Design and development of pH-responsive polyurethane membranes for intravaginal release of nanomedicines

Abstract

The objective of this study was to develop and characterize a novel intravaginal membrane platform for pH-triggered release of nanoparticles (NPs), which is essential for efficient intravaginal delivery of certain effective but acid-labile therapeutic agents for sexually transmitted infections, such as small interfering RNA (siRNA). pH-responsive polyurethane (PU) was electrospun into a porous nanofibrous membrane. The diameters of the fibers, as well as the thickness and pore sizes of the membrane under dry and wet conditions (pH 4.5 and 7.0), were determined from scanning electron microscopy (SEM) micrographs. pH-dependent zetapotential (ζ) of the membrane was evaluated using a SurPASS electrokinetic analyzer.Visiblex TM color-dyed polystyrene NPs (PSNs, 200 nm, -COOH) and CCR5 siRNAencapsulated solid lipid NPs (SLNs) were used for in vitro NP release studies in a vaginal fluid simulant (VFS) at pH 4.5 (normal physiological vaginal pH) and 7.0 (vaginal pH neutralization by semen). During 24 hours of incubation in VFS, close-to-zero PSNs (2 ± 1%) and 28 ± 4% SLNs were released through the PU membrane at pH 4.5, whereas the release of PSNs and SLNs significantly increased to 60 ± 6% and 59 ± 8% at pH 7.0, respectively. The pH-responsive release of NPs hinged on the electrostatic interaction between the pH-responsive membranes and the anionic NPs, and the change in pH-responsive morphology of the membrane. In vitro biocompatibility studies of the membranes showed no significant cytotoxicity to VK2/E6E7 human epithelial cells and Sup-T1 human T-cells and no significant changes in the expression of pro-inflammatory cytokines (IL-6, IL-8, and IL-1β). Overall, these porous pH-responsive PU membranes demonstrated their potential in serving as "window" membranes of reservoir-IVRs for pH-responsive intravaginal release of NPs.

Promising Drug Delivery Approaches to Treat Microbial Infections in the Vagina: A Recent Update

“…The opposite findings reported in the alkaline environment caused an accelerated drug release (Figure 8). The formulation did not cause any remarkable toxicity and changes in the expression of proinflammatory cytokines [125]. Cervical mucus is a natural barrier present in the vaginal lumen that impedes the diffusion of viral particles and cells.…”

“…pH-responsive changes in the morphology of the membrane and electrostatic interaction between the pH-responsive membranes and anionic nanoparticles contribute to the release of nanoparticles. Adapted from "Design and Development of pH-responsive Polyurethane Membranes for Intravaginal Release of Nanomedicines" by Kim et al[125].…”

Pharmaceutical Vehicles for Vaginal and Rectal Administration of Anti-HIV Microbicide Nanosystems

“…An interesting approach to the use of fibers for the administration of microbicide NPs has been recently proposed by Kim et al [121]. The researchers proposed electrospun fibers composed of a non-dissolving, pH-responsive polyurethane co-polymer, namely PEG-1,4-bis(2-hydroxyethyl)piperazine-4,4′-methylenebis(phenyl isocyanate)-propylene glycol, to be used for the controlled release of NPs.…”

“…In practice, and although pH-dependent behavior was also observed for a control polyurethane co-polymer without HEP, membranes allowed roughly 0% and 60% in vitro permeation after 24 h of model polystyrene NPs (≈200 nm) when tested at pH 4.5 and 7.0, respectively. Control of permeation for solid lipid NPs containing anti-CCR5 siRNA and presenting a mean diameter of around 270 nm was milder (around 30% and 60% at pH 4.5 and 7.0, respectively) [121]. Overall, developed fiber mats could be useful in the design of “smart” dosage forms able to release the majority of microbicide NPs only upon potential contact with the virus.…”

“…For example, vaginal ring technology has come a long way over the last decade and appears to offer enough versatility for the appropriate incorporation and release of nanosystems [123]. Although the pH-sensitive polyurethane fiber membrane described in the previous sub-section was suggested for the design of rings, only the concept was presented and sustained release over at least several days was not demonstrated [121]. Alternatively, simpler rings based on designs previously explored for macromolecule delivery using, for example, pod-inserts [124] or exposed cores [125] could be seen as promising, but pioneering work is required.…”