Morphologic design of sugar-based polymer nanoparticles for delivery of antidiabetic peptides.
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abstract
Zwitterionic polymer nanoparticles of diverse morphologies (spherical, cylindrical, and platelet-like) constructed from biocompatible sugar-based polymers are designed to extend the pharmacological activities of short- and long-acting insulin peptides, thereby providing potential for therapeutic systems capable of reducing the frequency of administration and improving patient compliance. Amphiphilic block copolymers composed of zwitterionic poly(d-glucose carbonate) and semicrystalline polylactide segments were synthesized, and the respective block length ratios were tuned to allow formation of nanoscopic assemblies having different morphologies. Insulin-loaded nanoparticles had similar sizes and morphologies to the unloaded nanoparticle counterparts. Laser scanning confocal microscopy imaging of three-dimensional spheroids of vascular smooth muscle cells and fibroblasts after treatment with LIVE/DEAD® stain and FITC-insulin-loaded nanoparticles demonstrated high biocompatibility for the nanoconstructs of the various morphologies and significant intracellular uptake of insulin in both cell lines, respectively. Binding of short-acting insulin and long-acting insulin glargine to nanoparticles resulted in extended hypoglycemic activities in rat models of diabetes. Following subcutaneous injection in diabetic rats, insulin- and insulin glargine-loaded nanoparticles of diverse morphologies had demonstrated up to 2.6-fold and 1.7-fold increase in pharmacological availability, in comparison to free insulin and insulin glargine, respectively. All together, the negligible cytotoxicity, immunotoxicity, and minimal cytokine adsorption onto nanoparticles (as have been demonstrated in our previous studies) provide exciting and promising evidence of biocompatible nanoconstructs that are poised for further development toward the management of diabetes.
