PLoS One. 2013 May 2;8(5):e62289.

Synthesis and biological evaluation of novel folic acid receptor-targeted, β-cyclodextrin-based drug complexes for cancer treatment.

Yin JJ, Sharma S, Shumyak SP, Wang ZX, Zhou ZW, Zhang Y, Guo P, Li CZ, Kanwar JR, Yang T, Mohapatra SS, Liu W, Duan W, Wang JC, Li Q, Zhang X, Tan J, Jia L, Liang J, Wei MQ, Li X, Zhou SF.

Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, United States of America.

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 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.

PMID: 23658721

 

SUPPLEMENT:

Nano-scaled, targeted drug delivery has attracted much attention as a means to maximize the efficacy of anticancer drugs and minimize untoward side effects such as nonspecific toxicity in the past decade. Targeting drug delivery strategies have been confirmed to be an effective approach to prevent the shortcomings of chemotherapy. Among various approaches to specifically target drug-loaded carrier systems to the required pathological sites, ligand-attached cyclodextrin-based targeting complexes are a promising drug delivery system, which is achieved mainly through specific molecular interactions between the drugs and cell surface receptors though active targeting. The principal targeting tactics include conjugation of cyclodextrin with targeting moieties or encapsulation drugs in cyclodextrins. While preparation and characterization of nanodrug formulations especially for aqueous drug complexes based on cyclodextrin remains a major challenge.

Herein, we report a facile method for synthesizing a novel and effective drug complex for folate receptor targeted drug delivery for chemotherapeutics. Folate receptor is highly frequently overexpressed on a wide range of primary and metastatic human cancers, while FR has the limited distribution in normal tissues, which has led to the exploitation of FA as an important ligand for specific targeting by diagnostic or therapeutic agents. Combining targeting molecules, drug carriers and cytotoxic agents into a complex should guarantee the stability of the conjugate in circulation and insure cleavability to release the drug. In our study, the β-CD was vectorized with folic acid to target folate receptors on the tumor cell surface. For the first time, Dox-containing folic acid receptor targeting β -CDs were synthesized by a multi-step reaction in which α- and γ-amide monomers as well as the di-CD substituted folic acid carrier were purified and fully characterized by a panel of spectral techniques. Our results show that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive carcinomatous cells. The novel folic acid-conjugated β-CD vectors reported here might be promising as anti-tumor drug carriers for the delivery of a great variety of chemotherapeutics. Importantly, the rational design of the tumor-site targeting based on cyclodextrins conjugated with tumor biomakers can optimize the cure efficiency and minimize the size effect to normal tissues in tumor treatment.

Figure-11Figure 1. The multifunctional, folic acid bound, cyclodextrin based drug complexes with tumor site-specific drug delivery. Folic acid with high-tumor affinity due to the overexpression of its receptors was conjugated onto the cyclodextrins for the specific delivery of adamantane-doxrorubicin through receptor mediated active targeting.
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