Xiaoye Gao

Biodegradable, pH-Responsive Carboxymethyl Cellulose/Poly(Acrylic Acid) Hydrogels for Oral Insulin Delivery

Biodegradable and pH-responsive carboxymethyl cellulose/poly(acrylic acid) hybrid hydrogels are synthesized. The hydrogels deswell in acidic artificial gastric fluid (AGF) but rapidly swell in neutral artificial intestinal fluid (AIF), rendering selective enzymatic degradation of the gels as well as accelerated drug release from insulin-loaded hydrogels in AIF. Oral administration of insulin-loaded hydrogels to streptozotocin-induced diabetic rats leads to a continuous decline in the fasting blood glucose level within 6 h post-administration, and the relative pharmacological availability increases more than 10 times compared to oral administration of free insulin solution. The relative bioavailability of hydrogel-encapsulated insulin after oral administration to healthy rabbits is 6.6%.

pH- and thermo-responsive poly(N-isopropylacrylamide-co-acrylic acid derivative) copolymers and hydrogels with LCST dependent on pH and alkyl side groups

A series of pH- and temperature-responsive poly(N-isopropylacrylamide-co-acrylic acid derivative) (P(NIPAM-co-AAD)) copolymers and hydrogels were prepared. The lower critical solution temperatures (LCSTs) of the copolymers exhibited a dependence on both pH and the hydrophobicity of the AAD unit. The influence of pH and temperature on the equilibrium swelling ratio of the hydrogels was investigated. The hydrogels displayed a unique thermo-induced swelling-deswelling transition that can be self-regulated to occur at above or below the physiological temperature in response to the environmental pH. Scanning electron microscopic (SEM) analysis revealed porous sponge-like microstructures of the hydrogels. Insulin was loaded into the hydrogels as a model protein, and the in vitro release profiles indicated that the loaded protein could be protected within the hydrogels in an acidic environment and selectively released in neutral medium. MTT assay proved that both the copolymers and hydrogels are nontoxic. After oral administration of the insulin-loaded hydrogels to streptozotocin-induced diabetic rats at 60 IU per kg, the fasting plasma glucose level was reduced continuously to 72.1% within 6 h. The bioavailability of hydrogel-encapsulated insulin via the oral administration to healthy rabbits reached 5.24%, which is much higher than that of pure insulin solution given orally. These results showed that the smart copolymers and hydrogels may hold great promise for pH-triggered drug delivery systems.

pH-Responsive Poly(ethylene glycol)/Poly(L-lactide) Supramolecular Micelles Based on Host-Guest Interaction.

pH-responsive supramolecular amphiphilic micelles based on benzimidazole-terminated poly(ethylene glycol) (PEG-BM) and β-cyclodextrin-modified poly(L-lactide) (CD-PLLA) were developed by exploiting the host-guest interaction between benzimidazole (BM) and β-cyclodextrin (β-CD). The dissociation of the supramolecular micelles was triggered in acidic environments. An antineoplastic drug, doxorubicin (DOX), was loaded into the supramolecular micelles as a model drug. The release of DOX from the supramolecular micelles was clearly accelerated as the pH was reduced from 7.4 to 5.5. The DOX-loaded PEG-BM/CD-PLLA supramolecular micelles displayed an enhanced intracellular drug-release rate in HepG2 cells compared to the pH-insensitive DOX-loaded PEG-b-PLLA counterpart. After intravenous injection into nude mice bearing HepG2 xenografts by the tail vein, the DOX-loaded supramolecular micelles exhibited significantly higher tumor inhibition efficacy and reduced systemic toxicity compared to free DOX. Furthermore, the DOX-loaded supramolecular micelles showed a blood clearance rate markedly lower than that of free DOX and comparable to that of the DOX-loaded PEG-b-PLLA micelles after intravenous injection into rats. Therefore, the pH-responsive PEG-BM/CD-PLLA supramolecular micelles hold potential as a smart nanocarrier for anticancer drug delivery.

Synthesis of temperature and pH-responsive crosslinked micelles from polypeptide-based graft copolymer

A polypeptide-based double hydrophilic graft copolymer was synthesized by the sequential grafting of poly(N-isopropylacrylamide) (PNIPAM) and 2-hydroxyethyl methacrylate (HEMA) onto poly(l-glutamic acid) (PGA) backbone. The copolymers were sensitive to both temperature and pH. The phase transition and aggregation behaviors of the graft copolymers in aqueous solutions were investigated by the turbidity measurements and dynamic laser scattering (DLS). The light transmittance decrease of the copolymers at temperature above lower critical solution temperature (LCST) was remarkably weakened at pH around 6.5 due to the coil to α helix change of PGA chain induced by pH. The copolymers can self-assembly into micelles with PNIPAM cores in the aqueous solution at pH 8.0 and 60°C. Subsequently, polymerization of HEMA led to the facile preparation of crosslinked micelles, which were observed directly by transmission electron microscopy (TEM). The temperature controlled shrinkage behaviors of crosslinked micelles highly depended on the pH values of the solution. The crosslinked micelles aggregated at pH 5.0 due to the increased hydrophobic interactions among them induced by the protonation of PGA component. These crosslinked micelles have promising applications as intelligent drug delivery vehicles.

Targeted dextran-b-poly(ε-caprolactone) micelles for cancer treatments

In this study, targeted drug deliveries with excellent biocompatibility have been investigated to improve the efficacy and reduce the systemic toxicity of drugs. First, amphiphilic dextran-b-poly(e-caprolactone) (Dex-PCL) copolymers were synthesized by a “click” reaction between α-alkyne terminated dextran and azido-terminated poly(e-caprolactone). Then, the targeted molecules, such as folic acid and galactose, were conjugated to Dex-PCL. To verify their feasibility as drug delivery vehicles, DOX was loaded into Dex-PCL micelles with or without a targeted molecule. The in vitro release of DOX from DOX-loaded micelles demonstrated that there was a continuous release after burst release in the first 6 h. The cell viability assay of DOX-loaded micelles conjugated with targeting molecules against HeLa and HepG2 cells was investigated. Targeted DOX-loaded micelles showed significant bindings with tumor cells and efficient inhibition to corresponding targeted cells. Therefore, targeted DOX-loaded micelles provided an efficient drug delivery platform for the inhibition of cancer cells.