Synergistic Cytotoxicity of Irinotecan and Cisplatin in Dual-Drug PSMA-Targeted Polymeric Nanoparticles

Aim—Two unexplored aspects for irinotecan and cisplatin (I&C) combination chemotherapy are (1) actively targeting both drugs to a specific diseased cell type and (2) delivering both drugs on the same vehicle to ensure their synchronized entry into the cell at a well-defined ratio. In this work we report the use of targeted polymeric nanoparticles (NPs) to co-encapsulate and deliver I&C to cancer cells expressing the Prostate Specific Membrane Antigen (PSMA). Method—We prepared targeted NPs in a single-step by mixing four different precursors inside microfluidic devices. Results—I&C were encapsulated in 55-nm NPs and showed an 8-fold increase in internalization by PSMA-expressing LNCaP cells compared to non-targeted NPs. NPs co-encapsulating both drugs exhibited strong synergism in LNCaP cells with a combination index of 0.2. Conclusion—The strategy of co-encapsulating both irinotecan and cisplatin in a single NP targeted to a specific cell type could potentially be used to treat different types of cancer. *To whom correspondence should be addressed: Omid C. Farokhzad, Laboratory of Nanomedicine and Biomaterials and Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115. Fax: 617-730-2801 [email protected]. Rohit Karnik, Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. Fax: 617-324-2805 [email protected]. FINANCIAL DISCLSURE O.C.F and R.L have financial interests in BIND Biosciences and Selecta Biosciences. O.C.F., R.L. and S.J.L. have financial interests in Blend Therapeutics. We thank the Koch Institute Flow Cytometry Core at MIT for the use of FACS and the Center for Material Science and Engineering (CMSE) imaging facility for the electron microscopy image acquisition. This research was supported by the Koch-Prostate Cancer Foundation Award in Nanotherapeutics (R.L. and O.C.F.) and by the NCI Center of Cancer Nanotechnology Excellence at MIT-Harvard (U54-CA151884). P.M.V. is supported by NSF graduate research fellowship. E.MP. is supported by a NDSEG graduate research fellowship. No writing assistance was utilized in the production of this manuscript. NIH Public Access Author Manuscript Nanomedicine (Lond). Author manuscript; available in PMC 2014 May 01. Published in final edited form as: Nanomedicine (Lond). 2013 May ; 8(5): 687–698. doi:10.2217/nnm.12.134. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript