspiration of DOPA containing adhesive proteins, a dopamine-modified poly(α,β-aspartic acid) derivative (PDAEA) was successfully synthesized by successive ring-opening reactions of polysuccinimide (PSI) with dopamine and ethanolamine, and an injectable bioadhesive hydrogel was prepared via simply mixing PDAEA and FeCl3 solutions. The formation mechanism of the hydrogel was investigated by ultraviolet-visible (UV-vis) spectroscopic, Fourier transformation infrared (FT-IR) spectroscopic, visual colorimetric measurements and EDTA immersion methods. The study demonstrated that the PDAEA-Fe3+ hydrogel is a dual cross-linking system composed of covalent and coordination crosslinks. The PDAEA-Fe3+ hydrogel is suitable to serve as a bioadhesive agent according to the rheological behaviors and the observed significant shear adhesive strength. The slow and sustained release of the model drug curcumin from the hydrogel in vitro demonstrated the hydrogel could also be potentially used for drug delivery. Moreover, the cytotoxicity tests in vitro suggested the prepared polymer and hydrogel possessed excellent cytocompatibility. All the results indicated that the dopamine modified poly(α,β-aspartic acid) derivative based hydrogel was a promising candidate for bioadhesive drug delivery system.

Synthesis and properties of temperature-sensitive and chemically crosslinkable poly(ether-urethane) hydrogel

Temperature-responsive and crosslinkable poly(ether-urethane)s (PEUs), which may be useful for tissue adhesives, are prepared through the polymerization of poly(ethylene glycol)s (PEG), mono-p-methoxybenzylidene-pentaerythritol and hexamethylene diisocyanate, the hydrolysis of acetals in PEUs and the grafting of methacrylate (MA) to PEUs. After gelating the PEU solution in a specific temperature range via a rapid reversible temperature response, the physical hydrogel is further self-cross-linked or cross-linked with PEG diacrylate (PEGDA) by photocuring. These PEU-MA gels are characterized by Fourier transform infrared spectra (FTIR), nuclear magnetic resonance (NMR) and size exclusion chromatography (SEC). The sol–gel phase transitions through temperature response and chemical crosslinking are investigated by rheology testing. It is found that the swelling ratio, degradation, adhesive strength and mechanical properties of the PEU-MA gels are affected by the ratio of hydrophilic and hydrophobic segments in PEU and the grafting ratios of MA in PEU-MA gels. The adhesive strengths on tissues with PEU-MA are stronger than those on glass and PBT. The adhesion of PEU-MA on artificial dura mater can be maintained for over one month, even when immersed in water. The good biocompatibility of the PEU-MA gels is demonstrated via cytotoxicity evaluation. As a result, these PEU-MA gels are promising candidates as tissue adhesives and drug-loading materials for soft tissue filling and regeneration.

A magnetic polypeptide nanocomposite with pH and near-infrared dual responsiveness for cancer therapy

A magnetic polypeptide nanocomposite with pH and near-infrared (NIR) dual responsiveness was developed as a drug carrier for cancer therapy, which was prepared through the self-assembly of Fe3O4 superparamagnetic nanoparticles, poly(aspartic acid) derivative (mPEG-g-PDAEAIM) and doxorubicin (DOX) in water. Fe3O4 nanoparticles were prepared to provide the superparamagnetic core of nanocomposites for tumor targeting via chemical co-precipitation. The protonable imidazole groups of mPEG-g-PDAEAIM with a pKa of ~7 were accountable for the pH-responsiveness of nanocomposites. The photothermal effect of nanocomposites under the irradiation of NIR laser was induced via the interactions between dopamine groups of mPEG-g-PDAEAIM and Fe3O4 superparamagnetic nanoparticles to trigger the drug release. NMR, FT-IR, TEM, hysteresis loop analysis and MRI were utilized to characterize the materials. The DOX loaded nanocomposites exhibited pH-responsive and NIR dependent on/off switchable release profiles. The nanocomposites without drug loading (Fe3O4@mPEG-g-PDAEAIM) showed excellent biocompatibility while DOX loaded nanocomposites caused MCF-7 cells’ apoptosis due to the photothermal/chemotherapy combination effects. Overall, the pH and near-infrared dual responsive magnetic nanocomposite had a great potential for cancer therapy.

Injectable Dual Redox Responsive Diselenide-Containing Polyethylene Glycol Hydrogel.

An injectable dual redox responsive diselenide-containing poly(ethylene glycol) (PEG) hydrogel was successfully developed by combining the conceptions of injectable hydrogels and dual redox responsive diselenides. In the first step, four-armed PEG was modified with N-hydroxysuccinimide (NHS)-activated esters and thereafter, crosslinked by selenocystamine crosslinkers to form injectable hydrogels via the rapid reaction between NHS-activated esters and amino groups. The cross-sectional morphology, mechanical properties, and crosslinking modes of hydrogels were well characterized via scanning electron microscope (SEM), rheological measurements, and Fourier transform infrared spectra, respectively. In addition, the oxidation- and reduction-responsive degradation behaviors of hydrogels were observed and analyzed. The model drug, rhodamine B, was encapsulated in the hydrogel. The drug-loaded hydrogel exhibited a dual redox responsive release profile, which was consistent with the degradation experiments. The results of all experiments indicated that the formulated injectable dual redox responsive diselenide-containing PEG hydrogel can have potential applications in various biomedical fields such as drug delivery and stimuli-responsive drug release.

Synthesis and characterization of biocompatible zwitterionic sulfobetaine polypeptides and their resistance to protein adsorption

A zwitterionic polypeptide derivative was successfully synthesized using 3-dimethylaminopropylamine as the ring-opening reagent to react with polysuccinimide, and a poly(α,β-L-dimethylamino propyl aspartamide) was obtained with tertiary amine side groups; the ring-opening reagent then reacted with 1,3-propanesultone to prepeare the poly(α,β-3-dimethyl propyl ammonium propanesulfonate aspartamide) (PSBA). PSBA possessed both cationic moiety in the form of quaternary ammonium and anionic functionality in the form of a sulfo-group on the same repeat unit; it also exhibited an isoelectric point (pI) and opposite charges at pH values far high or below the pI. FT-IR and 1H NMR spectroscopy were used to confirm the chemical structure of PSBA. Zwitterionic polypeptides were coated onto the amino functional silica wafers via electrostatic attraction. The PSBA-coated silica wafers were characterized by water contact angle analysis, X-ray photoelectron spectroscopy (XPS), and atomic force microscope (AFM). Protein adsorption measurements indicated that polypeptides with zwitterionic sulfobetaine structure had good anti-protein-fouling property. The amount of protein adsorbed on the coated surface could be controlled, depending on the pre-coated polymer concentration. Because of its good biocompatibility and anti-protein-fouling property, this zwitterionic polypeptide is a promising candidate for surface modification in many biomedical applications, such as medical implants, drug delivery carriers, and biosensors.