Hyperbranched polymer micelles with triple-stimuli backbone-breakable iminoboronate ester linkages

Hyperbranched polymers have attracted increasing interests due to their unique structure-related advantages and have been utilized as drug carriers for controlled delivery.However,it is still challenging to prepare multi stimuli-responsive hyperbranched polymers to sense and response the complex yet delicate changes in physiological environment.Herein,we propose a triple-stimuli backbone-breakable hyperbranched polymer(HBP(OEG-IB)),which is prepared via the convenient iminoboronate multicomponent reaction ofα,ω-di(1,2-diol)s oligo(ethylene glycol),tris(3-aminopropyl)amine and 2-formylphenylboronic acid.Upon the stimulation of CO2,lactic acid and glutathione,micelles formed by HBP(OEG-IB)could be disrupted via the dissociation of iminoboronate ester bond to subsequent release incorporated camptothecin(CPT).Cell experiments show that the HBP(OEG-IB)is non-toxic but can enhance the therapeutic effect of CPT thanks to the effect of the protonated tertiary amino groups.The demonstration made in this work can enrich the design of responsive HBPs and can be readily applied to other systems with tunable responsive properties and functions.

Acid-resistant ROS-responsive hyperbranched polythioether micelles for ulcerative colitis therapy

Drug-loaded micelles for oral administration are desired for its conve nience,low cost and flexibility,but current designs rely on introducing pH responsiveness,leaving problems like drug leakage and low accuracy of targeted delivery un-solved.Herein,we reported an acid-resistant ROS-responsive hyperbranched polythioether which can self-assemble into micellar structure and pass through the gastrointestinal tract without leaking drugs.At the inflammatory lesions,the thioester bonds are oxidized to sulphone groups to significantly increase the hydrophilicity in response to accumulated ROS species and efficiently release the encapsulated drugs.Animal experiments,including the evaluation of bodyweight,colon length,MPO activity,spleen index,histology and quantitative reverse transcription PCR,evidenced that the drug-loaded micelles have improved therapeutic efficiency compared to bare drug administration for the treatment of DSS-induced colitis in mice.This study provides an example of oral administrated micellar system can be extended for the treatment of other intestinal tract diseases.

Dual-labeled visual tracer system for topical drug delivery by nanoparticle-triggered P-glycoprotein silencing

Using nanoparticle-based drug delivery systems as enhancers is a robust strategy for transdermal delivery;however, the mechanisms by which these systems promote transdermal penetration are still unclear.Here, we fabricated a dual-labeled nano drug delivery system that allows discrete visualization of both the drug and the nanoparticle carrier. To comprehensively examine its potential mechanism, we investigated its effects on human epidermal keratinocyte Ha Ca T cells, including changes in cell membrane potential, intracellular Ca;concentration, and Ca;-ATPase activity. P-glycoprotein(P-gp) expression in nanoparticle-treated human dermal microvascular endothelial cells was detected by western blotting and immunofluorescence. Furthermore, the transdermal absorption and biodistribution of the dual-labeled nanoparticles were deeply investigated by skin permeability study in vitro and in vivo using fluorescence microscopy and in vivo imaging, respectively. In addition to reducing membrane potential, increasing the intracellular Ca;concentration, and decreasing Ca;-ATPase activity, our results indicate that the duallabeled nanoparticles can downregulate P-gp to promote transdermal absorption. Fluorescence and in vivo imaging visually demonstrated that the nanoparticle delivery system penetrated into the dermis through the stratum corneum. All these results indicate that this dual-labeled nano delivery system provides a new method for future in-depth visual explorations of transdermal drug delivery mechanisms.

Bottlebrush inspired injectable hydrogel for rapid prevention of postoperative and recurrent adhesion

Postsurgical adhesion is a common clinic disease induced by surgical trauma,accompanying serious subsequent complications.Current non-surgical approaches of drugs treatment and biomaterial barrier administration only show limited prevention effects and couldn’t effectively promote peritoneum repair.Herein,inspired by bottlebrush,a novel self-fused,antifouling,and injectable hydrogel is fabricated by the free-radical polymerization in aqueous solution between the methacrylate hyaluronic acid(HA-GMA)and N-(2-hydroxypropyl)methacrylamide(HPMA)monomer without any chemical crosslinkers,termed as H-HPMA hydrogel.The H-HPMA hydrogel can be tuned to perform excellent self-fused properties and suitable abdominal metabolism time.Intriguingly,the introduction of the ultra-hydrophilic HPMA chains to the H-HPMA hydrogel affords an unprecedented antifouling capability.The HPMA chains establish a dense hydrated layer that rapidly prevents the postsurgical adhesions and recurrent adhesions after adhesiolysis in vivo.The H-HPMA hydrogel can repair the peritoneal wound of the rat model within 5 days.Furthermore,an underlying mechanism study reveals that the H-HPMA hydrogel significantly regulated the mesothelial-to-mesenchymal transition(MMT)process dominated by the TGF-β-Smad2/3 signal pathway.Thus,we developed a simple,effective,and available approach to rapidly promote peritoneum regeneration and prevent peritoneal adhesion and adhesion recurrence after adhesiolysis,offering novel design ideas for developing biomaterials to prevent peritoneal adhesion.