Dai Phu Huynh

Controlled release of insulin from pH/temperature-sensitive injectable pentablock copolymer hydrogel.

A pH- and temperature-sensitive hydrogel of poly(beta-amino ester)-poly(epsilon-caprolactone)-poly (ethylene glycol)-poly(epsilon-caprolactone)-poly(beta-amino ester) (PAE-PCL-PEG-PCL-PAE) pentablock copolymer was evaluated as a sustained injectable insulin delivery system. Insulin was readily loaded into the matrix, forming an ionically linked insulin-PAE complex. Complex mixtures containing various concentrations of insulin and copolymer were subcutaneously injected into male Sprague-Dawley rats to study the profile of insulin release in vivo. The insulin-release profile showed that insulin was maintained at a constant steady-state level for 15 days, and further demonstrated that insulin levels were controlled by the amount of insulin loaded into the copolymer and the copolymer concentration in the hydrogel. The effect of the insulin-gel complex was further investigated in the streptozotocin (STZ) diabetic rat model. After subcutaneously injecting complex mixtures into STZ-induced diabetic rats, blood glucose and plasma insulin levels were measured. The results showed that the diabetic rats could be treated for more than 1 week with a single injection of the complex mixture containing 10 mg/mL insulin in a 30 wt.% copolymer solution, suggesting that this pH/temperature-sensitive insulin-hydrogel complex system may have therapeutic potential.

Biodegradable oligo(amidoamine/β-amino ester) hydrogels for controlled insulin delivery

An injectable biodegradable hydrogel system based on oligo(amidoamine/β-amino ester) (OAAAE) was designed and synthesized for controlled release of insulin under the physiological conditions. OAAAE was prepared in one step via the Michael-addition oligomerization of the secondary amine groups of 4,4-trimethylene dipiperidine (TMDP) with the vinyl groups of 1,8-octylene diacrylamide (ODA) and 1,6-hexane diol diacrylate (HDA). The formed oligomer was characterized by 1H NMR and gel permeation chromatography (GPC). OAAAE in aqueous solution (20 wt%) underwent a gel–sol transition in the pH range of 6.8–7.4. A complex hydrogel was formed when mixing insulin with the oligomer solution followed by increasing pH and temperature. Degradation of the hydrogel, influence of insulin on gel phase and gel strength, in vitro cytotoxicity of OAAAE, in vitro and in vivo release of insulin from the complex hydrogel were investigated. Furthermore, the in vivo release profile of insulin from the complex hydrogel was compared with that from the neutral hydrogel.

pH‐Sensitive Pentablock Copolymer Nanocapsules as Nontoxic and Efficient Gene Carriers

A biodegradable amphiphilic pentablock copolymer PAE-PCL-PEG-PCL-PAE with a pH-sensitive unit was synthesized for use as a nontoxic, biodegradable carrier for gene delivery by forming nanocapsules entrapping nucleic acid drugs. The PAE block can interact with plasmid DNA to form polyelectrolyte complexes in an acidic environment. At physiological pH, the PAE blocks are deprotonated and form an insoluble skin, resulting in the formation of nanocapsules that encapsulate plasmid DNA. The surface charges of the nanocapsules became almost neutral at pH = 7.4, and their size ranged from 210 to 280 nm. The nanocapsule maintained most of its transfection efficiency even in the presence of serum. These nanocapsules are therefore potential carriers for systemic gene therapy.

Fabrication and photochromic properties of Forcespinning® fibers based on spiropyran-doped poly(methyl methacrylate)

Spiropyran-functionalized poly(methyl methacrylate) (PMMA) Forcespinning® fibers were fabricated using a fiber making machine of our own design, employing 1′,3′,3′-trimethyl-6-nitrospiro[1(2H)-benzopyran-2,2′-indoline] (6-nitro BIPS) as the spiropyran. The effects of the polymer solution concentration (and hence the viscosity), the spinneret rotational rate, and the internal needle diameter on the formation and morphology of the fibers were examined, using scanning electron microscopy. A rotational speed of 3000 rpm and an internal nozzle diameter of 0.35 mm (23 G) in conjunction with a polymer concentration of 15 wt% produced 6-nitro BIPS/PMMA Forcespinning fibers having a smooth morphology with no beads. The photochromic properties of the resultant fibers were characterized by reflectance spectroscopy using the Kubelka–Munk function, fluorescence excitation emission matrix (EEM) analysis, and Raman spectroscopy. The thermal decoloration dynamics of the 6-nitro BIPS in the PMMA fibers were in good agreement with the properties observed in films. These results suggest that 6-nitro BIPS and other spiropyran dyes have significant potential as probes to assess the structures of micro/nanofibers.

Intraarterial gelation of injectable cationic pH/temperature-sensitive radiopaque embolic hydrogels in a rabbit hepatic tumor model and their potential application for liver cancer treatment

Poly(amino ester urethane) (PAEU) block copolymers have been reported as potential hydrogel systems for drug delivery because of such advantages as their non-toxicity, ability to form electrostatic linkages and hydrogen bonds with bioactive agents, and ability to exhibit a sol-to-gel phase transition after injection into the body to form a hydrogel to act as a depot for the subsequent controlled release of loaded bioactive molecules. In this study, PAEU bock copolymers were synthesized, and their chemical structures and properties were characterized. In aqueous solution, the copolymers exhibited a sol-to-gel phase transition with increasing pH, or a gel-to-sol phase transition with increasing temperature. The formation of in situ gels has been observed within 20 min of subcutaneous injection of copolymer solutions into SD rats due to the sol-to-gel phase transition which occurs in response to local pH and temperature. The prepared polymers were employed for the fabrication of injectable radiopaque embolic materials, which are mixtures of an aqueous copolymer solution and a commercial long-lasting X-ray contrast agent, Lipiodol. The formulated radiopaque embolic hydrogel precursor solutions were then intraarterialy injected via the hepatic arteries feeding the VX2 hepatic tumors in rabbits using a 2.0 Fr microcatheter to investigate their gelability for potential application in liver cancer treatment. CT images and histological examination of excised tumor tissues confirmed the formation of hydrogels in the hepatic arteries and tumors. Doxorubicin (DOX), an anticancer drug, was released from hydrogels with or without Lipiodol in sustained fashion, and the released DOX fully retained its bioactivity via inhibiting the proliferation of cancer cells in vitro. These results have demonstrated that the synthesized PAEU block copolymers can be used to prepare radiopaque embolic solutions, which then exhibit a sol-to-gel phase transition to form hydrogels acting as anticancer drug depots to induce chemoembolization after being injected into tumor-feeding arteries, and therefore offer potential applications for TACE in liver cancer.

Novel pH/Temperature-Sensitive Hydrogels Based on Poly(β-Amino Ester) for Controlled Protein Delivery

The concept of this research was to use poly(β-amino ester) (PAE) as a bi-functional group for synthesis of the novel stimuli-sensitive injectable hydrogels for controlled drug/protein delivery. Firstly, PAE was used as a pH-sensitive moiety to conjugate with the temperature-sensitive biodegradable triblock copolymer of poly(ethylene glycol)-poly(e-caprolactone)(PCL-PEG-PCL) or poly(ethylene glycol)-poly(e-caprolactone-co-D,L-lactide) (PACL-PEG-PCLA). Secondly, the cationic nature of PAE was used as the second function to make ionic complexes with anionic biomolecules loaded onto the hydrogel such as insulin. As a result, the release of the drug/protein from the hydrogel device can be controlled by the degradation of the copolymer.