Boosting RNAi therapy for orthotopic glioblastoma with nontoxic braintargeting chimaeric polymersomes

Yanan Shi, Yu Jiang, Jinsong Cao, Weijing Yang, Jian Zhang^*（张建） , Fenghua Meng, Zhiyuan Zhong^*（钟志远）

Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China

Journal of Controlled Release 292 (2018) 163--171

Glioblastoma with intracranial infiltrative growth remains an incurable disease mainly owing to existence of blood brain barrier (BBB) and off-target drug toxicity. RNA interference (RNAi) with a high specificity and low toxicity emerges as a new treatment modality for glioblastoma. The clinical application of RNAi technology is, however, hampered by the absence of safe and brain-targeting transfection agents. Here, we report on angiopep-2 peptide-decorated chimaeric polymersomes (ANG-CP) as a nontoxic and brain-targeting non-viral vector to boost the RNAi therapy for human glioblastoma in vivo. ANG-CP shows excellent packaging and protection of anti-PLK1 siRNA (siPLK1) in its lumen while quickly releasing payloads in a cytoplasmic reductive environment. Notably, in vitro experiments demonstrate that ANG-CP can effectively permeate the bEnd.3 monolayer, transport siRNA into the cytosol of U-87 MG glioblastoma cells via the LRP-1-mediated pathway, and significantly silence PLK1 mRNA and corresponding oncoprotein in U-87 MG cells. ANG-CP greatly prolongs the siPLK1 circulation time and enhances its accumulation in glioblastoma. RNAi with siPLK1 induces a strong anti-glioblastoma effect and significantly improves the survival time of glioblastoma carrying mice.

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