Fabricating nanoparticles co-loaded with survivin siRNA and Pt(IV) prodrug for the treatment of platinum-resistant lung cancer.

ABSTRACT

Resistance to platinum agents is a crucial challenge in the treatment of cancer using platinum drugs. To overcome the resistance of cells, the survivin protein is supposed to be decreased, since it has previously been found to be overexpressed in drug-resistant cancer cells in anti-apoptosis pathways, while the intracellular effective platinum accumulation should be increased. In the present work, a protamine/hyaluronic acid nanocarrier was used to load survivin siRNA with Pt(IV) loaded outside the coated polyglutamic acid (PGA) by chemical conjugation. The siRNA was released from the co-loaded nanoparticle prior to Pt(IV), in this way, the expression of survivin protein was effectively reduced, which, in turn, could avoid the anti-apoptosis of drug resistant cells. Here, Pt(IV) displayed a sustained release effect and gradually reduced to the toxic Pt(II) species, which reduced drug efflux and enhance apoptosis of the cancer cells. In vitro studies demonstrated that co-loaded nanoparticles resulted in similar cell killing performance in A549/DDP cells (cisplatin resistant) compared with non-siRNA loaded nanoparticles in A549 cells (cisplatin sensitive). NP-siRNA/Pt(IV) exhibited a greatly improved therapeutic effect (TIR, 82.46%) in a nude mice A549/DDP tumor model, with no serious adverse effects observed. Thus, co-loading of Pt(IV) and survivin siRNA nanoparticles could reverse cisplatin resistance and therefore has promising prospects for efficient cancer chemotherapy.