Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, β-Cyclodextrin-Based Drug Complexes for Cancer Treatment

Authors

Juan-Juan Yin, University of South Florida, Department of Pharmaceutical Sciences, College of Pharmacy
Sonali Sharma, University of South Florida, Department of Pharmaceutical Sciences, College of Pharmacy
Stepan P. Shumyak, University of South Florida, Department of Pharmaceutical Sciences, College of Pharmacy
Zhi-Xin Wang, University of South Florida, Department of Pharmaceutical Sciences, College of Pharmacy
Zhi-Wei Zhou, University of South Florida, Department of Pharmaceutical Sciences, College of Pharmacy
Yangde Zhang, Central South University, Changsha, Hunan, China, National Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital
Peixuan Guo, University of Kentucky, Nanobiotechnology Center and Markey Cancer Center, College of Pharmacy
Chen-Zhong Li, Florida International University, Nanobioengineering and Bioelectronics Laboratory, Department of Biomedical EngineeringFollow
Jagat R. Kanwar, Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (LIMBR), Centre for Biotechnology and Interdisciplinary Biosciences and Institute for Frontier Materials (IFM), Deakin University, Waurn Ponds, Victoria, Australia
Tianxin Yang, University of Utah, Department of Internal Medicine and Salt Lake Veterans Affairs Medical Center
Shyam S. Mohapatra, University of South Florida, Nanomedicine Research Center and Division of Translational Medicine, Department of Internal Medicine, Morsani College of Medicine
Wanqing Liu, Purdue University, Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy
Wei Duan, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
Jian-Cheng Wang, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Science, Peking University, Beijing, China
Qi Li, Department of Oncology, Shuguang Hospital (Western Campus), Shanghai University of Traditional Chinese Medicine, Shanghai, China
Xueji Zhang, Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, China
Jun Tan, James A. Haley Veterans' Administration Hospital, Tampa, Florida; Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, Morsani College of Medicine, University of South Florida; Department of Psychiatry and Behavioral Neurosciences, Silver Child Development Center, Rashid Laboratory for Developmental Neurobiology, Morsani College of Medicine, University of South Florida
Lee Jia, Cancer Metastasis Alert and Prevention Center, College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, China
Jun Liang, University of South Florida, Department of Pharmaceutical Sciences, College of Pharmacy
Ming Q. Wei, School of Medical Science, Division of Molecular and Gene Therapies, Griffith Health Institute, Griffith University, Gold Coast Campus, Australia
Xioatian Lee, Obstetrics and Gynecology Hospital and Institute of Biomedicine, Fudan University, Shanghai, China
Shu-Feng Zhou, University of South Florida, Department of Pharmaceutical Sciences, College of Pharmacy

Date of this Version

5-2-2013

Document Type

Article

Abstract

Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5–2.5 nm. 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. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated β-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.

Comments

This article was originally published in PLOS One.

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This work is licensed under a Creative Commons Attribution 3.0 License.

Recommended Citation

Yin J-J, Sharma S, Shumyak SP, Wang Z-X, Zhou Z-W, et al. (2013) Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, β-Cyclodextrin-Based Drug Complexes for Cancer Treatment. PLoS ONE 8(5): e62289. doi:10.1371/journal.pone.0062289