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

Autor: Zhi Xin Wang, Zhi Wei Zhou, Jun Tan, Shu-Feng Zhou, Jian Cheng Wang, Chen-Zhong Li, Ming Q. Wei, Juan Juan Yin, Jun Liang, Shyam S. Mohapatra, Wei Duan, Wanqing Liu, Qi Li, Tianxin Yang, Stepan P. Shumyak, Sonali Sharma, Xueji Zhang, Peixuan Guo, Xiaotian Li, Jagat R. Kanwar, Yangde Zhang, Lee Jia
Rok vydání: 2013
Předmět:
Circular dichroism
Protein Conformation
Intracellular Space
Cancer Treatment
Beta-Cyclodextrins
Chemistry Techniques
Synthetic
Mice
Drug Discovery
Nanotechnology
Myocytes
Cardiac
Drug Distribution
chemistry.chemical_classification
Drug Carriers
Multidisciplinary
Cyclodextrin
beta-Cyclodextrins
Glutathione
Molecular Docking Simulation
Oncology
Biochemistry
Drug delivery
Medicine
Hedgehog interacting protein
Drug carrier
Research Article
Biotechnology
Drugs and Devices
Drug Research and Development
Science
Materials Science
Antineoplastic Agents
Drug Absorption
Folic Acid
Cell Line
Tumor
Animals
Humans
Pharmacokinetics
Particle Size
Biology
Glutathione Peroxidase
Cancers and Neoplasms
Biological Transport
Fibroblasts
Chemotherapy and Drug Treatment
Amides
chemistry
Targeted drug delivery
Doxorubicin
Docking (molecular)
Bionanotechnology
Reactive Oxygen Species
Folic Acid Transporters
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 5, p e62289 (2013)
ISSN: 1932-6203
Popis: 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 β-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.
Databáze: OpenAIRE
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