Nanoparticles Coated with High Molecular Weight PEG Penetrate Mucus and Provide Uniform Vaginal and Colorectal Distribution in Vivo

Abstract

Aims We previously demonstrated that nanoparticles (NPs) densely coated with low molecular weight (MW, 2-5 kDa) polyethylene glycol (PEG) rapidly diffused through various mucus secretions, whereas NPs coated with 10 kDa PEG were mucoadhesive due to presumed polymer interpenetration and entanglement with mucins. Here, we demonstrate that PEG with MW as high as 40 kDa can be used as a mucoinert NP surface coating if sufficient surface density is achieved. Materials and Methods We compared two sets of reaction conditions for coating model polystyrene NPs with 10 kDa PEG and used the optimized reaction conditions to coat various sized NPs with PEG with MW as high as 40 kDa. We then characterized NP transport in human cervicovaginal mucus (CVM) ex vivo. We further administered PEG-coated NPs to the mouse cervicovaginal tract and colorectum to assess mucosal distribution in vivo. Results and Conclusions We demonstrate here that PEG with MW as high as 40 kDa can be densely grafted to the surface of NP to prevent interactions with mucus. NP coated with 10-40 kDa PEG rapidly diffused through human CVM ex vivo, and uniformly lined the mouse colorectal and vaginal epithelium in vivo. This not only suggests that the density of PEG on the NP surface, and thus the conformation, is key for preventing interactions with mucus, but also redefines and broadens the design criteria for drug and gene delivery systems for improved mucosal delivery.

The particle in the spider's web: transport through biological hydrogels

“…47,156,157 In addition, recently Maisel et al (2016) recently showed that PEG molecular weights as high as 40 kDa can be used for mucus penetration, with higher molecular weights requiring extremely high PEGylation density to reduce entanglements. 158 …”

Current State of Microbicide Development

“…designed polystyrene NPs densely coated with low‐molecular‐weight polyethylene‐glycol to prevent interaction with the mucus, which enhanced NP penetration. This NP formulation was capable of rapidly crossing the mucosal layer in a mouse model …”

“…The mucus at the mucosal surface of the FGT can hinder viral movement but can also slow down NPs crossing the mucosal barrier into the submucosa. Maisel et al 46 designed polystyrene NPs densely coated with low-molecular-weight polyethylene-glycol to prevent interaction with the mucus, which enhanced NP penetration. This NP formulation was capable of rapidly crossing the mucosal layer in a mouse model.…”

Synthesis of Polyphosphate‐Loaded Nanoparticles Using Inverse Miniemulsion Polymerization for Sustained Delivery to the Gastrointestinal Tract

“…Our group has focused on the production of nanoparticles composed of a polyethylene glycol diacrylate (PEGDA)–n‐vinyl pyrrolidone (NVP) crosslinked hydrogel matrix encapsulated with phosphate salts and synthesized using an inverse miniemulsion polymerization process . Polyethylene glycol (PEG)‐coated nanoparticles, or PEGylated nanoparticles have demonstrated significant promise in drug delivery research as their surface does not promote non‐specific tissue binding while allowing for deeper penetration and longer circulation times especially in mucosal tissues . However, it must be noted that in these prior studies the nanoparticles investigated were composed of different material structures (linear polymers or crystalline materials ) and subsequently surface‐coated with PEG.…”

“…Polyethylene glycol (PEG)‐coated nanoparticles, or PEGylated nanoparticles have demonstrated significant promise in drug delivery research as their surface does not promote non‐specific tissue binding while allowing for deeper penetration and longer circulation times especially in mucosal tissues . However, it must be noted that in these prior studies the nanoparticles investigated were composed of different material structures (linear polymers or crystalline materials ) and subsequently surface‐coated with PEG. The development of crosslinked hydrogel PEG nanoparticles for drug delivery applications is rare.…”