Nano-micelle System For Co-delivery Of Nucleic Acids And Small Drugs For Cancer Therapy

Apoptosis induction is the foundation of many anti-tumor strategies.Tumor necrosis factor(TNF)is effective to induce apoptosis of tumor cells.TRAIL,belonging to the tumor necrosis factor family,can bind with death reporters on the cancer cell surface and induce apoptosis via endogenous pathway,while sparing normal cells.The application of TRAIL-based gene therapy has attracted great attention.However,the cancer cells are readily develop resistance to TRAIL therapy.Combination therapy using TRAIL and the small-molecular sensitizer could be an efficient strategy to address this issue.In this study,a micelle system was developed for co-delivery of pTRAIL and salinomycin(Sali)to tumor sites.The co-delivery system ?-PGA/Sali@PS/pTRAIL could overcome the delivery barriers and carry the cargos to the tumor for cervical cancer therapy.The work developed a cationic micelle system composed of an amphiphilic material PEI5K-Steric acid(P-S)by covalent conjugation of the cationic material PEI5 k with stearic acid via amide reaction.Salinomycin(Sali)could be loaded into the hydrophobic core of the micelle,while pTRAIL subsequently bound on the cationic micelles,thus forming the Sali@P-S/pTRAIL nanocomplexes.In addition,?-polyglutamic acid(?-PGA)could be further bound on the nanocomplexes as a polyanionic corona of ?-PGA,thus forming the ?-PGA/Sali@P-S/pTRAIL.?-PGA can enhance the colloidal stability effectively.The ?-PGA/Sali@P-S/pTRAIL nanocomplexes were characterized.The particle size and zeta potential were measured by laser particle size analyzer,and transmission electron microscope(TEM)was used to observe the morphology.Furthermore,the biocompatibility,drug loading capacity,and drug release of the co-delivery system.The pH-dependent conformation of the surface-modified ?-PGA was also investigated.The cellular uptake of the nanocomplexes and transfection efficacy and transportation pathway were studied in the cancer cells.The antitumor activity and apoptosis were analyzed.The mechanisms of the synergistic effect of TRAIL and salinomycin was examined.The bio-distribution and treatment efficacy of the nanocomplexes was evaluated in the HeLa xenograft model on nude mice.The results showed that the nanocomplexes were about 100 nm.The loading capacity of Sali was around 5%.The surface modification of ?-PGA led to a decrease in zeta potential(from +45 to-25 mV)with an improved stability.The nanocomplexes efficiently entered the tumor cells and yielded high transfection efficiency comparable to PEI25 K,resulting in potent anti-tumor effect.Combination of TRAIL and salinomycin yielded a synergistic effect and significant treatment outcomes in animal studies.This work provides an evaluation of antitumor effect both in vitro and in vivo,and a preclinical evidence for the combination therppy of TRAIL and salinomycin.