Poly[platinum(IV)-alt-PEI]/Akt1 shRNA complexes for enhanced anticancer therapy

摘要

The co-delivery of platinum(IV) prodrugs and nucleic acids has emerged as a new modality for cancer therapy. However, as a result of the different molecular properties of nucleic acids and platinum(IV) prodrugs, the co-delivery of platinum(IV) prodrugs and nucleic acids encounter challenges (e.g., insufficient drug loading capacity and efficiency, less definable ratios of the two agents). To address these issues, a novel polymeric platinum(IV) prodrug, poly[platinum(IV)-alt-PEI] (DP), was synthesized by one-step Michael-addition reaction of platinum(IV) diacrylate with low molecular weight PEI (PEI 800). The loading efficiency of the platinum(IV) prodrug was nearly 100%, for cases where the platinum(IV) prodrug content in the polymer could be precisely regulated by simply changing the molar ratios of the reactants. The poly[platinum(IV)-alt-PEI]/Akt1 shRNA complex was constructed by the electrostatic condensation of negatively charged Akt1 shRNA (a RNAi sequence for serine-threonine kinase AKT pathway) with positively charged poly[platinum(IV)-alt-PEI]. Cellular assays involving A549, MCF-7, and PC-3 cancer cells indicated that poly[platinum(IV)-alt-PEI]/Akt1 shRNA complexes for platinum(IV) prodrug and Akt1 shRNA co-delivery offered combinational anticancer efficacy, inhibiting cancer cell proliferation more efficiently than the individual treatments. In conclusion, we proposed a convenient carrier assembly, which could achieve the co-delivery of small molecular chemotherapeutics and macromolecular nucleic acids.