Gold Nanorods For Platinum-based Drug Delivery

Cisplatin, carboplatin and oxaliplatin are widely used anticancer chemotherapeuticdrugs in clinic. Platinum drugs are currently used in over 50% of all cancerchemotherapeutic regimens, however, their application is limited by the side-effectsand the intrinsic and acquired drug resistence. Recently, drug delivery are of greatinterest as they can play important roles in overcoming drug resistance, enhancingdrug selectivity and reducing side-effects.In this dissertation, the drug delivery system Pt-PEG-GNRs have been preparedby tethering the inert and low-toxic platinum(IV) prodrug onto PEGylated goldnanorods (PEG-GNRs). The drug carrier, PEG-GNRs, was synthesized by doublePEGylation of gold nanorods. The PEG-GNRs were stable in phosphate bufferedsaline (PBS) or 10% fetal calf serum (FBS) and had low cytotoxicity to cancer cellsand normal cells. Pt-PEG-GNRs was obtained by covalently binding of Pt(IV)prodrug onto the PEG-GNRs.The cytotoxicity assays demonstrated that the Pt-PEG-GNRs conjugatessignificantly enhanced the cytotoxicity of cisplatin (9.1, 12.2 and 65.6 times higheron HeLa, A549 and MCF-7, respectively), while the empty carrier showed negligiblecytotoxicity. Drug accumulation analyses showed that the platinum uptake viaPt-PEG-GNRs is clearly more than that by cisplatin (2.1, 1.3 and 4.1 times higher onHeLa, A549 and MCF-7, respectively). This result reveals that the drug carrierpromotes drug efficacy by enhanced cellular drug uptake.As DNA is the ultimate target of platinum antitumor drugs, its platinationdetermines the drug efficacy. Insufficient binding of platinum to the target DNA is themajor cause of acquired drug resistance, which can be stemmed from impaired druguptake and increased platinum deactivation in cells. It was observed that the cisplatinresistance can be overcome by gold nanorods based Pt(IV) prodrug delivery system,which lowers the resistant factor from 7.1 to 1.3 on the cisplatin resistant cells A549R.Mechanism study showed that the reduced drug uptake resulted from low expressionof Ctr1 in cisplatin resistant cells can be circumvented by the nano drug carrierinduced endocytosis. The Pt(IV) prodrug delivered by gold nanorods is more inertthan cisplatin to the drug deactivation molecules GSH and metallothionein, which areover-expressed in cisplatin resistance cells. In summary, a stable platinum drug delivery system Pt-PEG-GNRs has beenprepared. This conjugate can improve drug efficacy, and also overcome the cisplatinresistance via enhanced drug uptake and decreased drug deactivation in cells.