Biochemistry and Pharmacology - Research Publications
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ItemInfluence of size, surface, cell line, and kinetic properties on the specific binding of A33 antigen-targeted multilayered particles and capsules to colorectal cancer cells(AMER CHEMICAL SOC, 2007-09)There has been increased interest in the use of polymer capsules formed by the layer-by-layer (LbL) technique as therapeutic carriers to cancer cells due to their versatility and ease of surface modification. We have investigated the influence of size, surface properties, cell line, and kinetic parameters such as dosage (particle concentration) and incubation time on the specific binding of humanized A33 monoclonal antibody (huA33 mAb)-coated LbL particles and capsules to colorectal cancer cells. HuA33 mAb binds to the A33 antigen present on almost all colorectal cancer cells and has demonstrated great promise in clinical trials as an immunotherapeutic agent for cancer therapy. Flow cytometry experiments showed the cell binding specificity of huA33 mAb-coated particles to be size-dependent, with the optimal size for enhanced selectivity at approximately 500 nm. The specific binding was improved by increasing the dosage of particles incubated with the cells. The level of specific versus nonspecific binding was compared for particles terminated with various polyelectrolytes to examine the surface dependency of antibody attachment and subsequent cell binding ability. The specific binding of huA33 mAb-coated particles is also reported for two colorectal cancer cell lines, with an enhanced binding ratio between 4 and 10 obtained for the huA33 mAb-functionalized particles. This investigation aims to improve the level of specific targeting of LbL particles, which is important in targeted drug and gene delivery applications.
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ItemUptake and Intracellular Fate of Disulfide-Bonded Polymer Hydrogel Capsules for Doxorubicin Delivery to Colorectal Cancer Cells(AMER CHEMICAL SOC, 2010-05)Understanding the interactions between drug carriers and cells is of importance to enhance the delivery of therapeutics. The release of therapeutics into different intracellular environments, such as the lysosomes or the cell cytoplasm, will impact their pharmacological activity. Herein, we investigate the intracellular fate of layer-by-layer (LbL)-assembled, submicrometer-sized polymer hydrogel capsules in a human colon cancer derived cell line, LIM1899. The cellular uptake of the disulfide-stabilized poly(methacrylic acid) (PMA(SH)) capsules by colon cancer cells is a time-dependent process. Confocal laser scanning microscopy and transmission electron microscopy reveal that the internalized capsules are deformed in membrane-enclosed compartments, which further mature to late endosomes or lysosomes. We further demonstrate the utility of these redox-responsive PMA(SH) capsules for the delivery of doxorubicin (DOX) to colon cancer cells. The DOX-loaded PMA(SH) capsules demonstrate a 5000-fold enhanced cytotoxicity in cell viability studies compared to free DOX.
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ItemTargeting of Cancer Cells Using Click-Functionalized Polymer Capsules(AMER CHEMICAL SOC, 2010-11-17)Targeted delivery of drugs to specific cells allows a high therapeutic dose to be delivered to the target site with minimal harmful side effects. Combining targeting molecules with nanoengineered drug carriers, such as polymer capsules, micelles and polymersomes, has significant potential to improve the therapeutic delivery and index of a range of drugs. We present a general approach for functionalization of low-fouling, nanoengineered polymer capsules with antibodies using click chemistry. We demonstrate that antibody (Ab)-functionalized capsules specifically bind to colorectal cancer cells even when the target cells constitute less than 0.1% of the total cell population. This precise targeting offers promise for drug delivery applications.