Injectable in situ forming hydrogel gene depot to improve the therapeutic effect of STAT3 shRNA.

Down-regulation of the signal transducer and activity of transcription 3 (Stat3) plays a crucial role in suppression of many solid tumors. Intratumoral injection of a gene carrier applying Stat3-small hairpin RNA (St3-shRNA) is a potential therapeutic strategy. To our knowledge, this is the first report of the intratumoral injection of St3-shRNA using a gene carrier. We herein designed biodegradable (methoxy)polyethylene glycol-b-(polycaprolactone-ran-polylactide) copolymer (MP) derivatized with a spermine group with cationic properties at the pendant position of the MP chain (MP-NH2). The designed MP-NH2 can act as a gene carrier of St3-shRNA by forming an electrostatic complex with cationic spermine. This can increase the stability of the complexes because of protection of PEG in biologic environments and can exhibit a sol-gel phase transition around body temperature for the formation of intratumorally injected MP-NH2 hydrogel depot for St3-shRNA. MP-NH2 was observed to completely condense with St3-shRNA to form St3-shRNA/MP-NH2 complexes. These complexes were protected for a relatively long time (≥72 h) from external biologic molecules of the serum, DNase, and heparin. St3-shRNA/MP-NH2 complexes in in vitro tumor cell experiments can enhance transfection of St3-shRNA, correspondingly enhance Stat3 knockdown efficiency, and inhibit tumor cell growth. St3-shRNA/MP-NH2 complexes and St3-shRNA/MP-NH2 complex-loaded hydrogel were intratumorally injected into the tumor as new efficient delivery carriers and depots of St3-shRNA. The intratumoral injection of St3-shRNA/MP-NH2 complexes and St3-shRNA/MP-NH2 complex-loaded hydrogel showed effective anti-tumor effect for an extended period of time due to the effect of Stat3 knockdown. Collectively, the development of MP-NH2 as a carrier and depot of St3-shRNA provides a new strategy for St3-shRNA therapy through intratumoral injection with high efficacy and minimal adverse effects.

Citation

Da Yeon Kim, Hyeon Jin Ju, Jae Ho Kim, Sangdun Choi, Moon Suk Kim. Injectable in situ forming hydrogel gene depot to improve the therapeutic effect of STAT3 shRNA. Biomaterials science. 2021 Jun 15;9(12):4459-4472

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PMID: 33997877

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