In Vitro Evaluation of pH-Responsive Nanoscale Hydrogels for the Oral Delivery of Hydrophobic Therapeutics

Abstract

About 70% of pharmaceutical drug candidates are poorly soluble and suffer from low oral bioavailability. Additionally, a large number of therapeutics are also substrates for P-glycoprotein (P-gp) receptors present on the intestinal cell lining and undergo efflux that further reduces their oral bioavailability drastically. Nanoscale hydrogels are promising candidates for oral delivery of hydrophobic therapeutics as they hold immense potential in improving solubility and increasing intestinal permeability of such therapeutics. In this report, we describe the in vitro evaluation and comparison of four novel, pH-responsive poly(methacrylic acid-g-polyethylene glycol-co-hydrophobic monomer) nanoscale hydrogels for their capacity to load and release chemotherapeutic doxorubicin, as well as their ability to modulate permeability in vitro for improving doxorubicin transport. The resulting nanoscale formulations showed appreciable loading, and in vitro release studies demonstrated excellent pH-triggered release kinetics. These nanoscale hydrogels can serve as carriers for oral delivery of doxorubicin, achieving drug loading efficiencies of 56−70%, and releasing up to 95% of drug within 6 h. Powder X-ray diffraction studies revealed a change from the crystalline nature of doxorubicin to an amorphous form when encapsulated within formulations, illustrating their potential of enhancing solubility and stability for oral delivery of the hydrophobic therapeutic. Furthermore, their ability to modulate in vitro intestinal permeability was also studied using transport studies with Caco-2 cells, and was complemented by assessing their antitumor activity against P-gp overexpressing, DOXresistant H69/LX4 cancer cells. In vitro cell culture tests demonstrated up to 50% reduction in cellular proliferation in the case of poly(methacrylic acid-g-polyethylene glycol-co-methyl methacrylate), suggesting that these carriers are most suitable as hydrophobic drug carriers that can potentially overcome solubility and permeability limitations typically faced by hydrophobic therapeutics in the gastrointestinal (GI) tract.

Stimulus-Responsive Nanomedicines for Disease Diagnosis and Treatment

“…In addition to oral insulin, many stimulus-responsive systems have been designed for the treatment of other diseases such as Helicobacter pylori [ 256 ], various cancers [ 257 , 258 , 259 ]. For example, Oupciky et al reported a nanostructured lipid carrier (NLC)-based PTT formulation that can be orally administered.…”

Transport and delivery of interferon-α through epithelial tight junctions via pH-responsive poly(methacrylic acid-grafted-ethylene glycol) nanoparticles

“…As shown in Figure 2A an increase in particle diameter from 103.1 nm to 134.5 nm was observed when the solution pH was increased above 5 which is close to the pKa of MAA. A swelling transition at pH 5 indicates that drug release as a result of decomplexation would occur in the upper small intestine [47,48]. Measurements of the effective surface ζ-potential of the P(MAA-g-EGco-tBMA) nanoparticles revealed a decrease in charge at pH 5 when the particles being to swell ( Figure 2B).…”

Fabrication of Multifunctional Stimuli‐Responsive Hydrogels Susceptible to both pH and Metal Cation for Visual Detections

“…The tetra-arm epoxy cross-linker (EC), [33] PEGdiamines (2 kDa, 4 kDa), [34] and rhodamine-NH 2 (RHB-NH 2 ) [35] were synthesized according to reported procedures. 1 H NMR spectra were recorded on Varian Mercury VX (400 MHz) spectrometer using CDCl 3 or DMSO as the solvent and tetramethylsiliane as the internal reference. Surface morphology of the hydrogels was examined by scanning electron microscopy and energy dispersive X-ray (EDX) studies.…”

“…Synthesis of multifunctional hydrogels responsive to various external stimuli by change in color, shape, or volume has many potential applications in several areas such as controlled drug delivery systems, wound healing dressings, cell scaffolds, or environmental applications . It is important that the synthetic approaches to such materials are simple enough to warrant widespread adaptation.…”

“…Synthesis of multifunctional hydrogels responsive to various external stimuli by change in color, shape, or volume has many potential applications in several areas such as controlled drug delivery systems, wound healing dressings, cell scaffolds, or environmental applications. [1][2][3][4][5] It is important that the synthetic approaches to such materials are simple enough to warrant widespread adaptation. It has emerged that "click" reaction-based chemical transformations that are efficient and proceed under mild conditions are useful tools for both fabrication and functionalization of polymeric materials, including hydrogels.…”