Hydrolytically Degradable Beta-Cyclodextrin-Based Nanoparticles Bearing Quaternary Amine Groups for Drug Delivery Across the Blood-Tissue Barriers

The blood-tissue barriers such as the blood-brain barrier and the blood-retinal barrier are selective and protective barriers. Most of therapeutic agents developed can not pass these barriers. Therefore, these barriers become a formidable obstacle to overcome when trying to deliver therapeutic agents to treat the diseases occurring behind these barriers.

The purpose of this study is to develop novel hydrolytically degradable b-cyclodextrin-based nanoparticles to enhance the permeability of drugs across the blood-tissue barriers. Recently, poly(amino ester) polymers have been developed as carriers for gene delivery because of their biodegradability and cationic nature^[1]. Previous work^[2] in our group has demonstrated that quaternary ammonium β-cyclodextrin nanoparticles are nontoxic and can significantly enhance the permeability of doxorubicin (DOX) across the in-vitro blood-brain barrier. Based on these previous studies, we developed a new generation of β-cyclodextrin-based nanoparticles. In these nanoparticles, quaternary amine groups were conjugated to β-cyclodextrin and hydrolytically degradable esters were incorporated in the crosslinking structure in the form of poly(amino ester) or poly(ester).

The chemical, physical and degradation properties of the developed nanoparticles were characterized using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), nuclear magnetic resonance (NMR), dynamic light scattering (DLS), and atomic force microscopy (AFM). The MTT assay was used to evaluate the cytotoxicity of the nanoparticles to human brain microvascular endothelial cells (HBMVEC). HBMVEC monolayers were used as an in vitro blood-tissue barrier model to assess the effects of the nanoparticles on the blood-tissue barrier permeability of model drugs. Model drugs such as DOX were loaded into the nanoparticles in dimethyl sulfoxide by partition. Studies were also conducted on the release kinetics of model drugs from the nanoparticles in phosphate buffered saline solution (pH 7.4) at 37 °C. Our preliminary results suggested that these hydrolytically degradable nanoparticles have great potential for delivering drugs across the blood-tissue barriers to treat retinoblastoma, brain tumors and other diseases behind these barriers.

References:

[1] Lynn, D.M. and Langer, R. J. Am. Chem. Soc., 2000, 122 (44): 10761–10768.

[2] Gil, E.S.; Li, J.; Xiao^, H. and Lowe, T.L. Biomacromolecules, 2009, 10 (3): 505–516.