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Targeted Delivery of Gemcitabine to Pancreatic Adenocarcinoma Using Cetuximab as a Targeting Agent

Departments of ¹ Biochemistry and Molecular Biology, ² Orthopedic Research, ³ Pharmacology and Experimental Therapeutics, and ⁴ Biomedical Engineering, Mayo Clinic, Rochester, Minnesota

Requests for reprints: Priyabrata Mukherjee, Department of Biochemistry and Molecular Biology, Department of Biomedical Engineering, Mayo Clinic, Rochester, MN 55905. Phone: 507-284-8563; Fax: 507-284-1767; E-mail: mukherjee.priyabrata{at}mayo.edu.

Key Words: gold nanoparticles • targeted delivery • pancreatic cancer • orthotopic model

One of the key challenges in anticancer therapy is the toxicity and poor bioavailability of the anticancer drugs. Nanotechnology can play a pivotal role by delivering drugs in a targeted fashion to the malignant cells that will reduce the systemic toxicity of the anticancer drug. In this report, we show a stepwise development of a nanoparticle-based targeted delivery system for in vitro and in vivo therapeutic application in pancreatic cancer. In the first part of the study, we have shown the fabrication and characterization of the delivery system containing gold nanoparticle as a delivery vehicle, cetuximab as a targeting agent, and gemcitabine as an anticancer drug for in vitro application. Nanoconjugate was first characterized physico-chemically. In vitro targeting efficacy, tested against three pancreatic cancer cell lines (PANC-1, AsPC-1, and MIA Paca2) with variable epidermal growth factor receptor (EGFR) expression, showed that gold uptake correlated with EGFR expression. In the second part, we showed the in vivo therapeutic efficacy of the targeted delivery system. Administration of this targeted delivery system resulted in significant inhibition of pancreatic tumor cell proliferation in vitro and orthotopic pancreatic tumor growth in vivo. Tumor progression was monitored noninvasively by measuring bioluminescence of the implanted tumor cells. Pharmacokinetic experiments along with the quantitation of gold both in vitro and in vivo further confirmed that the inhibition of tumor growth was due to targeted delivery. This strategy could be used as a generalized approach for the treatment of a variety of cancers characterized by overexpression of EGFR. [Cancer Res 2008;68(6):1970–8]