Gene/paclitaxel co-delivering nanocarriers prepared by framework-induced self-assembly for the inhibition of highly drug-resistant tumors

Abstract While drug resistance has been recognized as the main cause of unsuccessful chemotherapy, the efficient inhibition of highly drug-resistant tumors still remains a significant challenge, especially for in vivo treatments. Drug resistance has been associated with the high expression of the multi-drug resistance gene 1 (MDR1), which can encode an efflux transporter known as P-glycoprotein (P-gp) that is located in the cellular membrane. Therefore, the combined delivery of MDR1-inhibited genes and chemotherapeutic drugs is anticipated to enable the effective inhibition of drug-resistant tumors. Herein, highly paclitaxel (PTX)-resistant ovarian (OV) cancer with a drug resistance index reaching up to ~ 60 was chosen to evaluate the performance of an efficient gene/drug co-delivery nanocarrier. Inspired by the self-assembly that occurs in cells and exosomes, we designed a biomimetic lipid/dextran hybrid nanocarrier with a diameter of ~ 100 nm to enhance the endocytosis and the efficiency of drug/gene release within the cells. This nanocarrier was fabricated via the frame-guided self-assembly of lipid amphiphiles on the surfaces of redox-cleavable dextran-based nanogels. The anionic MDR1-siRNA and the hydrophobic drug PTX were respectively loaded into the cationic lipid shell and the hydrophobic internal core of the hybrid nanocarriers. MDR1-siRNA can knock down MDR1, promoting the accumulation of PTX in cells, and thus is expected to achieve an efficient inhibitory effect against highly PTX-resistant cancer cells. Both in vitro and in vivo studies revealed that this dual-delivery system significantly enhanced the therapeutic effect in comparison with that provided by a PTX-only system. Thus, the construction of gene/chemo co-delivered lipid/dextran nanocarriers provides a new strategy to inhibit highly drug-resistant tumors both in vitro and in vivo. In addition, this work will contribute toward the development of urgently needed tumor nanotherapy that is able to overcome drug resistance while also offering an unmatched range of effective therapeutic nanocarriers. Statement of significance The biomimetic lipid/dextran hybrid nanocarrier with a diameter of ~ 100 nm, which was fabricated via the frame-guided self-assembly of lipid amphiphiles onto the surface of redox-cleavable dextran-based nanogels, provides a model carrier to co-deliver MDR1-siRNA and PTX.  The MDR1-siRNA/PTX co-loaded biomimetic lipid/dextran hybrid nanocarriers demonstrate good capability in overcoming the PTX-resistance in highly chemo-resistant human ovarian (OV) cancer cells both in vitro and in vivo.