(110b) Responsive Nanoscale Hydrogels for the Oral Delivery of Chemotherapeutics

Responsive Nanoscale Hydrogels for the Oral Delivery of Chemotherapeutics                                           

Amey S. Puranik¹ and Nicholas A. Peppas^1,2,3                                                                                            

¹Department of Chemical Engineering, ²Department of Biomedical Engineering and ³College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712

Small-molecule chemotherapeutics, which are currently delivered intravenously, are predominantly associated with a large number of side effects owing to their inherent hydrophobicity, the resultant poor systemic pharmacokinetic profiles and an undifferentiating ability to kill cells. We hypothesize that the use of a nanoscale hydrogel-based delivery system could help overcome drug solubility and dissolution-related bottlenecks in the delivery of hydrophobic chemotherapeutics. A nanoscale drug delivery system was devised to offer an enhanced opportunity for orally delivering hydrophobic cancer therapeutics by selectively localizing the drug within the lipophilic core of a nanoscale hydrogel, which in turn, can respond to changing environmental conditions in the gastrointestinal tract. Hydrogel nanoparticles (size: 100-120 nm) comprising of methacrylic acid co-polymerized with a hydrophobic monomer, and colloidally stabilized by poly(ethylene glycol) tethers, were synthesized using an UV-initiated emulsion polymerization technique. Doxorubicin (DOX) was chosen to be a model hydrophobic chemotherapeutic to evaluate the loading and release capabilities of these nanoparticles. Nanoparticle formulations with varying crosslinking density and core hydrophobicity were able to load doxorubicin with efficiencies ranging from 36-55% within 2 hours of incubation with the drug solution. As the percentage of crosslinking density of the nanoparticles was increased, their ability to swell as well as their therapeutic agent loading and release capability, decreased. The physically encapsulated doxorubicin was completely released within a period of 4-6 hours, at pH 7.4, while still being retained at pH values representative of conditions in the stomach. The nanocarriers were also studied for their cytotoxicity, mucoadhesion and ability to enhance uptake of doxorubicin by cancer cells. The pH-responsive nanocarriers displayed amenable physicochemical characteristics that are considered crucial to hydrophobic drug delivery and achieved improved uptake of DOX by cancer cells.

Acknowledgement: This work was supported by a grant from the National Institutes of Health (EB 1R01-000246-18).