Hyperbranched-hyperbranched polymeric nanoassembly to mediate controllable co-delivery of siRNA and drug for synergistic tumor therapy.
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.
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Hui-Zhen
HZ
Jia
The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
Wei
W
Zhang
The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
Jun-Yi
JY
Zhu
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Bin
B
Yang
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Si
S
Chen
The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
Gang
G
Chen
The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China. Electronic address: yifang@whu.edu.cn.
Yi-Fang
YF
Zhao
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China. Electronic address: fengjun@whu.edu.cn.
Jun
J
Feng
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Xian-Zheng
XZ
Zhang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D016503:Drug Delivery Systems; D004357:Drug Synergism; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D049329:Nanostructures; D009369:Neoplasms / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D034741:RNA, Small Interfering; D004317:Doxorubicin
2-(bromomethyl) phenylboronic acid (PubChem CID: 2773278); Acetic acid (PubChem CID: 176); Combinational therapy; Core–corona nanostructure; Diethyl carbonate (PubChem CID: 7766); Disodium hydrogen phosphate (PubChem CID: 24203); Doxorubicin (PubChem CID: 443939); Drug/siRNA co-delivery; Hyperbranched polymer; Methylene (PubChem CID: 6344); Polyethylenimine (PubChem CID: 9033); Potassium carbonate (PubChem CID: 11430); Sodium acetate (PubChem CID: 517045); Sodium dihydrogen phosphate (PubChem CID: 23672064); pH-sensitivity