Curcumin loaded pH-sensitive hybrid lipid/block copolymer nanosized drug delivery systems

Curcumin is a perspective drug candidate with pleiotropic antineoplastic activity, whose exceptionally low aqueous solubility and poor pharmacokinetic properties have hampered its development beyond the preclinical level. A possible approach to overcome these limitations is the encapsulation of curcumin into nano-carriers, incl. liposomes. The present contribution is focused on feasibility of using hybrid pH-sensitive liposomes, whereby curcumin is entrapped as a free drug and as a water soluble inclusion complex with PEGylated tert-butylcalix[4]arene, which allows the drug to occupy both the phospholipid membranes and the aqueous core of liposomes. The inclusion complexes were encapsulated in dipalmithoylphosphathydilcholine:cholesterol liposomes, whose membranes were grafted with a poly(isoprene-b-acrylic acid) diblock copolymer to confer pH-sensitivity. The liposomes were characterized by DLS, ζ-potential measurements, cryo-TEM, curcumin encapsulation efficacy, loading capacity, and in vitro release as a function of pH. Free and formulated curcumin were further investigated for cytotoxicity, apoptosis-induction and caspase-8, and 9 activation in chemosensitive HL-60 and its resistant sublines HL-60/Dox and HL-60/CDDP. Formulated curcumin was superior cytotoxic and apoptogenic agent vs. the free drug. The mechanistic assay demonstrated that the potent proapoptotic effects of pH-sensitive liposomal curcumin presumably mediated via recruitment of both extrinsic and intrinsic apoptotic pathways in both HL-60 and HL-60/CDDP cells

Curcumin loaded pH-sensitive hybrid lipid/block copolymer nanosized drug delivery systems

Curcumin is a perspective drug candidate with pleiotropic antineoplastic activity, whose exceptionally low aqueous solubility and poor pharmacokinetic properties have hampered its development beyond the preclinical level. A possible approach to overcome these limitations is the encapsulation of curcumin into nano-carriers, incl. liposomes. The present contribution is focused on feasibility of using hybrid pH-sensitive liposomes, whereby curcumin is entrapped as a free drug and as a water soluble inclusion complex with PEGylated tert-butylcalix[4]arene, which allows the drug to occupy both the phospholipid membranes and the aqueous core of liposomes. The inclusion complexes were encapsulated in dipalmithoylphosphathydilcholine:cholesterol liposomes, whose membranes were grafted with a poly(isoprene-b-acrylic acid) diblock copolymer to confer pH-sensitivity. The liposomes were characterized by DLS, ζ-potential measurements, cryo-TEM, curcumin encapsulation efficacy, loading capacity, and in vitro release as a function of pH. Free and formulated curcumin were further investigated for cytotoxicity, apoptosis-induction and caspase-8, and 9 activation in chemosensitive HL-60 and its resistant sublines HL-60/Dox and HL-60/CDDP. Formulated curcumin was superior cytotoxic and apoptogenic agent vs. the free drug. The mechanistic assay demonstrated that the potent proapoptotic effects of pH-sensitive liposomal curcumin presumably mediated via recruitment of both extrinsic and intrinsic apoptotic pathways in both HL-60 and HL-60/CDDP cells

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Design and characterization of nanoparticles as platforms for delivery of curcumin

Curcumin, the yellow powder derived from the plant Curcuma Longa, exhibited numerous therapeutic applications against wide range of chronic diseases such as diabetes, pancreatitis, arthritis, neurodegenerative diseases and various types of cancer. The mechanism of antineoplastic activity of curcumin is through modulation of cell signaling pathways, mainly blockage of nuclear factor kappa B (NF-κB) activation and induction of apoptosis in different types of human cancer cell lines, associated with excellent safety profile. Despite the numerous advantages, the clinical realization of curcumin potential is limited because of its extremely low aqueous solubility and bioavailability after oral administration. An intriguing strategy to overcome these limitations is the design of nanosized vehicles for efficient delivery of curcumin. The present contribution is focused on newly-synthetized PEGylated tert-butylcalix[4]arene, used for preparation of various platforms for delivery of curcumin, such as inclusion complexes, supramolecular aggregates and hybrid liposomal systems. Curcumin:CX[4]PEG inclusion complexes as well as curcumin loaded polyoxyethylatedtert-buthylcalix[4]arene supramolecular aggregates were prepared using two methods: heating method and solvent-evaporation method. Free and formulated curcumin were additionally investigated for apoptogenic activity and cytotoxicity against human tumor cell lines

Preparation of curcumin loaded nanoparticles: physicochemical characterization and in vitro evaluation

Curcumin is the active principle of the spice turmeric, produced by the rhizome of Curcuma longa (Zingiberaceae), which is widely used in traditional eastern medicine as a hepatoprotective, anti-infectious and anti-inflammatory remedy. A compelling body of recent evidence has shown that curcumin is endowed by pleiotropic antineoplastic effects, due to modulation of NFkB and other cell signaling pathways, implicated in cell survival, apoptosis and angiogenesis

Application of Polymeric Micelles for Drug and Gene Delivery

Polymeric micelles have been extensively studied because of their ability to transfer biologically active agents, such as drugs and nucleic acids [...

Preparation and characterization of chitosan-aliginate-pegilated calx[4]arenes nanoparticles for delivery of curcumin

Curcumin, the constituent of Curcuma longa, is considered a very promising anticancer agent due to its potent and pleiotropic antineoplastic activity and low nonspecific toxicity to normal cells. A major hurdle towards clinical realization of curcumin‘s potential has been limited due to its poor aqueous solubility (11ng/ml) and very low systemic bioavailability. A possible aproach to overcome these limitations is the design of nanosized drug delivery systems. In this study we report the preparation, characterization and evaluation of drug release profiles of curcumin loaded Chitosan – Alginate –pegilated calix[4]arenes nanoparticles (CS-ALG-PEGCX NPs). Nanoparticles were prepared by ionotropic - pregelation of an alginate core, followed by chitosan polyelectrolyte complexation. In order to increase the entrapment efficiency of curcumin into the CH-ALG nanopartcles we used polyoxiethylated tert-butyl calix[4]aren which proved to drastically increase the aqueous solubility of curcumin by formation of the inclusion complexes. The physicochemical characteristics of the panrticles (size, size distribution and zeta potential were evaluated by DLS and the results revealed particles of app. 200 nm with monomodal distribution (PDI below 0.2) and zeta potential of – 31 mV. The encapsulation efficiency of curcumin in calixarene containing NPs was over 40% and was considerably higher than that of NPs without PEGCX. The in vitro drug release profiles were studied under simulated physiological conditions for different incubation periods from 2, 4, 6, 8, 10, 24, 48 and 96 hours. The results showed prolonged drug release. Taken together all these findings give us reason to consider CS-ALG-PEGCX NPs as promissing drug delivery platform for curcumin

Preparation and characterization of polyoxyethylated tert-buthylcalix[4]arene nanoparticles as platforms for delivery of curcumin

The contribution is focused on newly-synthetized octopus-shaped macromolecules, consisting of hydrophobic calix[4]arene core and four arms of hydrophilic poly(ethylene oxide) chains as platform for delivery of hydrophobic agent curcumin. Due to their amphiphilic nature, polyoxyethylated calyx(4)arenes (CX[4]PEG) can self-associate in water by forming well-defined spherical nanoparticles. At concentration below the CMC, CX[4]PEG drastically increased curcumin solubility by formation of inclusion complexes with high stability constant (Kc). A significantly higher solubility enhancement of curcumin was observed at concentration exceeding the critical micellar concentration, attributed with additional solubilization of curcumin into the hydrophobic domains of the supramolecular aggregates by non-covalent interactions. The curcumin:CX[4]PEG inclusion complexes as well as curcumin loaded polyoxyethylatedtert-buthylcalix[4]arene supramolecular aggregates were prepared using two methods: heating method and solvent-evaporation method. Physicochemical characteristics of the nanoparticles (size, size distribution and zeta potential were evaluated by DLS and the results revealed particles of app.180 nm with monomodal distribution (PDI below 0.2) and zeta potential of – 20 mV suitable for systemic application. The in vitro curcumin release profiles from supramolecular CX[4]PEG aggregates were studied under simulated physiological conditions for different incubation periods from 2, 4, 6, 8, 10 and 24 hours. The results showed initial burst release of curcumin, followed by slower drug release. These findings give us a reason to consider polyoxyethylatedtert-buthylcalix[4]arene nanoparticles as promising platforms for drug delivery