Hyperbranched–hyperbranched polymeric nanoassembly to mediate controllable co-delivery of siRNA and drug for synergistic tumor therapy

• Published in: Journal of controlled release Vol. 216; pp. 9 - 17
• Main Authors: Jia, Hui-Zhen, Zhang, Wei, Zhu, Jun-Yi, Yang, Bin, Chen, Si, Chen, Gang, Zhao, Yi-Fang, Feng, Jun, Zhang, Xian-Zheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28-10-2015
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Apoptosis Regulatory Proteins - genetics; Autophagy; Beclin-1; Cell Line, Tumor; Combinational therapy; Core–corona nanostructure; Cross-Linking Reagents; Delayed-Action Preparations; Doxorubicin - administration & dosage; Doxorubicin - therapeutic use; Drug Delivery Systems; Drug Synergism; Drug/siRNA co-delivery; Genetic Therapy - methods; Hyperbranched polymer; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanostructures; Neoplasms - therapy; pH-sensitivity; RNA Interference; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - adverse effects; RNA, Small Interfering - therapeutic use; Potassium carbonate (PubChem CID: 11430); Sodium acetate (PubChem CID: 517045); Sodium dihydrogen phosphate (PubChem CID: 23672064); 2-(bromomethyl) phenylboronic acid (PubChem CID: 2773278); Polyethylenimine (PubChem CID: 9033); Disodium hydrogen phosphate (PubChem CID: 24203); Combinational therapy; Core–corona nanostructure; Acetic acid (PubChem CID: 176); pH-sensitivity; Hyperbranched polymer; Doxorubicin (PubChem CID: 443939); Drug/siRNA co-delivery; Methylene (PubChem CID: 6344); Diethyl carbonate (PubChem CID: 7766)
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2015.08.006

This study reported a flexible nanoplatform constructed on the pH-dependent self-assembly of two kinds of hyperbranched polymers, and then validated its potency as the controllable siRNA/drug co-delivery vehicle for the combination of chemotherapy with RNA interfering (RNAi) therapy. By virtue of pH-reversible phenylboronate linking, phenylboronic acid-tethered hyperbranched oligoethylenimine (OEI600-PBA) and 1,3-diol-rich hyperbranched polyglycerol (HBPO) can be spontaneously interlinked together into a core–corona nanoconstruction. The special buildup of compactly clustering OEI600-PBA units around hydrophobic HBPO aggregate offered significant advantages over parent OEI600-PBA, including strengthened affinity to siRNA, ability of further loading anticancer drug, easier cellular transport, and acidity-responsive release of payloads. To evaluate the co-delivery capability, Beclin1 siRNA and antitumor DOX were used as the therapeutic models in order to suppress the post-chemotherapy survival of tumor cells caused by drug-induced autophagy. The nanoassembly-mediated single delivery of DOX displayed even better anticancer effects than free DOX, demonstrating the superiority of our pH-responsive nano-design. The nanoassembly-mediated co-delivery of siRNA together with DOX can effectively silence Beclin1 gene, suppress DOX-induced autophagy, and consequently provide strong synergism with a significant enhancement of cell-killing effects in cultured cancerous cells. The in vivo combinational treatment was shown to make the tumor more sensitive to DOX chemotherapy while displaying substantially improved safety as compared with the monochemotherapy.
Hyperbranched–hyperbranched polymeric nanoassembly with pH-dependent stability has been built to realize controlled co-delivery of anticancer drug and siRNA for synergistic tumor therapy. [Display omitted]