International Journal of Nanomedicine (Jun 2024)
Design and Application of pH-Responsive Liposomes for Site-Specific Delivery of Cytotoxin from Cobra Venom
Abstract
Qing Lin,1,2,* Yafei Jing,2,3,* Cailing Yan,2 Xinyi Chen,2 Qiong Zhang,2 Xinhua Lin,2,3 Yunlu Xu,2,4 Bing Chen2,3 1Department of Pharmacy, Affiliated Fuzhou First Hospital of Fujian Medical University, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2School of Pharmacy, Fujian Medical University, Fujian, People’s Republic of China; 3Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 4Center of Translational Hematology, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bing Chen, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China, Email [email protected]; [email protected] Yunlu Xu, Center of Translational Hematology, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, 350122, People’s Republic of China, Email [email protected]: Current immunotherapies with unexpected severe side effects and treatment resistance have not resulted in the desired outcomes for patients with melanoma, and there is a need to discover more effective medications. Cytotoxin (CTX) from Cobra Venom has been established to have favorable cytolytic activity and antitumor efficacy and is regarded as a promising novel anticancer agent. However, amphiphilic CTX with excellent anionic phosphatidylserine lipid-binding ability may also damage normal cells.Methods: We developed pH-responsive liposomes with a high CTX load (CTX@PSL) for targeted acidic-stimuli release of drugs in the tumor microenvironment. The morphology, size, zeta potential, drug-release kinetics, and preservation stability were characterized. Cell uptake, apoptosis-promoting effects, and cytotoxicity were assessed using MTT assay and flow cytometry. Finally, the tissue distribution and antitumor effects of CTX@PSL were systematically assessed using an in vivo imaging system.Results: CTX@PSL exhibited high drug entrapment efficiency, drug loading, stability, and a rapid release profile under acidic conditions. These nanoparticles, irregularly spherical in shape and small in size, can effectively accumulate at tumor sites (six times higher than free CTX) and are rapidly internalized into cancer cells (2.5-fold higher cell uptake efficiency). CTX@PSL displayed significantly stronger cytotoxicity (IC50 0.25 μg/mL) and increased apoptosis in than the other formulations (apoptosis rate 71.78± 1.70%). CTX@PSL showed considerably better tumor inhibition efficacy than free CTX or conventional liposomes (tumor inhibition rate 79.78± 5.93%).Conclusion: Our results suggest that CTX@PSL improves tumor-site accumulation and intracellular uptake for sustained and targeted CTX release. By combining the advantages of CTX and stimuli-responsive nanotechnology, the novel CTX@PSL nanoformulation is a promising therapeutic candidate for cancer treatment.Keywords: cobra venom cytotoxin, tumor microenvironment, pH-responsive, targeted delivery, liposomes
