Deoxycholic acid-chitosan coated liposomes combined with in situ colonic gel enhances renal fibrosis therapy of emodin.

BACKGROUND: Renal fibrosis is the final common pathological feature of various chronic kidney diseases (CKD). Despite recent advances, development of new treatments strategy is needed. Emodin (EMO), an important ingredient of Chinese medicine, rhubarb (Polygonaceae Rheum palmatum l.), has been reported to inhibit the development of renal fibrosis effectively. However, the poor oral bioavailability of EMO and the insufficient monotherapy therapy compromise its efficacy. PURPOSE: In order to enhance renal fibrosis therapy of emodin, an innovative combination therapy based on deoxycholic acid-chitosan coated liposomes (DCS-Lips) and in situ colonic gel (IGE) was developed. METHODS: For one, the DCS-Lips were prepared via electrostatic interaction by mixing anionic conventional Lips with cationic DCS, deoxycholic acid conjugated on the backbone of chitosan. The cellular uptake of FITC-labeled DCS-Lips in Caco-2 cell monolayer was evaluated by CLSM and flow cytometry, respectively. Permeability study was carried out using Caco-2 cell monolayer. For another, EMO-loaded in situ colonic gel (EMO-IGE) was prepared by mixing EMO nanosuspensions and plain in situ gel, which was obtained by the cold method. The EMO-IGE was assessed for morphology, gelation temperature, viscosity and in vitro drug release. Finally, the therapeutic efficacy of the combination strategy, oral DCS-Lips formulations and in situ colonic gel, was evaluated in unilateral ureteral obstruction (UUO) rat model. Additionally, 16S rDNA sequencing was performed on rats faces to investigate whether the combination strategy improves the microbial dysbiosis in UUO rats. RESULTS: The prepared DCS-Lips produced small, uniformly sized nanoparticles, and significantly enhanced the cellular uptake and in vitro permeability of EMO compared to non-coated liposomes. Moreover, the EMO-IGE was characterized by short gelation time, optimal gelling temperature, and excellent viscosity. In UUO model, the combination of DCS-Lips (gavage) and IGE (enema) attenuated renal fibrosis effectively. The results of 16S rDNA sequencing illustrated that IGE could restore the gut microbial dysbiosis of UUO rats. CONCLUSION: Overall, the combination of DCS-Lips and EMO-IGE alleviated renal fibrosis effectively, resulting from the improved oral bioavailability of EMO by DCS-Lips and the restoration of gut microbiota by EMO-IGE, thus, presenting an innovative and promising potential for renal fibrosis treatment.

Albumin-Embellished Arsenic Trioxide-Loaded Polymeric Nanoparticles Enhance Tumor Accumulation and Anticancer Efficacy via Transcytosis for Hepatocellular Carcinoma Therapy.

Arsenic trioxide (ATO) has efficient anticancer effect on hepatocellular carcinoma (HCC) in clinical trials, but its off-target distribution and side effects have limited its use. Here, we demonstrate an albumin-embellished ATO-loaded polyethylene glycol-polycaprolactone-polyethyleneimine (PEG-PCL-PEI) nanoparticle (AATONP) to enhance the tumor distribution and intratumor drug release of ATO for HCC therapy. AATONP is prepared by surface embellishment with albumin on the cationic ATO-loaded PEG-PCL-PEI nanoparticles (CATONP). Albumin embellishment can reduce the cationic material's hemolytic toxicity in blood cells while maintaining the rapid internalization and lysosome escape abilities of the positively charged CATONP. AATONP provides sustained and low pH-responsive drug release, facilitating the targeted drug release in the intratumor acidic microenvironment. Moreover, AATONP can significantly improve the circulation time and tumor distribution of ATO via albumin-mediated transcytosis in HCC tumor-bearing mice. Compared with free ATO and the clinically used nanomedicine Genexol/PM, AATONP shows potent antitumor activity against a human HCC xenograft mouse model, leading to a higher tumor inhibition rate of 89.4% in HCC therapy. In conclusion, this work presents an efficient strategy to achieve tumor accumulation and the intratumor drug release of ATO for HCC therapy. An albumin-embellished arsenic trioxide (ATO)-loaded polyethylene glycol-polycaprolactone-polyethyleneimine nanoparticle (AATONP) is designed to enhance tumor distribution and intratumor drug release of ATO for hepatocellular carcinoma therapy. AATONP can achieve enhanced tumor distribution via albumin-mediated transcytosis and exhibit intratumor drug release of ATO via tumor acidic microenvironment-response, leading to potent antitumor activity.

Hierarchically structured microcapsules for oral delivery of emodin and tanshinone IIA to treat renal fibrosis.

Renal fibrosis is the expected outcome of many chronic kidney diseases, and effective treatments are needed. Emodin (EMO) and tanshinone IIA (Tan IIA) are active ingredients in traditional Chinese herbs and have been effective in treating renal fibrosis. However, their application is greatly limited by inferior oral absorption, unexpected drug-drug interactions, and their ability to influence their respective pharmacokinetic profiles when used in combination. To mitigate these limitations, a new co-delivery approach based on a nano-in-micro system was designed by embedding Tan IIA-loaded nanoparticles (Tan IIA-NPs) in EMO-containing microcapsules. Microcapsules were prepared using the sharp flow technique that resulted in uniform spherical morphology and high encapsulation efficiency and drug loading. Furthermore, the encapsulated Tan IIA-NPs within the microcapsules exhibited superior cellular internalization and transmembrane transport due to the modification with cell-penetrating peptides and polyethylene glycol that facilitated the oral absorption of Tan IIA. Additionally, this nano-in-micro system exhibited evident sequential drug release. The oral bioavailability of EMO and Tan IIA was significantly improved when they were loaded into the hierarchically structured microcapsules, ultimately contributing to superior therapeutic outcomes in rats with unilateral ureteral obstruction. Therefore, the nano-in-micro carrier designed in this study could provide an efficient strategy for the effective oral delivery of combined therapies to treat renal fibrosis.

Deoxycholic acid-functionalised nanoparticles for oral delivery of rhein.

Rhein (RH) is a candidate for the treatment of kidney diseases. However, clinical application of RH is impeded by low aqueous solubility and oral bioavailability. Deoxycholic acid-conjugated nanoparticles (DNPs) were prepared by ionic interaction for enhancing intestinal absorption by targeting the apical sodium-dependent bile acid transporter in the small intestine. Resultant DNPs showed relatively high entrapment efficiency (90.7 ± 0.73)% and drug-loading efficiency (6.5 ± 0.29)% with a particle size of approximately 190 nm and good overall dispersibility. In vitro release of RH from DNPs exhibited sustained and pH-dependent profiles. Cellular uptake and apparent permeability coefficient (Papp) of the DNPs were 3.25- and 5.05-fold higher than that of RH suspensions, respectively. An in vivo pharmacokinetic study demonstrated significantly enhanced oral bioavailability of RH when encapsulated in DNPs, with 2.40- and 3.33-fold higher Cmax and AUC0-inf compared to RH suspensions, respectively. DNPs are promising delivery platforms for poorly absorbed drugs by oral administration.