Stepwise Stimuli-responsive Chitosan-based Multifunctional Nanoplatform For Effective Drug-resistant Breast Cancer Suppression

Chemotherapy is an irreplaceable treatment strategy in cancer treatment.However,the multi-drug resistance of tumor cells to chemotherapy drugs after a period of treatment is the main reason for the clinical failure of chemotherapy,and the mechanism of multidrug resistance is the increased expression and activity of drug transport pumps such as P-glycoprotein,as well as changes in apoptosis-related pathways.Compared with the treatment regimen of directly increasing the dose of administration in advanced cancer treatment,the substitution of the treatment regimen that directly targets the inhibition of the expression of the MDR1 gene in tumor cells combined with chemotherapy is considered a powerful strategy to fight cancer due to its high specificity and sustained efficacy.Efficient delivery systems for co-delivery of P-glycoprotein（P-gp）inhibitors and chemotherapeutic drugs are essential for inhibiting multidrug resistance（MDR）breast cancers.Herein,we present a multifunctional carboxymethyl chitosan（CMC）based coreshell nanoplatform to co-deliver MDR gene-silenced small interfering RNA（siMDR1）and doxorubicin（DOX）for optimal combinatorial therapy.DOX is linked to CMC through a disulfide bond to model a redox-responsive prodrug（CMC-DOX）as the inner core.siMDR1 is encapsulated in oligoethylenimine（OEI）,which is electrostatically adsorbed on CMC-DOX as the p H-responsive sheddable shielding shell.AS1411 aptamer and GALA peptide-functionalized hyaluronic acid（AHA/GHA）are provided on the surface for tumour-targeting and endo/lysosomal escape.The nanoplatform could stepwise release payloads with acid/redox triggered fashion.AHA effectively improves nanoplatform intracellular uptake and tumour accumulation.GHA facilitates cargos escape from the endo/lysosomes to the cytoplasm.The multifunctional nanoplatform provides 86.3 ± 2.2 % siMDR1 gene silencing and significantly downregulates P-gp expression in vitro and in vivo.Moreover,it ensures 55.7 ± 1.6 % MCF-7/ADR cell apoptosis at a low concentration of DOX（30 μg/m L）in vitro and performs synergistic therapeutic effects supressing tumour growth（inhibitory rate = 70.6 ± 3.7 %）in vivo.Overall,the multifunctional CMC-based biopolymers can be efficient siRNA/drug codelivery carriers for cancer chemotherapy.