Overexpression of p‑glycoprotein (encoded by MDR1 gene) is often associated with multidrug-resistant cancer. This protein leads to drug resistance by the efflux of chemotherapeutic drugs from the cancerous cells. Small interfering RNA (siRNA), also known as post-transcriptional gene silencer, can suppress the expression of specific disease-related genes by silencing specific complementary mRNA (such as MDR1 gene). However, the therapeutic uses of siRNA are unexplored due to shortcomings of the delivery system including enzymatic degradation of siRNA, limited non‑viral delivery systems, and failure to reach the site of action.
The invention puts forward a nanoparticular delivery system, that simultaneously delivers drug and siRNA to combat multidrug-resistant cancers.
This invention puts forward a novel tri‑block copolymer system for drug‑siRNA co‑delivery (PEG‑DOPE with modified G4‑PAMAM). Here, G(4)‑PAMAM dendrimer provides a cationic source for efficient siRNA condensation, DOPE enhances cell penetration and maintains hydrophilicity, PEG makes siRNA accessible to G(4)‑D for condensation and PEG‑DOPE provides a stable micellar system. Combined, these provide an efficient drug delivery system to combat multidrug-resistant cancer.