Intelligent nanoscale hydrogels for the oral delivery of hydrophobic therapeutics

Abstract

In this work, novel oral drug delivery formulations were developed for the administration of hydrophobic therapeutics, with the overarching goal of improving their solubility and permeability in the gastrointestinal tract. We have developed a set of four nanoscale hydrogels, formulated by incorporating different hydrophobic monomer components, and screen them for optimal physicochemical properties, drug loading and release, and ability to modulate intestinal permeability and P-glycoprotein related drug efflux. Here, we employ an evolved paradigm of in vitro tests to gauge the potential of these novel nanoscale carriers for the specific application of improving oral solubility and permeability of poorly water-soluble and less permeable therapeutics. All the responsive nanoscale hydrogels are capable of undergoing a transition in size in response to change in pH. We capitalize on the interplay between the incorporated hydrophobic monomer choices and screened resulting physicochemical properties to determine an optimal nanoscale formulation. Depending upon the selection of the hydrophobic monomer, the sizes of the nanoparticles vary widely from 120 nm to about 500 nm at pH 7.4. We also evaluate cytocompatibility of the nanoparticle formulations in vitro in the presence of an intestinal epithelial cell mode to find that all formulations are reasonably cytocompatible. Subsequently, we discuss some of the key findings and results of characterization studies that validate the success of achieving desired molecular architecture and physicochemical properties of the formulation. We then confirm the capacity of the nanocarrier to be able to load and release hydrophobic therapeutics in gastrointestinally relevant environments. Further, the ability of the nanocarriers to transport the hydrophobic therapeutic doxorubicin is determined by evaluating permeability of doxorubicin with intestinal epithelial cell monolayers. Furthermore, demonstrate functional abilities desired from a therapeutically relevant, oral delivery system is tested. Specifically, to overcome problems associated with P-glycoprotein related efflux and reduced drug permeability in the small intestine, we evaluated the ability of the nanoformulation to achieve therapeutic success in relevant and characteristic in vitro cancer cell lines. Finally, we make concluding remarks on the ability of the nanoparticles to function as improved formulations of hydrophobic therapeutics capable of performing and achieving the end-goal of delivering hydrophobic therapeutics orally for the treatment of cancer.