Lymph node targeting of cyclosporine ameliorates ocular manifestations in a mouse model of systemic lupus erythematosus (SLE) via PD-L1.

One-third of systemic lupus erythematosus (SLE) patients experience various degrees of ocular manifestations, with immunosuppressants recommended as a treatment option. Targeted immune suppression via oral administration is challenging due to the harsh gastrointestinal tract environment combined with complex physiological barriers. Here, we report the efficacy of orally administered cyclosporine (CsA)-laden polymer nanoparticles decorated with the ligand - Gambogic Acid (P2Ns-GA-CsA) in sustained lymph node delivery.

Polyester Nanoparticles with Controlled Topography for Peroral Drug Delivery Using Insulin as a Model Protein.

Receptor-mediated polyester drug delivery systems have tremendous potential for improving the clinical performance of existing pharmaceutical drugs. Despite significant progress made in this area, it remains unclear how and to what extent the polyester nanoparticle surface topography would affect the , and performance of a drug, and if there exists a correlation between and , as well as healthy versus pathophysiological states. Herein, we report a systematic investigation of the interactions between ligands and receptors as a function of the linker length, two-carbon (2C) versus four-carbon (4C).

Rationally Designed Naringenin-Conjugated Polyester Nanoparticles Enable Folate Receptor-Mediated Peroral Delivery of Insulin.

Receptor-mediated transcytosis of nanoparticles is paramount for the effective delivery of various drugs. Here, we report the design and synthesis of highly functional nanoparticles with specific targeting toward the folate receptor (FR) for the peroral delivery of insulin. In doing so, we demonstrate naringenin (NAR), a citrous flavonoid, as a targeting ligand to FR, with a similar affinity as folic acid.

Glucose-Responsive Microgel Comprising Conventional Insulin and Curcumin-Laden Nanoparticles: a Potential Combination for Diabetes Management.

Successful management of type 2 diabetes mellitus (T2DM), a complex and chronic disease, requires a combination of anti-hyperglycemic and anti-inflammatory agents. Here, we have conceptualized and tested an integrated "closed-loop mimic" in the form of a glucose-responsive microgel (GRM) based on chitosan, comprising conventional insulin (INS) and curcumin-laden nanoparticles (nCUR) as a potential strategy for effective management of the disease. In addition to mimicking the normal, on-demand INS secretion, such delivery systems display an uninterrupted release of nCUR to combat the inflammation, oxidative stress, lipid metabolic abnormality, and endothelial dysfunction components of T2DM.

Nanocurcumin combined with insulin alleviates diabetic kidney disease through P38/P53 signaling axis.

Treatments for diabetic kidney disease (DKD) mainly focus on managing hyperglycemia and hypertension, but emerging evidence suggests that inflammation also plays a role in the pathogenesis of DKD. This 10-week study evaluated the efficacy of daily oral nanoparticulate-curcumin (nCUR) together with long-acting insulin (INS) to treat DKD in a rodent model. Diabetic rats were dosed with unformulated CUR alone, nCUR alone or together with INS, or INS alone.

Oral Nanocurcumin Alone or in Combination with Insulin Alleviates STZ-Induced Diabetic Neuropathy in Rats.

Diabetes mellitus (DM), a multifaceted metabolic disorder if not managed properly leads to secondary complications. Diabetic peripheral neuropathy (DPN) is one such complication caused by nerve damage that cannot be reversed but can be delayed. Recently, diabetes patients are using dietary supplements, although there remains a general skepticism about this practice.

Paclitaxel and Urolithin A Prevent Histamine-Induced Neurovascular Breakdown Alike, in an Rat Eye Model.

Neurovascular eye problems are better prevented than managed or treated. Despite growing concern of occurrence in aging populations and development secondary to diseases such as diabetes and hypertension, we currently have very few options to tackle this global problem. Creating effective and high-throughput screening strategies is as important as the intervention itself.

Nanoparticles that do not compete with endogenous ligands - Molecular characterization in vitro, acute safety in canine, and interspecies pharmacokinetics modeling to humans.

A vast majority, if not all of the receptor-mediated drug delivery systems utilize nanoparticles that are conjugated to physiological mimic ligands, with testing restricted to in vitro and rodent models. In this report, we present for the first time, a full spectrum characterization of transferrin receptor 1 (TfR1)-targeted polymeric nanoparticles (abbreviated, P2Ns-GA) that do not compete with endogenous transferrin, and serve as a versatile platform for oral drug delivery. Based on endocytosis inhibitors and receptor knockdown, the cellular uptake of P2Ns-GA is clathrin-mediated and dependent on TfR1 expression, but other trafficking mechanisms, particularly those involving caveolae/lipid rafts, can also play a role.

A highly potent lymphatic system-targeting nanoparticle cyclosporine prevents glomerulonephritis in mouse model of lupus.

Cyclosporine A (CsA) is a powerful immunosuppressant, but it is an ineffective stand-alone treatment for systemic lupus erythematosus (SLE) due to poor target tissue distribution and renal toxicity. We hypothesized that CD71 (transferrin receptor 1)-directed delivery of CsA to the lymphatic system would improve SLE outcomes in a murine model. We synthesized biodegradable, ligand-conjugated nanoparticles [P2Ns-gambogic acid (GA)] targeting CD71.

Curcumin Can Decrease Tissue Inflammation and the Severity of HSV-2 Infection in the Female Reproductive Mucosa.

Herpes Simplex Virus Type 2 (HSV-2) is one of the most prevalent sexually transmitted viruses and is a known risk factor for HIV acquisition in the Female Genital Tract (FGT). Previously, we found that curcumin can block HSV-2 infection and abrogate the production of inflammatory cytokines and chemokines by genital epithelial cells in vitro. In this study, we investigated whether curcumin, encapsulated in nanoparticles and delivered by various in vivo routes, could minimize inflammation and prevent or reduce HSV-2 infection in the FGT.

Oral delivery of nanoparticle urolithin A normalizes cellular stress and improves survival in mouse model of cisplatin-induced AKI.

The popular anticancer drug cisplatin causes many adverse side effects, the most serious of which is acute kidney injury (AKI). Emerging evidence from laboratory and clinical studies suggests that the AKI pathogenesis involves oxidative stress pathways; therefore, regulating such pathways may offer protection. Urolithin A (UA), a gut metabolite of the dietary tannin ellagic acid, possesses antioxidant properties and has shown promise in mouse models of AKI.

Urolithin A Mitigates Cisplatin-Induced Nephrotoxicity by Inhibiting Renal Inflammation and Apoptosis in an Experimental Rat Model.

Cumulative kidney toxicity associated with cisplatin is severe and there is no clear consensus on the therapeutic management of the same. The pathogenesis involves activation of inflammatory and apoptotic pathways; therefore, regulating these pathways offers protection. Given the anti-inflammatory and antioxidant effects of urolithin A, a gut microbial metabolite of ellagic acid, our aim was to explore the potential use of urolithin A in the prevention of cisplatin-induced nephrotoxicity in an experimental rat model.

Ex Vivo Rat Eye Model for Investigating Transport of Next Generation Precision-Polyester Nanosystems.

We present for the first time a robust ex vivo rat eye model for investigating the transport of precision-polyester nanosystems (P2Ns) across the blood-retinal barrier, intended for systemic administration. The P2Ns-GA actively transport exploiting transferrin receptors present in the inner retinal barrier and colocalize in ganglion cells. Such delivery approaches have the potential to deliver drugs to posterior segments of the eye, which is still a major challenge in treating posterior ocular disorders.

Nano-curcumin safely prevents streptozotocin-induced inflammation and apoptosis in pancreatic beta cells for effective management of Type 1 diabetes mellitus.

Background And Purpose: Approaches to prevent selective and progressive loss of insulin-producing beta cells in Type 1 diabetes mellitus (T1DM) will help to manage this prevalent and devastating disease. Curcumin (CUR), a natural anti-inflammatory substance, suppresses diabetes-associated inflammation and cell death. However, very high doses need to be used because of poor oral bioavailability, making it difficult to translate the anti-inflammatory actions to clinical situations.

Next Generation Precision-Polyesters Enabling Optimization of Ligand-Receptor Stoichiometry for Modular Drug Delivery.

The success of receptor-mediated drug delivery primarily depends on the ability to optimize ligand-receptor stoichiometry. Conventional polyesters such as polylactide (PLA) or its copolymer, polylactide-co-glycolide (PLGA), do not allow such optimization due to their terminal functionality. We herein report the synthesis of 12 variations of the PLA-poly(ethylene glycol) (PEG) based precision-polyester (P2s) platform, permitting 5-12 periodically spaced carboxyl functional groups on the polymer backbone.

Noncompetitive Active Transport Exploiting Intestinal Transferrin Receptors for Oral Delivery of Proteins by Tunable Nanoplatform.

Here we present a "thinking-outside-the-box", tunable nanoplatform for oral delivery of proteins using insulin as a model protein. These nanosystems offer noncompetitive active transport exploiting transferrin receptors present in the intestine and permit tailored release in vivo. Such delivery approaches have the potential to individualize insulin therapy to a regimen that is compatible with the patient's glucose profile.

Gedunin abrogates aldose reductase, PI3K/Akt/mToR, and NF-κB signaling pathways to inhibit angiogenesis in a hamster model of oral carcinogenesis.

Aberrant activation of oncogenic signaling pathways plays a central role in tumor development and progression. The aim of this present study was to investigate the chemopreventive effects of the neem limonoid gedunin in the hamster model of oral cancer based on its ability to modulate aldose reductase (AR), phosphatidyl inositol-3-kinase (PI3K)/Akt, and nuclear factor kappa B (NF-κB) pathways to block angiogenesis. Administration of gedunin suppressed the development of HBP carcinomas by inhibiting PI3K/Akt and NF-κB pathways through the inactivation of Akt and inhibitory kappa B kinase (IKK), respectively.

Response of small heat shock proteins in diabetic rat retina.

Purpose: Small heat shock proteins (sHsps) have a critical role under stress conditions to maintain cellular homeostasis by their involvement in protein-folding and cytoprotection. The hyperglycemia in diabetes may impose cellular stress on the retina. Therefore, we investigated the expression of sHsps, phosphoregulation of αB-crystallin (αBC), and their localization in the diabetic rat retina.

Efficacy of biodegradable curcumin nanoparticles in delaying cataract in diabetic rat model.

Curcumin, the active principle present in the yellow spice turmeric, has been shown to exhibit various pharmacological actions such as antioxidant, anti-inflammatory, antimicrobial, and anti-carcinogenic activities. Previously we have reported that dietary curcumin delays diabetes-induced cataract in rats. However, low peroral bioavailability is a major limiting factor for the success of clinical utilization of curcumin.

Inhibition of protein glycation by procyanidin-B2 enriched fraction of cinnamon: delay of diabetic cataract in rats.

Accumulation of advanced glycation endproducts (AGE) from nonenzymatic glycation of proteins has been implicated in several diabetic complications including diabetic cataract. Previously, we have reported that extracts of dietary agents such as cinnamon have the potential to inhibit AGE formation. In this study, we have shown procyanidin-B2 as the active component of cinnamon that is involved in AGE inhibition using bioassay-guided fractionation of eye lens proteins under in vitro conditions.

Ellagic acid inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and prevents atheroma formation in streptozotocin-induced diabetic rats.

Plant-derived polyphenolic compounds have beneficial health effects. In the present study, we determined the ability of ellagic acid (EA) to prevent platelet-derived growth factor-BB (PDGF-BB)-induced proliferation of primary cultures of rat aortic smooth muscle cells (RASMCs). We also determined the ability of EA to prevent atherosclerosis in streptozotocin-induced diabetic rats.