Gd:DOTA-Modified 2-Hydroxypropyl-β-Cyclodextrin/4-Sulfobutyl Ether-β-Cyclodextrin-Based Polyrotaxanes as Long Circulating High Relaxivity MRI Contrast Agents.

A family of five water-soluble Gd:1,4,7,10-tetraazacyclododecane-1,4,7-tetraacetic acid-modified polyrotaxane (PR) magnetic resonance contrast agents bearing mixtures of 2-hydroxypropyl-β-cyclodextrin and 4-sulfobutylether-β-cyclodextrin macrocycles threaded onto Pluronic cores were developed as long circulating magnetic resonance contrast agents. Short diethylene glycol diamine spacers were utilized for linking the macrocyclic chelator to the PR scaffold prior to Gd chelation. The PR products were characterized by H NMR, gel permeation chromatography/multiangle light scattering, dynamic light scattering, and analytical ultracentrifugation.

Structure-property relationship for in vitro siRNA delivery performance of cationic 2-hydroxypropyl-β-cyclodextrin: PEG-PPG-PEG polyrotaxane vectors.

Nanoparticle-mediated siRNA delivery is a promising therapeutic approach, however, the processes required for transport of these materials across the numerous extracellular and intracellular barriers are poorly understood. Efficient delivery of siRNA-containing nanoparticles would ultimately benefit from an improved understanding of how parameters associated with these barriers relate to the physicochemical properties of the nanoparticle vectors. We report the synthesis of three Pluronic(®)-based, cholesterol end-capped cationic polyrotaxanes (PR(+)) threaded with 2-hydroxypropyl-β-cyclodextrin (HPβCD) for siRNA delivery.

Impact of Mixed β-Cyclodextrin Ratios on Pluronic Rotaxanation Efficiency and Product Solubility.

Water-soluble polyrotaxanes have been prepared under heterogeneous conditions from mixtures of β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), methyl-β-cyclodextrin, or 6-monoazido-β-cyclodextrin with 4-sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and Pluronic L81 copolymer modified with cholesterol end caps. Threading reactions gave polyrotaxane products in modest chemical yield that were reflective of the β-CD feed ratios in the reaction. Polyrotaxanes containing mixtures of HP-β-CD and SBE-β-CD were screened and found to be biologically active in an in vitro model of Niemann-Pick Type C disease where they mobilize aberrantly stored cholesterol similarly to monomeric cyclodextrin controls.

Synthesis of 2-hydroxypropyl-β-cyclodextrin/pluronic-based polyrotaxanes via heterogeneous reaction as potential Niemann-Pick type C therapeutics.

Five polyrotaxanes were synthesized by threading 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) onto a variety of α,ω-ditriethylenediamino-N-carbamoyl-poly-(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic) triblock copolymers using a two-pot strategy under heterogeneous, nonaqueous conditions. The threaded HP-β-CD units were retained on the pseudopolyrotaxane precursors by end-capping the branched diamine termini with sodium 2,4,6-trinitrobenzene sulfonate. Inclusion of the Pluronic copolymers within the HP-β-CD cavities was more favorable in nonpolar solvents, such as diethyl ether and n-hexane, both of which gave better coverage ratios than polar solvents.