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学科主题: 药学
题名:
Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, beta-Cyclodextrin-Based Drug Complexes for Cancer Treatment
作者: Yin, Juan-Juan1; Sharma, Sonali1; Shumyak, Stepan P.1; Wang, Zhi-Xin1; Zhou, Zhi-Wei1; Zhang, Yangde2; Guo, Peixuan3; Li, Chen-Zhong4; Kanwar, Jagat R.5,6; Yang, Tianxin7,8; Mohapatra, Shyam S.9,10; Liu, Wanqing11; Duan, Wei12; Wang, Jian-Cheng13; Li, Qi14; Zhang, Xueji15; Tan, Jun16,18; Jia, Lee13; Liang, Jun1,17,19; Wei, Ming Q.20; Li, Xiaotian21,22; Zhou, Shu-Feng1
刊名: PLOS ONE
发表日期: 2013-05-02
DOI: 10.1371/journal.pone.0062289
卷: 8, 期:5
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Multidisciplinary Sciences
研究领域[WOS]: Science & Technology - Other Topics
关键词[WOS]: HUMAN CYTOCHROME-P450 2D6 ; CHINESE HERBAL MEDICINE ; MOLECULAR DOCKING ; DELIVERY SYSTEMS ; FOLATE ; DOXORUBICIN ; BINDING ; LIGAND ; CARDIOTOXICITY ; ANTHRACYCLINES
英文摘要:

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 K-a 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 beta-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.

语种: 英语
项目资助者: College of Pharmacy, University of South Florida, Tampa, Florida
WOS记录号: WOS:000321200500022
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/59442
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Deakin Univ, Inst Frontier Mat, Waurn Ponds, Vic, Australia
2.Salt Lake Vet Affairs Med Ctr, Salt Lake City, UT USA
3.Univ S Florida, Coll Pharm, Dept Pharmaceut Sci, Tampa, FL 33620 USA
4.Cent S Univ, Natl Hepatobiliary & Enter Surg Res Ctr, Changsha, Hunan, Peoples R China
5.Univ Kentucky, Coll Pharm, Nanobiotechnol Ctr & Markey Canc Ctr, Lexington, KY USA
6.Florida Int Univ, Nanobioengn & Bioelect Lab, Dept Biomed Engn, Miami, FL 33199 USA
7.Deakin Univ, Nanomed Lab Immunol & Mol Biomed Res LIMBR, Ctr Biotechnol & Interdisciplinary Biosci, Waurn Ponds, Vic, Australia
8.Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA
9.Univ S Florida, Nanomed Res Ctr, Tampa, FL USA
10.Univ S Florida, Dept Internal Med, Div Translat Med, Morsani Coll Med, Tampa, FL 33612 USA
11.Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, Indiana, PA USA
12.Deakin Univ, Sch Med, Waurn Ponds, Vic, Australia
13.Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100871, Peoples R China
14.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Oncol, Shanghai, Peoples R China
15.Univ Sci & Technol Beijing, Res Ctr Bioengineering & Sensing Technol, Beijing 100083, Peoples R China
16.James A Haley Vet Adm Hosp, Tampa, FL USA
17.Univ S Florida, Dept Neurosurg & Brain Repair, Ctr Excellence Aging & Brain Repair, Morsani Coll Med, Tampa, FL USA
18.Univ S Florida, Dept Psychiat & Behav Neurosci, Morsani Coll Med, Silver Child Dev Ctr,Rashid Lab Dev Neurobiol, Tampa, FL USA
19.Fuzhou Univ, Coll Chem & Chem Engn, Canc Metastasis Alert & Prevent Ctr, Fuzhou 350002, Peoples R China
20.Griffith Univ, Griffith Hlth Inst, Div Mol & Gene Therapies, Sch Med Sci, Nathan, Qld 4111, Australia
21.Fudan Univ, Obstet & Gynecol Hosp, Shanghai 200433, Peoples R China
22.Fudan Univ, Inst Biomed, Shanghai, Peoples R China

Recommended Citation:
Yin, Juan-Juan,Sharma, Sonali,Shumyak, Stepan P.,et al. Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, beta-Cyclodextrin-Based Drug Complexes for Cancer Treatment[J]. PLOS ONE,2013,8(5).
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