Abstract 4467: Treating brain tumors with targeted-micelles containing rapamycin (2014)

Abstract The development of selectively targeted nanoparticles that can act as drug delivery vehicles is critical for improving the treatment and monitoring of glioblastoma, a life threatening disease. Rapamycin (Sirolimus, rapa), a large, lipophilic carboxylic lactone-lactam macrolide antibiotic, is recognized for its potent anti-proliferative and immunosuppressive effects in vitro and in vivo. These properties make rapa a potential chemotherapeutic agent against several tumors. Despite its promising properties, clinical applications of rapa have been limited due to its hydrophobicity, limiting its utility as an intravenously administered drug. Presently, the commercially available formulations of rapa include tablet or oral forms. Nevertheless, the low oral bioavailability of rapa limits the effectiveness of both of these forms. In addition, the lipophilicity makes the drug susceptible to attachment to the lipid membranes of normal as well as cancer cells. A selectively targeted carrier for rapa will enhance its delivery to malignant cells, avoid non-specific interactions, and reduce non-tumor toxicity. In order to design an efficient and effective drug carrier, we created a multifunctional nanocarrier that contains a tailored surface on the carrier to attach biomolecules for targeted drug delivery; a biocompatible coating which can efficiently encapsulate the hydrophobic drug thereby reducing cytotoxicity; and the capability for stimuli-induced (pH) disruption of the carrier agent for slow and controlled drug release to the desired environment, Micelles are the preferred choice of carrier as they fulfill these requirements based on their composition. Micelles containing rapamycin drug are synthesized using PEG-PE-Amine and N-palmitoyl homocysteine (PHC, pH sensitive lipid breaks in endosome pH 5.5). Specific targeting of the micelles to glioblastoma cells is achieved by PDGF (platelet derived growth factor) or EGF (epidermal growth factor) coupled to the amine moeity of the DSPE-PEG. In addition these micelles have been labeled with a NIR fluorphore to track them for cellular uptake. These micelles have an advantage of small size (&lt;50 nm, to cross blood brain barrier) and reduced toxicity due to robust packaging of rapa drug inside the core. Leaching of the drug out of the micelle is prevented and reduces offsite cytotoxicity. Preliminary cellular uptake studies via fluorescence imaging of glioblastoma cells treated with targeted and untargeted labeled-micellar particles demonstrate receptor-mediated endocytosis. Uptake occurs rapidly within 1 to 4 hours after treatment. Once released from the micelle, the rapa kills the cells. Future experiments involve performing cytotoxicity assays, pharmacokinetic and tissue distribution studies in in vivo animal models. Note: This abstract was not presented at the meeting. Citation Format: Ann-Marie Broome, Suraj K. Dixit, Kayla Miller, Alfred Moore, Amy-Lee Bredlau. Treating brain tumors with targeted-micelles containing rapamycin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4467. doi:10.1158/1538-7445.AM2014-4467