Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy.

Abstract

BACKGROUND:

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)n, 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.

RESULTS:

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.

CONCLUSION:

These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment.

• Authors: Ting Zhao, Ce Liang, Yanrong Zhao, Xiangdong Xue, Zhao Ma, Jinlong Qi, Haitao Shen, Shaokun Yang, Jia Zhang, Qingzhong Jia, Qing Du, Deying Cao, Bai Xiang, Hailin Zhang, Xianrong Qi
• Journal: Journal of nanobiotechnology (J Nanobiotechnology) Vol. 20 Issue 1 Pg. 177 (Apr 02 2022) ISSN: 1477-3155 [Electronic] England
• PMID: 35366888 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Antineoplastic Agents
• Liposomes
• RNA, Small Interfering
• Docetaxel

Topics

• Antineoplastic Agents (chemistry)
• Docetaxel (pharmacology)
• Hydrogen-Ion Concentration
• Liposomes (chemistry)
• Neoplasms (drug therapy)
• RNA, Small Interfering