Stimuli-responsive Nanomedicine For Treating Drug-resistant Cancers

Objective:Chemodrug resistance is a major cause accounting for chemotherapy failure and recurrence of malignant tumors.The mechanisms of chemoresistance are multifactorial,including overexpressed drug efflux transporters(such as P-gp),drug inactivation,oncogenic bypass,DNA damage repair,and deregulation of apoptosis.Considering the complex and implicated mechanisms of chemoresistance,conventional chemodrugs often fail to eradicate drug-resistant cancer cells,and even promote chemoresistance through activating alternative pathways.Herein,a new method for the treatment of drug-resistant tumors was developed by preparing stimuli-responsive nanomedicine.Methods:Two nanosystems were designed for treating drug-resistant cancers:(1)a nanosized copper and catechol-based metal-organic framework(Cu HPT);(2)a hyaluronic acid(HA)-coated,p H and redox dual-responsive nanosystem(HPMSNs),which codelivered doxorubicin(DOX)and GCN5 si RNA(DOX/si GCN5@HPMSNs).Next,we characterized the two nanosystems and explored the antitumor effects of these nanosystems against durg-resistant cancers in vitro and in vivo.Results:Drug-resistant cancer cells possess a high-level but dynamically-balanced cellular redox homeostasis.Cu HPT started disassembly that was triggered by the consumption of high-level cellular glutathione(GSH).The disassembly of Cu HPT simultaneously released two structural elements:catechol ligands(HPT)and reductive copper ions(Cu~+).They cooperatively increased the production of intracellular reactive oxygen species(ROS)via auto-oxidation and Fenton-like reactions,respectively.The consumption of GSH and the production of ROS disturbed the redox homeostasis and tilted the balance to oxidation stress.Based on this,Cu HPT displayed selective and effective cytotoxicity to different drug-resistant cancer cells.Preclinical animal experiments revealed that Cu HPT effectively inhibited the in vivo drug-resistant tumor growth and significantly prolonged the survival time of tumor-bearing mice.DOX/si GCN5@HPMSNs effectively encapsulated DOX and si RNA thus preventing premature leakage and releasing these cargos intracellularly through its p H/redox dual responsiveness.Via CD44-mediated targeting,DOX/si GCN5@HPMSNs promoted drug internalization in CD44 overexpressed cancer cells,and greatly incresead DOX’s retention by down-regulating P-gp expression through silencing GCN5 in drug-resistant cancer cells.In a drug-resistant tumor model,HPMSNs codelivering DOX and si GCN5 inhibited MDR tumor growth,abrogated P-gp-mediated drug resistance,and minimized DOX’s systemic toxicity.Conclusion:DOX/si GCN5@HPMSNs downregulated P-gp epigenetically,increased the intratumor chemodrug’s accumulation,thus reversing chemoresistance.Nevertheless,just down-regulation of P-gp expression had limited effect on the treatment of drug resistance.Cu HPT disrupted the characteristic high-level redox homeostasis in drug-resistant cancer cells,exhibiting broader killing effect.The two nanosystems are promising therapeutic approachs for the treatment of drug-resistant tumors.