However, in the recent PRODIGE 4/ACCORD 11 trial, Conroy et al demonstrated that a gemcitabine-free, CPT-11-containing regimen, FOLFIRINOX (CPT-11, oxaliplatin plus intermittent infusion of 5-FU/leucovorin), provided significantly better objective tumor response rate, progression-free survival and overall survival versus gemcitabine monotherapy in patients with metastatic VX-809 mouse pancreatic cancer. Notable and not unexpectedly, this triplet regimen is associated with significant hematologic toxicity including higher rates of grade-3/4 febrile neutropenia.

The results of the PRODIGE/ACCORD 11 trial have revived interest in CPT-11-based therapy in advanced pancreatic cancer (6),(7). Inhibitors,research,lifescience,medical Although the original CPT-11 drug is now of interest in pancreatic cancer management, potentially superior versions incorporating drug delivery technologies offer a next generation approach. CPT-11 exhibits well-known pharmacologic Inhibitors,research,lifescience,medical liabilities and significant associated toxicities, which in turn make it an obvious candidate for drug delivery

strategies The camptothecins exist in a pH-dependent equilibrium between an inactive carboxylate form (predominant Inhibitors,research,lifescience,medical at neutral-to-basic pH) and an active lactone form (predominant under acidic conditions); hence, intravenous injection of free CPT-11 results in rapid inactivation as well as clearance. Furthermore, CPT-11 is largely a prodrug which is converted Inhibitors,research,lifescience,medical into the much more potent metabolite SN-38. Hepatic activation and hepatobiliary excretion of SN-38 result in substantial risk of GI injury, especially in individuals having impaired SN-38 glucuronidation. These metabolic conversions contribute to notable heterogeneities in both Inhibitors,research,lifescience,medical efficacy and toxicity, and ultimately to a rather narrow therapeutic index. The concept of nanoparticle delivery of CPT-11 is thus very attractive based on potential advantages including: overcoming solubility limitations of the camptothecins; protecting drug in the active lactone

configuration; chaperoning drug away from sites of toxicity such as the GI tract; prolonging circulation time and increasing tumor accumulation via the enhanced permeability and retention (EPR) effect; and providing sustained release and prolonged tumor exposure. To realize the potential advantages of nanoparticle delivery, a novel liposome-based construct termed “nanoliposomal those CPT-11 (nLs-CPT-11)” was developed, which encapsulates CPT-11 with unprecedented efficiency and stability (27). PK studies showed long circulation times for the carrier and undetectable drug release in plasma. Furthermore, nanoliposomal CPT-11 provides protection of drug in its active lactone form within the liposome aqueous interior, preventing its hydrolysis as well as premature conversion to the potent and toxigenic metabolite, SN-38.