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.
Highlights
IntroductionCancer is a leading killer of human beings worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in 2008 [1]
Cancer is a leading killer of human beings worldwide, accounting for 7.6 million deaths in 2008 [1]
Ammonium molybdate tetrahydrate was purchased from Alfa Aesar Inc. (Ward Hill, MA). p-Toluenesulfonyl chloride, N, N’-dicyclohexyl-carbodiimide (DCC), folic acid (FA), Nhydroxysuccinimide (NHS), doxorubicin hydrochloride, 1-adamantanecarbonyl chloride, ammonium bicarbonate, sodium azide, triphenylphosphine, 29, 79-dichlorofluorescein diacetate (DCFHDA), 5, 59-dithiobis(2-nitrobenzoic acid) (DTNB), reduced glutathione (GSH), hydrogen peroxide, potassium hydroxide, sodium hydroxide, phosphoric acid, ammonia hydroxide, ninhydrin, hydrochloric acid, iodine, sulfuric acid, acetic acid, deuterium oxide, chloroform-d, dimethyl sulfoxide-d6, and CM sephadex C25 were all purchased from Sigma-Aldrich Chemicals Co
Summary
Cancer is a leading killer of human beings worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in 2008 [1]. The four major modules of cancer treatment include surgery, radiation, chemotherapy and immunotherapy [3] These therapies are only successful when the cancer is detected at an early stage, or limited to certain types of cancer (e.g., leukemia). Chemotherapeutic agents generally have a narrow margin of safety, and are used in combination usually given at a maximum tolerated dose to achieve maximum cancer cell killing [4]. They kill tumor cells by direct cytotoxicity, or activating host immune response, inhibiting the proliferation processes of tumor cells, and inducing apoptosis [5]. The preparation and characterization of nanodrug formulations especially for aqueous drug complexes remains a major challenge
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