Abstract
A major challenge in the clinical use of cytotoxic chemotherapeutics is maximizing efficacy in tumors while sparing normal tissue. Irinotecan is used for colorectal cancer treatment but the extent of its use is limited by toxic side effects. Liposomal delivery systems offer tools to modify pharmacokinetic and safety profiles of cytotoxic drugs. In this study, we defined parameters that maximize the antitumor activity of a nanoliposomal formulation of irinotecan (nal-IRI). In a mouse xenograft model of human colon carcinoma, nal-IRI dosing could achieve higher intratumoral levels of the prodrug irinotecan and its active metabolite SN-38 compared with free irinotecan. For example, nal-IRI administered at doses 5-fold lower than free irinotecan achieved similar intratumoral exposure of SN-38 but with superior antitumor activity. Tumor response and pharmacokinetic modeling identified the duration for which concentrations of SN-38 persisted above a critical intratumoral threshold of 120 nmol/L as determinant for antitumor activity. We identified tumor permeability and carboxylesterase activity needed for prodrug activation as critical factors in achieving longer duration of SN-38 in tumors. Simulations varying tumor permeability and carboxylesterase activity predicted a concave increase in tumor SN-38 duration, which was confirmed experimentally in 13 tumor xenograft models. Tumors in which higher SN-38 duration was achieved displayed more robust growth inhibition compared with tumors with lower SN-38 duration, confirming the importance of this factor in drug response. Overall, our work shows how liposomal encapsulation of irinotecan can safely improve its antitumor activity in preclinical models by enhancing accumulation of its active metabolite within the tumor microenvironment.
Highlights
Liposomal carriers have become clinically accepted in cancer therapy as delivery systems that can enhance the utility of existing anticancer drugs [1]
The pharmacokinetic profiles of the prodrug CPT-11 and its active metabolite SN-38 were measured in plasma and tumors following administration of either free irinotecan or nanoliposomal formulation of irinotecan (nal-IRI) (Fig. 1A)
Nal-IRI Activity Depends on CPT-11 Deposition and Activation
Summary
Liposomal carriers have become clinically accepted in cancer therapy as delivery systems that can enhance the utility of existing anticancer drugs [1]. The potential benefits of these macromolecular carriers include overcoming solubility issues for certain drug classes, protecting the drug from unwanted metabolism and extending the residence time in plasma and tissue. Liposomes tend to preferentially accumulate in tumors as a result of an enhanced permeability and retention (EPR) effect. The EPR effect is attributed to the abnormal tumor vasculature permitting extravasation of macromolecules, as well as impaired lymphatic drainage that promote the retention of these molecules within the tumor microenvironment, thereby providing sustained release at the tumor site mimicking a metronomic dosing [2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)
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