Nanoparticle albumin-bound (nab) rapamycin as an anticancer agent

4719 Background: The mammalian target of rapamycin (mTOR) is involved in the control of cellular growth and proliferation. Abnormal activation of signaling pathways both proximal and distal to this kinase occurs frequently in human cancer, making mTOR an attractive target for antineoplastic therapies. Due to insolubility and poor bioavailability of rapamycin, water soluble analogs, such as CCI-779, RAD001 and AP23573 are in development, which have demonstrated potent antitumor activity in vitro and in xenograft models. Here we report on rapamycin albumin-bound nanoparticles using nanoparticle albumin-bound (nab) technology, which allows the direct administration of the drug at high dose. Methods: Overall toxicity of nab-rapamycin was determined in a dose-ranging study in Sprague-Dawley rats. The dose levels of nab-rapamycin used were 0, 15, 30, 45, 90, and 180 mg/kg with a q4dx3 schedule. Pharmacokinetics (PK) of nab-rapamycin was investigated in Sprague-Dawley rats at dose levels of 1, 15, 30, and 45 mg/kg. Antitumor activity of nab-rapamycin was examined using three tumor models in athymic mice (MX-1, breast, N=5; HCT-116, colon, N=10; and HT29, colon, N=8) at a dose level of 40 mg/kg with a 3x wkly/4wks schedule. Tumor growth data were analyzed by ANOVA. Results: nab-Rapamycin was nontoxic at the highest dose of 180 mg/kg on a q4dx3 schedule. No changes in blood chemistry,CBC, hypercholesterolemia, or hypertriglyceridemia were observed. nab-Rapamycin exhibited linear PK with respect to dose and rapid extravascular distribution as demonstrated by large Vss and Vz, and typical for nab technology, e.g. nab-paclitaxel and nab-docetaxel. nab-Rapamycin was highly effective against all tumor models tested, achieving a tumor growth inhibition (TGI) of 80.7% against HT29 xenograft (p Conclusion: nab-Rapamycin was well tolerated, showed linear PK, and was highly effective against a number of tumor models in vivo.