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Ulcerative colitis (UC) is a chronic inflammatory disease that affects the gastrointestinal tract and is characterized by immune dysregulation. Oral administration of nanoformulations containing immunomodulators is a desirable approach to treating UC. However, low drug-loading (<10%, typically), premature drug release, and systemic absorption of these nanoformulations continue to be significant challenges restricting clinical applications. Herein, we developed colon-targeted piperine–glycyrrhizic acid nanocrystals (ES100-PIP/GA NCs) to treat UC through the regulation of macrophages. The ES100-PIP/GA NCs exhibited ultra-high drug loading and colon-specific drug release. In vitro studies demonstrated that the ES100-PIP/GA NCs could effectively be internalized by lipopolysaccharide (LPS)-induced RAW 264.7 and Caco-2 cells. More importantly, the ES100-PIP/GA NCs could downregulate pro-inflammatory factors (IL-1β, IL-17A), upregulate anti-inflammatory factors (TGF-β1), and repair the intestinal mucosal barrier. In a murine model of acute colitis induced by dextran sodium sulfate (DSS), ES100-PIP/GA NCs could protect PIP and GA from gastric acid destruction, reach the colon, and significantly inhibit colitis. Surprisingly, ES100-PIP/GA NCs enhance M2 macrophages by increasing the mammalian target of rapamycin (mTOR), and inhibit M1 macrophages by reducing hypoxia-inducible factor-1α (HIF-1α). Overall, this study shows that ES100-PIP/GA NCs have synergistic immunotherapy capabilities with macrophage regulation, which offers a promising blueprint for the oral delivery of multicomponent drugs in UC therapy. [ABSTRACT FROM AUTHOR]

Multicomponent formulations have attracted increasing attention because of their favourable patient compliance and greater therapeutic effect. The aim of this study was to develop a multicomponent nanosuspension formulation of bufadienolides, the antitumor components of a traditional Chinese medicine, toad venom, using a wet-milling technique to improve its dissolution behaviour. Croscarmellose sodium (CCS) and sodium lauryl sulfate (SLS) were chosen as the combined stabilizers of the nanosuspension. A Taguchi orthogonal array design was used for this study to optimize the formulation and process parameters. The optimized nanosuspension was characterized by its particle size distribution, zeta potential, morphology, crystallinity, molecular interactions, stability and dissolution. The results showed that the nanosuspension was a homogeneous amorphous system with average particle sizes of <100 nm and significantly improved dissolution behaviour. It was also physically stable for at least 2 months; steric and kinetic stabilization were its main stability mechanisms. These findings suggested that the use of wet milling to fabricate nanosuspensions is a promising method for achieving the fast and synchronized dissolution of multicomponent formulations, presumably increasing the bioavailability of poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) that utilizes Fenton-type reactions to convert endogenous hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals ( • OH) is a promising strategy in anticancer treatment, but the overexpression of glutathione (GSH) and limited endogenous H 2 O 2 make the efficiency of CDT unsatisfactory. Here, an intelligent nanoplatform CuO 2 @mPDA/DOX-HA (CPPDH), which induced the depletion of GSH and the self-supply of H 2 O 2 , was proposed. When CPPDH entered tumor cells through the targeting effect of hyaluronic acid (HA), a release of Cu 2+ and produced H 2 O 2 were triggered by the acidic environment of lysosomes. Then, the Cu 2+ was reduced by GSH to Cu + , and the Cu + catalyzed H 2 O 2 to produce • OH. The generation of • OH could be distinctly enhanced by the GSH depletion and H 2 O 2 self-sufficiency. Besides, an outstanding photothermal therapy (PTT) effect could be stimulated by NIR irradiation on mesoporous polydopamine (mPDA). Meanwhile, mPDA was an excellent photoacoustic reagent, which could monitor the delivery of nanocomposite materials through photoacoustic (PA) imaging. Moreover, the successful delivery of doxorubicin (DOX) realized the integration of chemotherapy, PTT, and CDT. This strategy could solve the problem of insufficient CDT efficacy caused by the limited H 2 O 2 and overexpression of GSH. This multifunctional nanoplatform may open a broad path for self-boosting CDT and synergistic therapy.