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van Vlerken LE , Duan ZF , Little SR , Seiden MV , Amiji MM
Augmentation of Therapeutic Efficacy in Drug-Resistant Tumor Models Using Ceramide Coadministration in Temporal-Controlled Polymer-Blend Nanoparticle Delivery Systems
Aaps Journal. 2010 Jun;12(2) :171-180
PMID: ISI:000275975700007   
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The development of multidrug resistance (MDR) is a major hindrance to cancer eradication as it renders tumors unresponsive to most chemotherapeutic treatments and is associated with cancer resurgence. This study describes a novel mechanism to overcome MDR through a polymer-blend nanoparticle platform that delivers a combination therapy of C6-ceramide (CER), a synthetic analog of an endogenously occurring apoptotic modulator, together with the chemotherapeutic drug paclitaxel (PTX), in a single formulation. The PTX/CER combination therapy circumvents another cellular mechanism whereby MDR develops, by lowering the threshold for apoptotic signaling. In vivo studies in a resistant subcutaneous SKOV3 human ovarian and in an orthotopic MCF7 human breast adenocarcinoma xenograft showed that the PTX and CER nanoparticle combination therapy reduced the final tumor volume at least twofold over treatment with the standard PTX therapy alone. The study also revealed that the cotherapy accomplished this enhanced efficacy by generating an enhancement in apoptotic signaling in both tumor types. Additionally, acute evaluation of safety with the combination therapy did not show significant changes in body weight, white blood cell counts, or liver enzyme levels. The temporal-controlled nanoparticle delivery system presented in this study allows for a simultaneous delivery of PTX + CER in breast and ovarian tumor model drug, leading to a modulation of the apoptotic threshold. This strategy has tremendous potential for effective treatment of refractory disease in cancer patients.
van Vlerken, Lilian E. Duan, Zhenfeng Little, Steven R. Seiden, Michael V. Amiji, Mansoor M. National Cancer Institute's Alliance in Nanotechnology for Cancer [R01-CA119617]; National Science Foundation This project was supported by the National Cancer Institute's Alliance in Nanotechnology for Cancer Platform Partnership grant (R01-CA119617). Lilian E. van Vlerken was a fellow in the IGERT Nanomedical Science and Technology doctoral training program, which is jointly funded by the National Cancer Institute and the National Science Foundation. We deeply appreciate the assistance from Dr. Bo Rueda's group at the Mass General Hospital in the development of MCF7<INF>TR</INF> tumor model. 21 Springer; 233 spring st, new york, ny 10013 usa 574fx