摘要：

MM-398 is a stable nanotherapeutic encapsulation of the pro-drug irinotecan (CPT-11). Irinotecan, a topoisomerase inhibitor is currently being used in clinical practice for treatment of several indications; however, associated toxicities, mainly, neutropenia and gastrointestinal toxicity, have limited its clinical utility. Previously, we have demonstrated that MM-398 treatment resulted in significantly higher intratumor concentrations of both irinotecan (142-fold) and SN-38 (9-fold), thereby exhibiting enhanced anti-tumor activity compared to free irinotecan in different xenograft models. Multiple phase 1 and 2 studies have established a pharmacokinetic and safety profile. Recent data support continued clinical development for the drug in various indications, including pancreatic, gastric, colorectal and potentially other solid tumors. In order to further understand the enhanced anti-tumor activity of MM-398 we developed a mechanism-based PK model of MM-398 and free irinotecan designed to predict intratumor levels of SN-38. Based on this model, we evaluated the role of various determinants of response of MM-398. Sensitivity analysis revealed that the local activation of MM-398 was important for obtaining higher SN-38 intratumor levels compared to free irinotecan. To identify cell types responsible for local activation of MM-398 we investigated cellular liposome phagocytosis ability. In vitro studies demonstrated preferential uptake of MM-398 by phagocytic macrophages compared to tumor cells. FACS analysis of tumor samples (from subcutaneous xenografts) highlighted higher uptake of labeled liposomes by CD11b + and F4/80+ cells as compared to tumor cells. We are developing in vivo systems using engineered cell lines overexpressing growth factors to recruit macrophages (CSF1) or overexpressing irinotecan conversion enzymes to further investigate the role of macrophagesin local tumor conversion of MM-398 and to validate the model prediction that local activation is critical to MM-398 mechanism of action. The extent of tumor vascularization and permeability were also highlighted in the sensitivity analysis. To determine the effect of MM-398 on these parameters, we treated mice bearing HT29 (colorectal cancer) xenografts with a single dose of MM-398 and measured hypoxic markers (CAIX) and microvessel density (CD31) by immunohistochemistry. Tumors treated with MM-398 showed a greater degree of CD31 staining and lower CAIX staining, indicating that MM-398 may be able to affect the tumor microenvironment. We are currently evaluating how the ability of MM-398 to alter the tumor microenvironment affects the activity of other chemotherapeutic agents in combination therapy. These findings could support the use of MM-398 as a combination modality against tumors that may have acquired resistance to traditional chemotherapeutic agents.

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