Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy

• Published in: Journal of nanobiotechnology Vol. 20; no. 1; pp. 177 - 23
• Main Authors: Zhao, Ting, Liang, Ce, Zhao, Yanrong, Xue, Xiangdong, Ma, Zhao, Qi, Jinlong, Shen, Haitao, Yang, Shaokun, Zhang, Jia, Jia, Qingzhong, Du, Qing, Cao, Deying, Xiang, Bai, Zhang, Hailin, Qi, Xianrong
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02.04.2022; BioMed Central; BMC
• Subjects: Anticancer properties; Antineoplastic Agents - chemistry; Antitumor agents; Apoptosis; Biocompatibility; Cancer; Cancer therapies; Cancer therapy; Care and treatment; Cell membranes; Chemotherapy; Co-delivery system; Combinatorial analysis; Cytoplasm; Docetaxel; Docetaxel - pharmacology; Drug delivery; Drug delivery systems; Drugs; Endosomes; Fluid pressure; Gene expression; Gene therapy; Health aspects; Hydrogen-Ion Concentration; In vivo methods and tests; Kinases; Liposome; Liposomes; Liposomes - chemistry; Lysosomes; Methods; MicroRNAs; Nanoparticles; Neoplasms - drug therapy; Peptides; Permeability; pH effects; pH-responsive; Physiological effects; Physiology; Polo-like kinase; RNA, Small Interfering; Shielding; Side effects; siRNA; Small interfering RNA; Tumors; Vehicles; China; Co-delivery system; Liposome; Small interfering RNA; Cancer therapy; pH-responsive; Docetaxel
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-022-01383-z

Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect. However, the elevated tumor interstitial fluid pressure and efficient cytoplasmic release are still two significant obstacles to siRNA delivery. Co-delivery of chemotherapeutic drugs and siRNA represents a potential strategy which may achieve synergistic anticancer effect. Herein, we designed and synthesized a dual pH-responsive peptide (DPRP), which includes three units, a cell-penetrating domain (polyarginine), a polyanionic shielding domain (ehG) , and an imine linkage between them. Based on the DPRP surface modification, we developed a pH-responsive liposomal system for co-delivering polo-like kinase-1 (PLK-1) specific siRNA and anticancer agent docetaxel (DTX), D-Lsi/DTX, to synergistically exhibit anti-tumor effect. In contrast to the results at the physiological pH (7.4), D-Lsi/DTX lead to the enhanced penetration into tumor spheroid, the facilitated cellular uptake, the promoted escape from endosomes/lysosomes, the improved distribution into cytoplasm, and the increased cellular apoptosis under mildly acidic condition (pH 6.5). Moreover, both in vitro and in vivo study indicated that D-Lsi/DTX had a therapeutic advantage over other control liposomes. We provided clear evidence that liposomal system co-delivering siPLK-1 and DTX could significantly downregulate expression of PLK-1 and inhibit tumor growth without detectable toxic side effect, compared with siPLK-1-loaded liposomes, DTX-loaded liposomes, and the combinatorial administration. These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment.