No abstract

Mesangial cells-mediated glomerulonephritis is a frequent cause of end-stage renal disease. Here, we show that celastrol is effective in treating both reversible and irreversible mesangioproliferative glomerulonephritis in rat models, but find that its off-target distributions cause severe systemic toxicity. We thus target celastrol to mesangial cells using albumin nanoparticles. Celastrol-albumin nanoparticles crosses fenestrated endothelium and accumulates in mesangial cells, alleviating proteinuria, inflammation, glomerular hypercellularity, and excessive extracellular matrix deposition in rat anti-Thy1.1 nephritis models. Celastrol-albumin nanoparticles presents lower drug accumulation than free celastrol in off-target organs and tissues, thereby minimizing celastrol-related systemic toxicity. Celastrol-albumin nanoparticles thus represents a promising treatment option for mesangioproliferative glomerulonephritis and similar glomerular diseases.

Due to the critical correlation between inflammation and carcinogenesis, a therapeutic candidate with anti-inflammatory activity may find application in cancer therapy. Here, we report the therapeutic efficacy of celastrol as a promising candidate compound for treatment of pancreatic carcinoma via naïve neutrophil membrane-coated poly(ethylene glycol) methyl ether- block -poly(lactic- co -glycolic acid) (PEG-PLGA) nanoparticles. Neutrophil membrane-coated nanoparticles (NNPs) are well demonstrated to overcome the blood pancreas barrier to achieve pancreas-specific drug delivery in vivo . Using tumor-bearing mice xenograft model, NNPs showed selective accumulations at the tumor site following systemic administration as compared to nanoparticles without neutrophil membrane coating. In both orthotopic and ectopic tumor models, celastrol-loaded NNPs demonstrated greatly enhanced tumor inhibition which significantly prolonged the survival of tumor bearing mice and minimizing liver metastases. Overall, these results suggest that celastrol-loaded NNPs represent a viable and effective treatment option for pancreatic carcinoma.

Metastasis is a multistep biological process regulated by multiple signaling pathways. The integrity of the Golgi apparatus plays an important role in these signaling pathways. Inspired by the mechanism and our previous finding about accumulation of chondroitin sulfate in Golgi apparatus in hepatic stellate cells, we developed a Golgi apparatus-targeting prodrug nanoparticle system by synthesizing retinoic acid (RA)-conjugated chondroitin sulfate (CS) (CS–RA). The prodrug nanoparticles appeared to accumulate in the Golgi apparatus in cancer cells and realized RA release under an acidic environment. We confirmed that CS–RA exhibited successful inhibition of multiple metastasis-associated proteins expression in vitro and in vivo by disruption of the Golgi apparatus structure. Following loading with paclitaxel (PTX), the CS–RA based nanoformulation (PTX–CS–RA) inhibited migration, invasion, and angiogenesis in vitro and suppressed tumor growth and metastasis in 4T1-Luc bearing mice. This multistep targeted nanoparticle system potentially enhanced the effect of antimetastasis combined with chemotherapy.

Liver fibrosis is a serious liver disease associated with high morbidity and mortality. The activation of hepatic stellate cells (HSCs) and the overproduction of extracellular matrix proteins are key features during disease progression. In this work, chondroitin sulfate nanomicelles (CSmicelles) were developed as a delivery system targeting HSCs for the treatment of liver fibrosis. CS-deoxycholic acid conjugates (CS–DOCA) were synthesized via amide bond formation. Next, retinoic acid (RA) and doxorubicin (DOX) were encapsulated into CSmicells to afford a DOX+RA-CSmicelles codelivery system. CSmicelles were selectively taken up in activated HSCs and hepatoma (HepG2) cells other than in normal hepatocytes (LO2), the internalization of which was proven to be mediated by CD44 receptors. Interestingly, DOX+RA-CSmicelles preferentially accumulated in the Golgi apparatus, destroyed the Golgi structure, and ultimately downregulated collagen I production. Following tail-vein injection, DOX+RA-CSmicelles were delivered to the cirrhotic liver and showed synergistic antifibrosis effects in the CCl4-induced fibrotic rat model. Further, immunofluorescence staining of dissected liver tissues revealed CD44-specific delivery of CS derivatives to activated HSCs. Together, our results demonstrate the great potential of CS based carrier systems for the targeted treatment of chronic liver diseases.

Systemic uncontrolled inflammatory response, also termed as sepsis, is responsible for many mortalities. Bacterial endotoxin, lipopolysaccharide (LPS), is a major cause of sepsis in endothelial cells. Even though a lot of research has been done to define underlying mechanisms of LPS induced sepsis, the role of long non-coding RNAs (lncRNAs), a group of >200 kb RNAs in sepsis is not well-defined. Expression of pro-inflammatory mediators IL6, ICAM1, and VCAM1 (which encodes interleukin-6, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, respectively) were determined following LPS treatment of human dermal microvascular endothelial cells (HMECs) for 24 h to confirm sepsis induction. RNA immunoprecipitation (RIP) analysis was performed using the chromatin modifying proteins (CMPs), heterogeneous nuclear ribonucleoprotein (hnRNP) K and corepressors of the RE-1 silencing transcription factor (coREST) as individual baits. Quantitative real time polymerase chain reaction (qRT-PCR) was performed on RNA isolated from immunoprecipitated pellets for six different lncRNAs. The effect of the differentially expressed lncRNAs were determined by ectopic overexpression of the lncRNAs before induction of sepsis. Expression of IL6, ICAM1, and VCAM1 were significantly upregulated following treatment of the HMECs with LPS for 24 h confirming induction of sepsis. RIP and qRT-PCR analysis revealed that the lncRNAs HULC, UCA1, and MALAT-1 were significantly enriched with the CMPs after sepsis. RNA interference using siRNAs targeting HULC and UCA1, but not MALAT-1, decreased the expression of IL6, ICAM1, and VCAM1 to endogenous levels. Our results were further validated in an in vivo model of sub-lethal LPS-induced sepsis, whereby siRNA mediated knockdown of UCA1 and HULC lncRNAs prevented induction of VCAM1, ICAM1, and IL6, as assayed by immunohistochemistry. Cumulatively, these results suggest that LPS induced in vitro sepsis in endothelial cells and induction of pre-inflammatory mediators are at least in part due to increased expression of the UCA1 and HULC lncRNAs.

In our study, we aimed to develop a codelivery nanoparticulate system of pirarubicin (THP) and paclitaxel (PTX) (Co-AN) using human serum albumin to improve the therapeutic effect and reduce systemic toxicities. The prepared Co-AN demonstrated a narrow size distribution around 156.9 ± 3.2 nm (PDI = 0.16 ± 0.02) and high loading efficiency (87.91 ± 2.85% for THP and 80.20 ± 2.21% for PTX) with sustained release profiles. Significantly higher drug accumulation in tumors and decreased distribution in normal tissues were observed for Co-AN in xenograft 4T1 murine breast cancer bearing BALB/c mice. Cytotoxicity test against 4T1 cells in vitro and antitumor assay on 4T1 breast cancer in vivo demonstrated that the antitumor effect of Co-AN was superior to that of the single drug or free combination. Also, Co-AN induced increased apoptosis and G2/M cell cycle arrest against 4T1 cells compared to that of the single drug formulation. Remarkably, Co-AN exhibited significantly lower side effects regarding bone marrow suppression and organ and gastrointestinal toxicities. This human serum albumin-based codelivery system represents a promising platform for combination chemotherapy in breast cancers.

Multidrug resistance has remained a major cause of treatment failure in chemotherapy due to the presence of P-glycoproteins (P-gp) that actively pump drugs from inside the cell to the outside. P-gp inhibitors were developed and coadministered with chemotherapeutic drugs to overcome the effect of efflux pumps thus enhancing the chemosensitivity of therapeutics. Our study aimed at developing a lipid nanoemulsion system for the coencapsulation of doxorubicin (DOX) and bromotetrandrine (W198) to reverse multidrug resistance (MDR) in breast cancer. W198 was a potent P-gp inhibitor, and DOX was selected as a model compound which is a common substrate for P-gp. Coencapsulated DOX and W198 lipid nanoemulsions (DOX/W198-LNs) displayed significantly enhanced cytotoxicity in DOX-resistant human breast cancer cells (MCF-7/ADR) compared with DOX loaded lipid nanoemulsions (DOX-LNs) (p < 0.05), which is due to the enhanced intracellular uptake of DOX in MCF-7/ADR cells. The biodistribution study was performed using a nude mice xenograft model, which demonstrates enhanced tumor uptake of DOX in the DOX/W198-LN treated group. Compared with DOX solution, DOX/W198-LNs showed reduced cardiac toxicity and gastrointestinal injury in rats. Taken together, DOX/W198-LNs represent a promising formulation for overcoming MDR in breast cancer.