Targeted delivery of celastrol to renal interstitial myofibroblasts using fibronectin-binding liposomes attenuates renal fibrosis and reduces systemic toxicity

Li, Rui; Li, Yanping; Zhang, Jinhang; Liu, Qinhui; Wu, Tong; Zhou, Jian; Huang, Hui; Tang, Qin; Huang, Cuiyuan; Huang, Yi; Zhang, Zijing; Zhang, Guorong; Zhao, Yingnan; Ma, Liang; Feng, Yanhuan; Mo, Li; Han, Min; He, Jinhan

doi:10.1016/j.jconrel.2020.01.017

Cited by 51 publications

(33 citation statements)

References 45 publications

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“…After loading liposomes with the fluorescent dye DiD to allow their tracking, 23,34 flow cytometry showed that HSC-T6 cells internalized 3-to 4-fold more DiD after 2 and 4 h when the dye was delivered in liposomes than when it was delivered free in solution (Figure 3). This may reflect the particular uptake pathway for liposomes, which enter the cell mainly through endocytosis and can fuse with intracellular membranes because of their biocompatible phospholipid bilayer.…”

Section: Increased Uptake Of Cur and Cyc When Delivered In Liposomesmentioning

confidence: 99%

Curcumin- and Cyclopamine-Loaded Liposomes to Enhance Therapeutic Efficacy Against Hepatic Fibrosis

Zhang

Song

et al. 2020

DDDT

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Background and Purpose Hepatic fibrosis is a public health problem characterized by activation of hepatic stellate cells (HSCs), which triggers excessive production of extracellular matrix (ECM). Inhibition of HSC activation may be an effective treatment. Since various pathways control HSC activation, a combination of drugs with different mechanisms may be more effective than monotherapy. Methods Here, we prepared liposomes loaded with curcumin and cyclopamine to inhibit HSC activation. We systematically analyzed the physicochemical characteristics of liposomes loaded with the two drugs, as well as their effects on HSC proliferation, activation and collagen production on gene, protein and cellular levels. Results The prepared liposomes helped solubilize both drugs, contributing to their uptake by cells. Liposomes loaded with both drugs inhibited cell proliferation, migration and invasion, as well as induced more apoptosis and perturbed the cell cycle more than the free combination of both drugs in solution or liposomes loaded with either drug alone. Liposomes loaded with both drugs strongly suppressed HSC activation and collagen secretion. Conclusion Our results suggest that liposome encapsulation can increase the uptake of curcumin and cyclopamine as well as the synergism between them in anti-fibrosis. This approach shows potential for treating hepatic fibrosis.

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Section: Increased Uptake Of Cur and Cyc When Delivered In Liposomesmentioning

confidence: 99%

Curcumin- and Cyclopamine-Loaded Liposomes to Enhance Therapeutic Efficacy Against Hepatic Fibrosis

Zhang

Song

et al. 2020

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“…Targeted delivery of CLT to tubular epithelial cells using K3-HBc NCs has demonstrated to circumvent restraints such as systemic toxic effects. Li et al reported that targeted loading of CLT by CREKA-coupled liposomes to interstitial myofibroblast allowed the drug to alleviate UUO-induced renal fibrosis [35]. Meanwhile, targeted delivery of celastrol to mesangial cells is also effective against mesangio proliferative glomerulonephritis [12].…”

Section: Discussionmentioning

confidence: 99%

Tubule-specific protein nanocages potentiate targeted renal fibrosis therapy

et al. 2021

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Background Despite the dramatic advances in modern medicine, efficient therapeutic measures for renal fibrosis remain limited. Celastrol (CLT) is effective in treating renal fibrosis in rat models, while causing severe systemic toxicity. Thus, we designed a tubule-specific nanocage (K3-HBc NCs) that effectively deliver CLT to tubular epithelial cell in a virus-like manner. The targeting ligand (K3) to tubular epithelial cells was displayed on the surface of Hepatitis B core protein (HBc) NCs by genetic fusion to the major immunodominant loop region. Ultra-small CLT nanodots were subtly encapsulated into the cavity through electrostatic interaction with the disassembly and reassembly of K3-HBc NCs, to yield K3-HBc/CLT complex. The efficacy of K3-HBc/CLT NCs were demonstrated in Unilateral ureteral obstruction (UUO)-induced renal fibrosis. Results The self-assembled K3-HBc/CLT could specifically target tubular epithelial cells via affinity with K3 ligand binding to the megalin receptor, significantly attenuating renal fibrosis. Remarkably, K3-HBc/CLT NCs significantly increased therapeutic efficacy and reduced the systemic toxicity in comparison with free CLT in UUO-induced mouse renal fibrosis model. Importantly, analysis of RNA sequencing data suggested that the anti-fibrotic effect of K3-HBc/CLT could be attributed to suppression of premature senescence in tubular epithelial cells via p21Cip1 and p16Ink4a pathway. Conclusion The tubule-specific K3-HBc/CLT represented a promising option to realize precise treatment for renal fibrosis.

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“…Pharmacokinetic study of AN-FTS was performed in SD rats as previously described. 25 Briefly, SD rats were randomly divided into two groups and injected intravenously with free DiD or AN-DiD (200 μg/kg DiD). At predetermined time points, blood was collected from fundus veins and diluted with acetone, and then determined by a multifunctional microplate reader (Thermo Fisher Scientific, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Real-time RT-PCR was performed as previously described. 25 The primers are listed in Supplementary Table 1 .…”

Section: Methodsmentioning

confidence: 99%

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Farnesylthiosalicylic Acid-Loaded Albumin Nanoparticle Alleviates Renal Fibrosis by Inhibiting Ras/Raf1/p38 Signaling Pathway

Huang¹,

Liu²,

Zhang³

et al. 2021

IJN

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Background Renal fibrosis is the common pathway in chronic kidney diseases progression to end-stage renal disease, but to date, no clinical drug for its treatment is approved. It has been demonstrated that the inhibitor of proto-oncogene Ras, farnesylthiosalicylic acid (FTS), shows therapeutic potential for renal fibrosis, but its application was hindered by the water-insolubility and low bioavailability. Hence, in this study, we improved these properties of FTS by encapsulating it into bovine serum albumin nanoparticles (AN-FTS) and tested its therapeutic effect in renal fibrosis. Methods AN-FTS was developed using a classic emulsification-solvent ultrasonication. The pharmacokinetics of DiD-loaded albumin nanoparticle were investigated in SD rats. The biodistribution and therapeutic efficacy of AN-FTS was assessed in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO). Results AN-FTS showed a uniform spherical shape with the size of 100.6 ± 1.12 nm and PDI < 0.25. In vitro, AN-FTS displayed stronger inhibitory effects on the activation of renal fibroblasts cells NRK-49F than free FTS. In vivo, AN-FTS showed significantly higher peak concentration and area under the concentration-time curve. After intravenous administration to UUO-induced renal fibrosis mice, AN-FTS accumulated preferentially in the fibrotic kidney, and alleviated renal fibrosis and inflammation significantly more than the free drug. Mechanistically, the improved anti-fibrosis effect of AN-FTS was associated with greater inhibition in renal epithelial-to-mesenchymal transformation process via Ras/Raf1/p38 signaling pathway. Conclusion The study reveals that AN-FTS is capable of delivering FTS to fibrotic kidney and showed superior therapeutic efficacy for renal fibrosis.

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Targeted delivery of celastrol to renal interstitial myofibroblasts using fibronectin-binding liposomes attenuates renal fibrosis and reduces systemic toxicity

Cited by 51 publications

References 45 publications

Curcumin- and Cyclopamine-Loaded Liposomes to Enhance Therapeutic Efficacy Against Hepatic Fibrosis

Curcumin- and Cyclopamine-Loaded Liposomes to Enhance Therapeutic Efficacy Against Hepatic Fibrosis

Tubule-specific protein nanocages potentiate targeted renal fibrosis therapy

Farnesylthiosalicylic Acid-Loaded Albumin Nanoparticle Alleviates Renal Fibrosis by Inhibiting Ras/Raf1/p38 Signaling Pathway

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