Dendrimer-PLGA based multifunctional immuno-nanocomposite mediated synchronous and tumor selective delivery of siRNA and cisplatin: potential in treatment of hepatocellular carcinoma

摘要

Considering the subdued efficacy of a single therapeutic modality in successful treatment of cancer, cooperative inhibition of cancer progression employing a combination of two or more therapeutic approaches is currently in vogue. An example of this strategy is the combination of chemotherapy and siRNA based therapy. However, development of delivery systems capable of successfully loading siRNA as well as a chemotherapeutic drug simultaneously and delivering both the cargos to the target site has been considered an uphill task. The present study demonstrates the development of an innovative polyfunctional delivery system capable of loading siRNA and a chemotherapeutic drug concurrently and delivering the two payloads to the tumor site in a targeted manner. In the present study, liver cancer specific antibody conjugated PAMAM-dendrimer-siRNA complex functionalized and cisplatin loaded PLGA nanocomposites were developed. PAMAM dendrimers being cationic polymers facilitate binding of negatively charged siRNA. In this nanocomposite system (Ab@PAMAM-siRNA@Cis-PLGA NC), liver cancer specific antibody (Ab) serves the purpose of targeting the immuno-nanocomposite to the cells expressing liver cancer antigens; siRNA is the gene knockdown agent; cisplatin is the therapeutic anticancer-drug; PLGA NPs act as cisplatin delivery vehicle, provide a scaffold to dendrimer and also subdue its cytotoxicity; PAMAM acts as siRNA carrier and may facilitate endosomal escape. The promise of polyfunctional Ab@PAMAM-siRNA@Cis-PLGA NC to be used in cancer therapy was highlighted from the in vivo data enumerating synergistic anti-cancer effect of the two payloads resulting in enhanced apoptosis of cancer cells and augmenting survival of the treated animals.