Most therapeutic proteins are classified as class III drugs according to the Biopharmaceutical Classification System means that the low permeability across the intestinal epithelium is the rate-limited step for their oral absorption. Cationic chitosan nanoparticles have been found to open the tight junctions between epithelial cells. On the other hand, bioadhesive delivery devices could prolong the gastrointestinal residence time . In the present study, we developed a novel nano-reservoir bioadhesive tablets that combining the advantages of cationic nanoparticles and bioadhesive delivery devices anticipated achieving effective transport of sufficient protein drugs across the intestinal epithelium. The nano-reservoir in bioadhesive tablets was composed of chitosan nanoparticles (CS-NPs) loading a model protein drug bovine serum albumin (BSA). The formula of bioadhesive tablets was optimized by using rotatable central composite design and response surface methodology. The nano-reservoir, BSA-loaded CS-NPs, had an average particle diameter of 312.5 ± 12.89 nm and zeta-potential value of 26.76 ± 3.56 mV. Carboxymethyl chitosan added to the formula significantly ameliorated the tight junction damage of the Caco-2 cell monolayer induced by CS-NPs, meanwhile maintained the high transport efficiency of BSA. Permeability study exhibited that these nano-reservoir bioadhesive tablets combining the advantages of cationic nanoparticles and bioadhesive tablets significantly enhanced BSA transport through rabbit small intestine in comparison with either conventional bioadhesive tablets or CS-NPs. Therefore, these nano-reservoir bioadhesive tablets provided a great potential dosage form design for the oral delivery of protein drugs.
Yuan Yuehui,Wu Hao,Ren Xueyang,Wang Jianwu,Liu Ruiqing,Hu Benhui,Gu Ning
In recent years, remarkable progress has been made in the research of injectable hydrogel for internal tissue healing. However, the therapeutic outcome is usually limited when the hydrogel is used for the treatment of gastric perforation due to the high acidic gastric juice and violent deformation of the gastric wall. Regarding these challenges, we proposed an ionic nano-reservoir (INR)-based dual-network hydrogel, which has excellent adhesion and mechanical properties, and can be easily applied to the perforation site to block the perforation while promoting tissue repairing. The results showed that the first network made of polyacrylamide had cross-linked on the stomach tissue within 5 s under blue light, and enhanced the adhesion performance through mechanical interlock. The nano-hydroxyapatite acted as ionic INR, which can gradually release Ca2+ under acid environments to form the second network with sodium alginate and inhibit the swelling of hydrogel in gastric juice. Meanwhile, the adhesion was further enhanced through amide covalent bonds at the hydrogel-tissue interface with the presence of 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC/NHS). The dual network hydrogels obtained by the INR strategy could be employed as a potential therapeutic option for gastric perforation and other similar biomedical prolems.
In situ regeneration of tissue-engineered heart valves (TEHV) is a promising strategy to overcome the limitations of existing heart valve prostheses. Although, decellularized aortic valves (DAVs) are widely regarded as a scaffold in the construction of TEHV, the poor hemocompatibility and adverse immune responses make DAV scaffolds prone to thrombosis and degradation, thus hindering recellularization and in situ regeneration. Our study developed an immune-regulatory strategy involving the use of hydrogel-encapsulated nanoparticles to modify DAV scaffolds. Specifically, folic acid- and hyaluronic acid-modified mesoporous silica nanoparticles (FA-HA-MSNs@CY-09) were engineered to deliver NOD-like receptor family, pyrin domain containing 3 (NLRP3) inhibitor CY-09, thereby targeting macrophages, modulating their polarization and establishing a pro-regenerative immune microenvironment. The reactive oxygen species (ROS)-responsive hydrogel delivering FA-HA-MSNs@CY-09 enabled intelligent nanoparticle release and ROS scavenging. Results demonstrated that the hydrogel-modified DAV scaffold exhibited ROS-responsive release of FA-HA-MSNs@CY-09, which effectively induced macrophage polarization toward the pro-remodeling M2 phenotype. In vitro, the scaffold showed favorable mechanical properties, cytocompatibility, and hemocompatibility. Transcriptome sequencing elucidated the macrophage-reprogramming mechanism of the scaffold. In vivo, the scaffolds promoted significant M2 macrophage infiltration shortly after implantation, facilitating endothelial tissue formation. This resulted in enhanced endothelialization and interstitial cell infiltration under blood flow, without thrombosis or calcification. The novel heart valve overcomes various limitations of conventional heart valve prostheses and demonstrates considerable promise for clinical translation, particularly as an immunomodulatory biomaterial strategy.
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