Introduction: Diabetic nephropathy (DN) is the primary root of morbidity and mortality in diabetic patients. Unfortunately, currently, no effective therapeutic strategies are available to ameliorate and reverse the progression of DN. Rhein (RH) is an anthraquinone derivative extracted from herbal medicines with various pharmacological effects on DN. However, its clinical administration is limited by its poor solubility, low bioavailability, reduced distribution into the kidney and adverse effects. Methods and results: To improve the delivery of RH into kidney and the therapeutic effect on DN, we synthesized and utilized polyethyleneglycol-co-polycaprolactone-co-polyethylenimine triblock amphiphilic polymers to prepare RH-loaded polyethyleneglycol-co-polycaprolactone-co-polyethylenimine nanoparticles (PPP-RH-NPs). PPP-RH-NP size was optimized to 75 ± 25 nm for kidney-targeted drug delivery; the positive zeta potential allowed an effective cellular uptake and the polyethylenimine amine groups facilitate the endosomal escape quickly. The distribution and pharmacodynamics of PPP-RH-NPs were studied in a streptozocin-induced DN model, which explicitly demonstrated kidney-targeted distribution and improved the therapeutic effects of RH on DN by ameliorating several pathological indicators. Conclusion: Therefore, this study not only stimulates further clinical research on RH but also, more importantly, proposes a promising DN therapy consisting of an effective kidney-targeted drug delivery.

Background: Renal fibrosis is a progressive process associated with chronic kidney disease (CKD), contributing to impaired kidney function. Active constituents in traditional Chinese herbs, such as emodin (EMO) and asiatic acid (AA), exhibit potent anti-fibrotic properties. However, the oral administration of EMO and AA results in low bioavailability and limited kidney accumulation. Additionally, while oral probiotics have been accepted for CKD treatment through gut microbiota modulation, a significant challenge lies in ensuring their viability upon administration. Therefore, our study aims to address both renal fibrosis and gut microbiota imbalance through innovative co-delivery strategies. Results: In this study, we developed yeast cell wall particles (YCWPs) encapsulating EMO and AA self-assembled nanoparticles (NPYs) and embedded them, along with Lactobacillus casei Zhang, in chitosan/sodium alginate (CS/SA) microgels. The developed microgels showed significant controlled release properties for the loaded NPYs and prolonged the retention time of Lactobacillus casei Zhang (L. casei Zhang) in the intestine. Furthermore, in vivo biodistribution showed that the microgel-carried NPYs significantly accumulated in the obstructed kidneys of rats, thereby substantially increasing the accumulation of EMO and AA in the impaired kidneys. More importantly, through hitchhiking delivery based on yeast cell wall and positive modulation of gut microbiota, our microgels with this synergistic strategy of therapeutic and modulatory interactions could regulate the TGF-β/Smad signaling pathway and thus effectively ameliorate renal fibrosis in unilateral ureteral obstruction (UUO) rats. Conclusion: In conclusion, our work provides a new strategy for the treatment of renal fibrosis based on hitchhiking co-delivery of nanodrugs and probiotics to achieve synergistic effects of disease treatment and targeted gut flora modulation. Graphical

Objective: This article aims to design low molecular weight chitosan (LMWC)-based conjugates of Rhein (RH) by means of an amino acid linker (Alanine) for improved solubility and enhanced bioavailability. Significance: Rhein is a potential candidate for the therapy of kidney disease. However, the poor solubility, inadequate bioavailability, and lack of proper formulation restrict its clinical applicability. LMWC-drug conjugates offer the potential to improve the water-solubility of RH, increase its oral absorption, and thereby enhance its bioavailability. Methods: The conjugates were synthesized via a carbodiimide reaction and confirmed using UV-vis, FTIR, and ¹H-NMR spectroscopy. The water-solubility and in vitro release properties were evaluated. Free RH and RH-LMWC conjugates were administered at an equivalent oral gavage dose of RH at 35 mg/kg for pharmacokinetic studies in Sprague Dawley rats. Results: The conjugates with RH content of 9.65% were successfully synthesized and featured a satisfactory water-solubility of 9.73 mg/mL, which exhibited a sustained release pattern over 72 h, and the enzymes present may promote the degradation of the conjugate to increase the release of Rhein. Oral administration of RH-LMWC conjugates to rats led to seven-folds and 3.1-folds increase in the T_1/2 and AUC_0–∞, respectively, as compared to RH suspension. Conclusion: The present work demonstrated that the RH-LMWC conjugates exhibited sustained release properties with outstanding oral bioavailability enhancements compared to administration of RH itself. Potentially, RH-LMWC conjugates may serve as a promising lead for developing a new platform for RH oral delivery.

The aim of this work is to develop biodegradable nanoparticles for improved kidney bioavailability of rhein (RH). RH-loaded nanoparticles were prepared using an emulsification solvent evaporation method and fully characterized by several techniques. Kidney pharmacokinetics was assessed by implanting a microdialysis probe in rat's kidney cortex. Blood samples were simultaneously collected (via femoral artery) for assessing plasma pharmacokinetics. Optimized nanoparticles were small, with a mean particle size of 132.6 ± 5.95 nm, and homogeneously dispersed. The charge on the particles was nearly zero, the encapsulation efficiency was 62.71 ± 3.02%, and the drug loading was 1.56 ± 0.15%. In vitro release of RH from the nanoparticles showed an initial burst release followed by a sustained release. Plasma and kidney pharmacokinetics showed that encapsulation of RH into nanoparticles significantly increased its kidney bioavailability (AUC_kidney/AUC_plasma = 0.586 ± 0.072), clearly indicating that nanoparticles are a promising strategy for kidney drug delivery.