Biodegradable mucus-penetrating nanoparticles composed of diblock copolymers of polyethylene glycol and poly(lactic-co-glycolic acid)

Abstract

Mucus secretions coating entry points to the human body that are not covered by skin efficiently trap and clear conventional drug carriers, limiting controlled drug delivery at mucosal surfaces. To overcome this challenge, we recently engineered nanoparticles that readily penetrate a variety of human mucus secretions, which we termed mucus-penetrating particles (MPP). Here, we report a new biodegradable MPP formulation based on diblock copolymers of poly(lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA-PEG). PLGA-PEG nanoparticles prepared by a solvent diffusion method rapidly diffused through fresh, undiluted human cervicovaginal mucus (CVM) with an average speed only eightfold lower than their theoretical speed in water. In contrast, PLGA nanoparticles were slowed more than 12,000-fold in the same CVM secretions. Based on the measured diffusivities, as much as 75% of the PLGA-PEG nanoparticles are expected to penetrate a 10-μm-thick mucus layer within 30 min, whereas virtually no PLGA nanoparticles are expected to do so over the same duration. These results encourage further development of PLGA-PEG nanoparticles as mucus-penetrating drug carriers for improved drug and gene delivery to mucosal surfaces.

Nanoparticle penetration of human cervicovaginal mucus: The effect of polyvinyl alcohol

“…We thus sought to test whether the use of PVA with similar PEG-PLGA diblock copolymers could yield a biodegradable MPP platform. PEG-PLGA NP formulated without surfactants exhibited unobstructed Brownian transport in human CVM (Figure 3C), consistent with our recent work [25, 26]. In contrast, the time-lapse traces of PEG-PLGA nanoparticles formulated in PVA (PEG-PLGA/PVA NP), as well as PEG-PLGA/PVA NP washed twice in water (PEG-PLGA/PVA(w) NP), were highly constrained and non-Brownian (Figure 3D and E).…”

“…We previously showed that nanoparticles composed of biodegradable PEG-containing diblock copolymers (poly(ethylene glycol)-co-poly(sebacic acid), PEG-PSA; or PEG-PLGA) rapidly penetrate human mucus [25, 26]. Nevertheless, to stabilize the formation of nanoparticles, surfactants such as PVA are typically required during particle formulation.…”

On the synthesis of mucus permeating nanocarriers

“…Cu and Saltzman [6] also demonstrated that the incorporation of PEG onto the surface of PLGA particles can improve their diffusion in cervical mucus and that the diffusion is dependent on PEG MW and density. More recently, Yu and coworkers [7] presented novel biodegradable mucus-penetrating particles (MPP) based on PLGA-PEG. These NPs were found to diffuse rapidly through fresh, undiluted human CVM with an average speed only 8-fold lower than their theoretical speed in water.…”

Polymer-based nanocarriers for vaginal drug delivery

“…In order to address these issues and develop mucus-penetrating NPs, Hanes and collaborators proposed the dense surface coating of NPs with short chain PEG. This was achieved by either covalent PEG linkage [71][72] or physical adsorption of PEG-or PEO-containing surfactants (e.g., poloxamers) [73][74].…”