Abstract B05: Self-assembling platinum-acridine loaded carbon nanotubes for triple-negative breast cancer chemotherapy
Authors: Fahrenholtz Cale D. , Ding Song , Bernish Brian W. , Wright Mariah , Bierbach Ulrich , Singh Ravi N. 
Published: May 2016

Abstract
Triple-negative breast cancer (TNBC) accounts for 10-15% of breast cancers, has the highest levels of recurrence, and the lowest five-year survival of all breast cancer subtypes. TNBC does not express estrogen or progesterone receptors and does not overexpress HER2 receptors. Therefore, TNBC does not benefit from current FDA-approved targeted therapies against HER2 or hormone-positive cancers. Early clinical trials show that TNBC is susceptible to platinum chemotherapy, but dose-limiting toxicities and cross-resistance amongst current FDA-approved platinum agents may limit clinical efficacy. To address this issue, we have developed a novel drug delivery system consisting of a potent, non-classical platinum chemotherapeutic that self-assembles onto the surface of carbon nanotubes. Our pharmacophore, termed platinum-acridines (PA), is an anticancer agent composed of a platinum group modified with an acridine. The platinum-group of the PA functions to bind and platinate DNA, while the acridine group functions as a classical DNA intercalator. This coordination allows for platination of DNA near the intercalation site, leading to a more severe form of damage than the crosslinks induced by cisplatin which may increase potency and limit cross-resistance. Platinum-acridines show efficacy against breast cancer in vitro, but preclinical studies show a possibility of dose-limiting toxicities; thus PA may be most beneficial specifically delivered to the tumor using a nanocarrier such as carbon nanotubes (CNT). Carbon nanotubes have a large surface area to volume ratio for high capacity drug loading, can be made safe for systemic administration, and selectively accumulate in tumors due the enhanced permeability and retention (EPR) effect. Platinum-acridines readily adsorb onto biocompatible carbon nanotubes (CNTs) through non-covalent pi stacking. Therefore, CNTs can be used for controlled delivery of high dose platinum chemotherapy to the tumor and may decrease dose-limiting toxicities. Transmission electron microscopy confirmed that PA loads onto biocompatible CNTs. We found that these platinum-acridine loaded carbon nanotubes (PA-CNTs) are stable in physiological solution for extended periods of time. PA-CNTs were found intracellularly and successfully delivered PA chemotherapy to MDA-MB-231 TNBC cells. Furthermore, PA-CNTs were cytotoxic to several models of TNBC (MDA-MB-231, MDA-MB-468, SUM159, BT20); whereas, control CNTs were not appreciably cytotoxic. PA-CNTs induced non-apoptotic cell death in MDA-MB-231 breast cancer cells, whereas free PA favored apoptosis. Our nanotube-mediated delivery system is also readily adaptable to load a variety of cargo such as imaging agents or additional chemotherapeutics for multi-modal therapy and diagnostic applications. These findings indicate our self-assembling carbon nanotube delivery system loaded with platinum-acridines may be beneficial for the treatment of triple-negative breast cancer and warrants further preclinical evaluation.
Citation Format: Cale D. Fahrenholtz, Song Ding, Brian W. Bernish, Mariah Wright, Ulrich Bierbach, Ravi N. Singh. Self-assembling platinum-acridine loaded carbon nanotubes for triple-negative breast cancer chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B05.