Construction Of NuBCP-9 And DOX Co-delivery Hybrid Nanocomposites For Treating Drug Resistant Cancer

Multidrug resistance(MDR)caused by therapeutic drugs is the major cause to the failure of cancer chemotherapy.Over expression of Bcl-2 in cancer cells enhances their viability and resistance to the apoptotic effect of various cytotoxic factors,which is closely related to the occurrence of MDR.NuBCP-9(N9),a short peptide derived from the orphan nuclear receptor Nur77,can specifically bind to Bcl-2 protein and convert it from a cell protector to a killer,showing great promise for drug-resistant cancer.Unfortunately,N9 has the huge limitation in clinical application due to the short circulation half-life and the weak cell-penetrating capability.Thus,design of a nano-delivery system that can deliver peptide drugs into the target location in vivo will have the great significance in clinical application.In this study,we aimed at preparing a unique MSNs with small particle size(-30 nm)and large pore size(?7 nm),followed by the appropriate surface functionality and integration with PAMAM G5 to construct N9 and DOX co-delivery hybrid nanocomposites for treating drug-resistant cancer with high efficiency.To address the above objective,HeLa-Bcl2 and HepG2-Bcl2 cancer cell lines were constructed as the resistant cancer models,various measurements such as laser confocal microscope,flow cytometry and MTT were taken to investigate the anticancer efficiency of N9 and DOX co-delivery nanocomposites both in vitro and in vivo.Our results showed that the co-delivery nanocomposites induced 85%HeLa-Bcl2 cells into apoptosis after 48h of incubation at the DOX concentration of 1 ?g/ml,and the value of IC50 was just thirteenth of free drugs,demonstrating their excellent antitumor efficiency in vitro.The in vivo studies showed that the co-delivery nanocomposites had great targeting and retention abilities to tumors in HepG2-Bcl2 xenograft mice model,in which the fluorescence signal of nanocomposites was detected in tumor regions at 3 h and remained strong after 24 h.Moreover,the tumor inhibition rate of nanocomposites was as much as 89%,which was 5.6 times than free drug groups at the same dose,confirming their prominent capability against resistant tumors in vivo.In conclusion,we constructed a dual drug delivery system,which could deliver bio-macromolecular and chemotherapeutic drugs simultaneously into drug-resistant cancer cells for the synergistic treatment.Our study provides new strategy for the efficient intracellular delivery of peptide drugs and drug combinations against resistant cancers.