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Background

Unlike traditional drug delivery that targets the entire colon, inflammation-targeting drug delivery is expected to achieve high drug concentrations locally at the site of inflammation with minimal exposure of healthy or distant tissues, thereby enabling safer and more efficacious therapies for the treatment of inflammatory bowel disease. Inflammation of the colonic mucosa is accompanied by depletion of the mucus layer and in situ accumulation of positively charged proteins, including transferrin, bactericidal/permeability-increasing protein, and antimicrobial peptides, which lead to the buildup of positive charges at the damaged epithelial surface, providing a molecular target and anchor for drug carriers with negative surface charge. We previously reported an inflammation-targeting hydrogel with an overall negative charge for selective adhesion to ulcers in ulcerative colitis. Here we propose to develop a hydrogel drug depot with thermo-responsiveness and tunable negative charge densities, for effective targeting to ulcers via rectal administration and potentially improved treatment of ulcerative colitis.

Methods

Poly(N-isopropylacrylamide) (PNIPAM), a well-studied thermo-responsive polymer for medical applications, was chosen as the backbone of the hydrogel for functionalization. We then conjugated different entities with negative charge to the PNIPAM for tunable charge densities. For effective drug loading and controlled drug release from the hydrogel, we formulated nanoparticles to incorporate both small-molecule drugs and biologics. The drug loading was quantified by High Performance Liquid Chromatography (HPLC) and ELISA, respectively. To evaluate colon adhesion of the drug delivery systems, colons from mice with dextran sulfate sodium (DSS)-induced colitis and healthy mice were collected and used for comparison.

Results

We used a one-on-one approach to directly conjugate taurine to PNIPAM, and a multiple-on-one approach to conjugate dendrimeric taurine to PNIPAM, to modulate the charge densities on the polymer backbone. The structures of the functionalized polymers were analyzed by H-NMR, Infrared Spectroscopy, and Mass Spectrometry. Determined by UV-Vis spectroscopy, the sol-to-gel transition temperature (lower critical solution temperature, LCST) of the functionalized PNIPAM is affected by the charge density and the polymer concentration. We formulated nanoparticles of sizes ∼100 nm, ∼180 nm, and ∼270 nm in diameter, respectively, and compared their drug loading capacity and selective adhesion to the inflamed colon. Using budesonide and granulocyte-macrophage colony-stimulating factor (GM-CSF) as model drugs, we show that nanoparticles can encapsulate both hydrophobic and hydrophilic drugs. Larger nanoparticles (∼270 nm) show higher drug encapsulation efficiency, and preferential adhesion to the inflamed colon than to healthy colon, demonstrated by an ex vivo assay.

Conclusions

We synthesized PNIPAM functionalized with different entities for tunable charge densities. We also formulated nanoparticles for loading of hydrophobic and hydrophilic drugs that could be used as a drug-loading platform. Further studies will investigate the treatment efficacy of the synthesized polymers and nanoparticles in animal models of ulcerative colitis.

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Copyright © 2017 Crohn's & Colitis Foundation of America, Inc.
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