Abstract 3711: Smart therapy: Using CCND1- targeted siRNA-loaded liposomes to sensitize mantle cell lymphoma cells to cisplatin

Mantle cell lymphoma (MCL) is the most aggressive subtype of B-cell non-Hodgkin's lymphoma, due to its refractory nature and high relapse rate. It is characterized by the aberrant overexpression of the cell cycle regulatory oncogene, cyclin D1 (CCND1), which occurs as a result of a t (11; 14) chromosomal translocation event, the initiating lesion for MCL tumorigenesis. Current therapy includes a series of different chemotherapy regimens often involving a combination of at least four drugs, but there is no gold standard combination treatment regimen. One of the most commonly used drugs in combination treatment is the chemotherapeutic agent, cisplatin. High concentrations of cisplatin in the body cause nausea, vomiting, loss of taste and, more severely, nephrotoxicity. A commonly used approach to reduce the concentration of a chemotherapeutic agent is to use it in combination with a molecular targeting agent. Since cyclin D1 is overexpressed in MCL, we hypothesize that knocking down CCND1 by using siRNA will sensitize MCL cells to cisplatin. We developed CCND1 primers to detect reduction in CCND1 mRNA levels after RNAi using PCR. The greatest challenge against siRNA delivery is its poor stability in vivo and low efficacy of transfection into tumor cells. Our objective is to formulate a dosage form that could be practically adapted in a clinical setting in the future. We developed a liposome formulation that uses a balanced ratio of neutral and cationic lipids to serve as a carrier for the siRNA and improves delivery to tumor cells. Our CCND1 siRNA and control siRNA-loaded liposomes have an average particle size below 150 nm and an overall cationic charge less than 30V. These characteristics are important for the trafficking of the liposome carrier in vivo and its eventual uptake into tumor tissue. Fluorescence assays were used to detect and quantify the amounts of siRNA bound to the liposome. We determined the effect of the liposomes in combination with cisplatin on MCL cell viability using a colorimetric MTT assay. The novel CCND1 siRNA-loaded liposome combined with cisplatin was found to show a dose-dependent decrease in cell viability and was more potent than either CCND1 siRNA liposomes or cisplatin alone (p