Mucopenetrating micelles with a PEG corona

Abstract

Crossing the intestinal mucus layer is a long-standing challenge for orally delivered nanoparticles carrying therapeutic cargo. We report the assembly of mucopenetrating cargo-loaded micelles using block copolymers consisting of either linear poly(ethylene glycol) (PEG) or bottle-brush poly(oligo(ethylene glycol)methacrylate) (PEG) as the hydrophilic block and poly(caprolactone) (PCL) or poly(cholesteryl methacrylate) (PCMA) as the hydrophobic extension. The micelles were shown to preserve their stability and retain ∼50% of their cargo in simulated gastric fluid. The ability of micelles to diffuse through reconstituted porcine mucus was assessed in a microfluidic set-up. Finally, the delivery of Nile Red as a hydrophobic model cargo across a mucus layer produced by epithelial cells was demonstrated. These engineered mucopenetrating micelles have potential to be developed into efficient absorption enhancers, contributing a nanotechnology solution to oral drug delivery.

Mucopenetrating Zwitterionic Micelles

“…The CMC was determined to be 0.17 mg mL −1 for M1 and 0.12 mg mL −1 for M2 (Figure ci and 2cii, respectively). These CMCs were approximately the same as previously measured for poly(cholesteryl methacrylate)‐ block ‐poly(2‐(dimethylamino)ethyl methacrylate) and ∼3× lower than the CMC previously obtained for micelles assembled from of block copolymers with a hydrophobic pCMA block and a pPEGMA extension . However, in the latter case, the method to determine the CMC was different, which might explain this finding.…”

“…Since the mucus layer was not perfectly homogenous, determining the amount of green pixels in the different images and independent repeats was tricky, resulting in rather larger error bars. Nonetheless, this cell culture experiments nicely showed the time‐resolved mucopenetrating properties of M1 F , but they were slower in crossing the mucus compared to our previously reported micelles based on pCMA‐block‐pPEGMA that penetrated within 10 min . We would like to note that the integrity of the micelles could not be determined after crossing the mucus.…”

“…HT29‐MTX‐E12 represents the mucus‐secreting goblet cells of the intestine . We previously characterized the basic properties of this co‐culture including cell viability, the transepithelial electrical resistance and the mucus secretion of the co‐culture that could trap large 500 nm poly‐L‐lysine‐coated silica particles, while small hydrophilic molecules, such as fluorescein, could penetrate . In order to determine the mucopenetration of the zwitterionic micelles using CLSM, a mixture of P1 F1 and P1 F2 was used during the assembly.…”

Recent Advancements in Using Polymers for Intestinal Mucoadhesion and Mucopenetration

“…iii) Confocal laser scanning microscopy images of the mucopenetration of Nile‐Red‐loaded micelles (NR‐loaded P6 F micelles) after 10 min incubation using a Caco‐2/HT29‐MTX‐E12 co‐culture. Reproduced with permission 14. 2017, RSC.…”

“…We recently assembled micelles from amphiphilic block copolymers with a PEG corona (Figure 1ai) and demonstrated that these micelles penetrated the mucus in a microfluidic setup (Figure 1aii) and in Caco‐2/HT29‐MTX‐E12 co‐cultures within 10 min (Figure 1aiii). 14 Copolymer of PEG and chitosan complexed with insulin showed PEG‐graft ratio dependent mucus permeation in rat intestine 15…”