Mi-Ran Park

Injectable Polyplex Hydrogel for Localized and Long-Term Delivery of siRNA

Here, we describe a concept for localized and long-term delivery of short interfering RNA (siRNA) using an injectable polyplex hydrogel possessing thermosensitivity and biodegradability properties. We prepared a low molecular weight polyethyleneimine-poly(organophosphazene) conjugate as a thermosensitive and cationic polymer that has a cleavable ester linkage. The conjugates formed about 100 nm sized polyplexes with siRNAs, and the polyplex solution turned into a polyplex hydrogel at body temperature via a hydrophobic interaction. We injected the polyplex hydrogel with siRNA of cyclin B1, an essential protein for controlling the cell cycle, into the tumor xenograft model. Polyplexes were slowly released from the polyplex hydrogel by dissolution and degradation, allowing an in vivo antitumor effect via cyclin B1 gene silencing for 4 weeks with only a single injection.

Dual ionic interaction system based on polyelectrolyte complex and ionic, injectable, and thermosensitive hydrogel for sustained release of human growth hormone.

A dual ionic interaction system composed of a positively charged polyelectrolyte complex (PEC) containing human growth hormone (hGH) and anionic thermosensitive hydrogel has been suggested for sustained delivery of bioactive hGH. The PEC was prepared by ionic interaction between negatively charged hGH and positively charged protamine sulfate (PS) to suppress diffusion of hGH. Moreover, we loaded the positively charged PEC into an anionic, injectable, and thermosensitive poly(organophosphazene) hydrogel to enhance sustained release of hGH by dual ionic interactions. PS formed a spherical complex with hGH, and their ionic interaction grew stronger with increasing amounts of PS. From a weight ratio of 0.5, the PS/hGH complex had a size and zeta-potential that were constantly maintained around 500 nm and +8 mV, respectively, in 0.9% NaCl. The PEC-loaded hydrogels suppressed the initial burst release of hGH and extended the release period in vitro and in vivo. In a pharmacokinetic study in rats, the PEC-loaded anionic hydrogel extended half-life 13-fold with similar area under the curve (AUC) compared to hGH solution. Furthermore, single injection of PEC-loaded anionic hydrogel showed a more increased growth rate than daily injection of hGH solution for 7 days in hypophysectomized rats, demonstrating its potential as an injectable, sustained delivery system that can release bioactive hGH.

Galactosylated chitosan-g-PEI/DNA complexes-loaded poly(organophosphazene) hydrogel as a hepatocyte targeting gene delivery system

Hydrogels are widely used in drug delivery systems because they can control the release and thereby enhance the efficiency of locally delivered bioactive molecules such as therapeutic drugs, proteins, or genes. For gene delivery, localized release of plasmid DNA or polymer/DNA complexes can transfect cells and produce sustained protein production. We tested the galactosylated chitosan-graft-polyethylenimine (GC-g-PEI)/DNA complexes-loaded poly(organophosphazene) thermosensitive biodegradable hydrogel as a hepatocyte targeting gene delivery system. The poly(organophosphazene) hydrogel loaded with GC-g-PEI/DNA complexes showed low cytotoxicity and higher transfection efficiency than PEI/DNA complexes, as well as good hepatocyte specificity in vitro and in vivo. Our results indicate that poly(organophosphazene) hydrogels loaded with GC-g-PEI/DNA complexes may be a safe and efficient hepatocyte targeting gene delivery system.

An injectable cell penetrable nano-polyplex hydrogel for localized siRNA delivery.

An approach for application of cell penetration to selective small interference RNA (siRNA) localized delivery system, cell penetrable nano-polyplex assembled hydrogel system, is presented. The cell penetrable nano-polyplex assembled hydrogelisprepared by protamine conjugation to poly(organophos-phazene) and inducement of nano-polyplexes with siRNAs. After an injection of cell penetrable nano-polyplex solution into the body, it turns into a gel due to thermosensitivity of poly(organo- phosphazene). The gel maintains up to 4 weeks and the released 30 nm-sized nano-polyplexes from the gel induces highly effective siRNA delivery due to cell penetration. Accordingly, the new system shows a high gene silencing efficiency on only the target site in long-term with a single injection.