(38e) 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.