Worm-like micelles facilitate the intestinal mucus diffusion and drug accumulation for enhancing colorectal cancer therapy

Local delivery of nanoparticles holds promise for colorectal cancer(CRC)therapy.However,the presence of the mucus layer on the epithelium poses a significant challenge to drug delivery,thereby adversely affecting treatment efficiency.It is crucial to develop efficient drug delivery carriers that can effectively overcome mucus barriers to treat colorectal cancer.Herein,we utilized poly(1,4-butadiene)-b-poly(ethylene oxide)polymers to prepare four distinct geometries of polymeric micelles,namely linear micelles(LMs),worm-like micelles(WLMs),large spherical micelles(LSMs),and small spherical micelles(SSMs)to investigate the influence of shape effects on overcoming colonic mucosal barrier.We found that the carriers exhibited diverse shapes while maintaining comparable physicochemical properties.Of these,WLMs had an aspect ratio similar to segmented filamentous bacteria,which exhibited superior mucus penetration ability,leading to prolonged drug release kinetics and faster entry into epithelial cells compared to LSMs.Furthermore,rectally administrated 10-hydroxycamptothecin-loaded WLMs traversed the colorectal mucus in orthotopic CRC nude mice model,penetrated and accumulated within tumor tissue,and effectively aggregated within cancer cells,thereby inducing significantly robust antitumor outcomes in vivo.These findings underscore the significance of shape design in overcoming colonic mucosal absorption barriers,offering a novel approach for the development of drug delivery carriers tailored for effective tumor therapy.

Supersaturated polymeric micelles for oral silybin delivery: the role of the Soluplus–PVPVA complex

Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system(SDDS). In this study, we reported a complex system of Soluplus–Copovidone(Soluplus–PVPVA)loaded with the model drug silybin(SLB) that could not only maintain the stability of a supersaturated solution but also effectively promote oral absorption. The antiprecipitation effect of the polymers on SLB was observed using the solvent-shift method. In addition, the effects of the polymers on absorption were detected by cellular uptake and transport experiments. The mechanisms by which the Soluplus–PVPVA complex promotes oral absorption were explored by dynamic light scattering, transmission electron microscopy, fluorescence spectra and isothermal titration calorimetry analyses. Furthermore, a pharmacokinetic study in rats was used to demonstrate the advantages of the Soluplus–PVPVA complex. The results showed that Soluplus and PVPVA spontaneously formed complexes in aqueous solution via the adsorption of PVPVA on the hydrophilichydrophobic interface of the Soluplus micelle, and the Soluplus–PVPVA complex significantly increased the absorption of SLB. In conclusion, the Soluplus–PVPVA complex is a potential SDDS for improving the bioavailability of hydrophobic drugs.

The complexation of insulin with sodium N-[8-(2-hydroxybenzoyl)amino]-caprylate for enhanced oral delivery:Effects of concentration, ratio, and pH

Permeation enhancers(PEs),such as N-[8-(2-hydroxybenzoyl)amino]-caprylate(SNAC),have been reported to improve the oral absorption of various macromolecules.However,the bioavailabilities of these formulations are quite low and variable due to the influences of enzymes,pH and other gastrointestinal barriers.In this study,we revealed that SNAC could interact with insulin to form tight complexes in a specific concentration(insulin≥ 40μg/mL)-,ratio(SNAC/insulin≥ 20:1)-and pH(≥ 6.8)-dependent manner,thus contributing to a significantly high efficacy of oral insulin delivery.Specifically,absorption mechanism studies revealed that the SNAC/insulin complexes were internalized into the cells by passive diffusion and remained intact when transported in the cytosol.Furthermore,the complexes accelerated the exocytosis of insulin to the basolateral side,thereby enhancing its intestinal mucosal permeability.Eudragit;S100-entrapped SNAC/insulin microspheres were then prepared and exhibited an apparent permeability coefficient(P;) that was 6,6-fold higher than that of the insulin solution.In diabetic rats,hypoglycemic activity was sustained for more than 10 h after the microspheres were loaded into entericcoated capsules.Further pharmacokinetic studies revealed an approximately 6.3% oral bioavailability in both the fasted and fed states,indicating a negligible food effect.Collectively,this study provides insight into the interaction between PEs and payloads and presents an SNAC-based oral insulin delivery system that has high oral bioavailability and patient-friendly medication guidance.