Abstract 4559: Synthesis and biological evaluation of a novel cancer treatment based on folic acid receptor-targeted, β-cyclodextrin-based drug complexes.
Authors: Yin Juan-Juan , Zhou Shufeng 
Published: August 2014

Drug targeting is a very active area of research and nano-scaled drug delivery systems hold tremendous potential for improving the therapeutic efficacy of neoplasms while the side effects are reduced. The folate receptor (FR) is highly over-expressed (&gt;90%) on primary and metastatic human cancers of the ovary, lung, breast, colon, endometrium, kidney, and brain. Cyclodextrin (CDs) are widely used as functional macrocyclic host molecules in supramolecular chemistry due to their low cost, water solubility, and biocompatible properties, along with their substantial ability to entrap drug molecules within their internal cavity. In this study, a novel CD-based nanoparticle drug delivery system has been assembled and investigated for the treatment of FR-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and the structures were characterized by 1D/2D NMR (g-COSY, HMBC, and HMQC), UV spectroscopy, FTIR, HR-MALDI-TOF-MS, and HPLC. Drug complexes of cytotoxic adamatane (Ada) and doxorubicin (Dox) with FA-conjugated β-CD were readily obtained by mixed solvent precipitation. The host-guest association constant, Ka, was 1,639 M−1 as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. The interaction of Ada-Dox with CDs resulted in β-CD with an inner-cavity diameter of ∼7.0 Å. The adamantyl group of Ada-Dox also had a diameter of ∼7 Å, and it has been confirmed that the strongest binding occurred between adamantine and β-CD, consistent with the near-perfect match between the cavity and guest diameter. The conjugation of Dox with FA greatly improved its cytotoxicity in comparison with the prodrug Ada-Dox and non-targeting drug complex, N-FACD-Ada-Dox, specifically to FR (+) JAR cells. Sustained in vitro drug release was seen and delivery of Dox into FR (+) cancer cells via endocytosis was observed by confocal microscopy. Drug uptake of the targeted nanoparticles was eightfold greater than that of non-targeting drug complexes in FR(+) cancer cells. Normal fibroblast cells exposed to the FA-targeted Dox complexes had lower levels of reactive oxygen species (ROS), with increased activity of both glutathione (GSH) and glutathione peroxidase (GPx), indicating a reduced potential for Dox cardiotoxicity. In conclusion, we have reported the successful synthesis and purification of novel water soluble, folic acid-conjugated β-cyclodextrin-based targeting drug supramolecules with adamantine-doxorubicin as the therapeutic cargo. The FR-targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability.

Citation Format: Juan-Juan Yin, Shufeng Zhou. Synthesis and biological evaluation of a novel cancer treatment based on folic acid receptor-targeted, β-cyclodextrin-based drug complexes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4559. doi:10.1158/1538-7445.AM2013-4559