Abstract 5516: Biodistribution of liposomal docetaxel prodrug MNK-010 in mice bearing A549 human NSCLC xenografts

Abstract

Abstract The anti-mitotic taxanes belong to one of the most important families of anticancer drugs that have broad anti-tumor activity and are widely used for a variety of human cancer types. However, the taxanes are limited by a number of serious pharmacological and toxicological effects. We are developing a unique delivery system for docetaxel, comprised of a PEGylated liposomal nanoparticle containing a prodrug of docetaxel to improve solubility, tolerability and increase efficacy through improved pharmacokinetics and biodistribution. In this study we evaluated the biodistribution of MNK-010, a liposomal formulation of a docetaxel prodrug in immunodeficient mice bearing A549 Human Non-Small Cell Lung Carcinoma (NSCLC) xenografts. This study tested the hypothesis that MNK-010 can produce greater plasma and tumor accumulation of docetaxel than with delivery of standard of care free docetaxel in tumor-bearing mice. Female nude mice bearing A549 human NSCLC xenografts were given a single intravenous (IV) dose of MNK-010 (40 mg/kg docetaxel molar equivalent) or free docetaxel (50 mg/kg). For each treatment group, three animals were sacrificed at various time points between 1 hr and 504 hr post injection. After euthanasia, blood, tumor, liver, kidney, spleen, lung and skeletal muscle specimens were collected. Tissue and blood samples were assayed to determine docetaxel concentrations. Administration of MNK-010 IV provided a reservoir for the continual slow release of docetaxel in the circulation and in tumors. MNK-010 increased systemic docetaxel exposure (AUC) ten-fold greater than free docetaxel injected at similar doses. MNK-010 produced sustained docetaxel levels in tumor through the 21 day observation period, resulting in four-fold greater docetaxel tumor exposure (AUC) compared to free docetaxel. The increase in MNK-010 plasma exposure as well as the enhanced permeability effect observed with liposomes likely contributed to the increased tumor exposure. In addition to improved accumulating in tumor tissue, docetaxel derived from MNK-010 also accumulated in liver, spleen and kidney. These tissues contain phagocytic cells (macrophages or mesangial) and serve as organs of elimination for chemotherapeutics. Docetaxel derived from MNK-010 was not detectable in skeletal muscle and was only found in lung over the first 24 hours post administration. In contrast, IV injection of free docetaxel produced high initial concentrations of docetaxel in all tissues evaluated, before falling quickly over time. Tumor levels decreased below levels of quantitation after nine days. This study demonstrated that Mallinckrodt Pharmaceuticals’ PEGylated liposomal docetaxel prodrug MNK-010 provided a reservoir for the continual release of docetaxel into the systemic circulation and produced an enhanced accumulation of docetaxel in A549 human NSCLC xenografts in mice compared to the standard of care docetaxel. Citation Format: Richard M. Fitch, James H. Wible, James A. Blackledge, William D. McGhee. Biodistribution of liposomal docetaxel prodrug MNK-010 in mice bearing A549 human NSCLC xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5516. doi:10.1158/1538-7445.AM2015-5516