Polyamidoamine dendrimers-based nanomedicine for combination therapy with siRNA and chemotherapeutics to overcome multidrug resistance.

ABSTRACT: Multidrug resistance (MDR) significantly decreases the therapeutic efficiency of anti-cancer drugs. Its reversal could serve as a potential method to restore the chemotherapeutic efficiency. Downregulation of MDR-related proteins with a small interfering RNA (siRNA) is a promising way to reverse the MDR effect. Additionally, delivery of small molecule therapeutics simultaneously with siRNA can enhance the efficiency of chemotherapy by dual action in MDR cell lines. Here, we conjugated the dendrimer, generation 4 polyamidoamine (G4 PAMAM), with a polyethylene glycol (PEG)-phospholipid copolymer. The amphiphilic conjugates obtained spontaneously self-assembled into a micellar nano-preparation, which can be co-loaded with siRNA onto PAMAM moieties and sparingly water-soluble chemotherapeutics into the lipid hydrophobic core. This system was co-loaded with doxorubicin (DOX) and therapeutic siRNA (siMDR-1) and tested for cytotoxicity against MDR cancer cells: human ovarian carcinoma (A2780 ADR) and breast cancer (MCF7 ADR). The combination nanopreparation effectively downregulated P-gp in MDR cancer cells and reversed the resistance towards DOX.

SUBMITTER: Pan J 

PROVIDER: S-EPMC6377860 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature