Abstract
Triolimus is a first-in-class, multidrug-loaded micelle containing paclitaxel, rapamycin, and 17-AAG. In this study, we examine the antitumor mechanisms of action, efficacy, and toxicity of Triolimus in vitro and in vivo. In vitro cytotoxicity testing of Triolimus was conducted using two aggressive adenocarcinomas including the lung cancer cell line, A549, and breast cancer cell line, MDA-MB-231. The three-drug combination of paclitaxel, rapamycin, and 17-AAG displayed potent cytotoxic synergy in both A549 and MDA-MB-231 cell lines. Mechanistically, the drug combination inhibited both the Ras/Raf/mitogen-activated protein kinase and PI3K/Akt/mTOR pathways. Triolimus was advanced into tumor xenograft models for assessment of efficacy, toxicity, and mechanisms of action. In vivo, a three-infusion schedule of Triolimus inhibited A549 and MDA-MB-231 tumor growth far more potently than paclitaxel-containing micelles and effected tumor cures in MDA-MB-231 tumor-bearing animals. Tumor growth delays resulted from a doubling in tumor cell apoptosis and a 50% reduction in tumor cell proliferation compared with paclitaxel-containing micelles. Enhanced antitumor efficacy was achieved without clinically significant increases in acute toxicity. Thus, Triolimus displays potent synergistic activity in vitro and antitumor activity in vivo with comparable toxicity to paclitaxel. These observations provide strong support for further development of Triolimus and an important proof of concept for safe, effective nanoparticle-based delivery of three complementary anticancer agents.