pH-responsive microparticles of rifampicin for augmented intramacrophage uptake and enhanced antitubercular efficacy.

In this study we present pH-responsive rifampicin (RIF) microparticles comprising lecithin and a biodegradable hydrophobic polymer, polyethylene sebacate (PES), to achieve high intramacrophage delivery and enhanced antitubercular efficacy. PES and PES-lecithin combination microparticles (PL MPs) prepared by single step precipitation revealed average size of 1.5 to 2.7 µm, entrapment efficiency âˆ¼ 60 %, drug loading 12-15 % and negative zeta potential. Increase in lecithin concentration enhanced hydrophilicity. PES MPs demonstrated faster release in simulated lung fluid pH 7.4, while lecithin MPs facilitated faster and concentration dependent release in acidic artificial lysosomal fluid (ALF) pH 4.5 due to swelling and destabilization confirmed by TEM. PES and PL (1:2) MPs exhibited comparable macrophage uptake which was âˆ¼ 5-fold superior than free RIF, in the RAW 264.7 macrophage cells. Confocal microscopy depicted intensified accumulation of the MPs in the lysosomal compartment, with augmented release of coumarin dye from the PL MPs, confirming pH-triggered increased intracellular release. Although, PES MPs and PL (1:2) MPs displayed comparable and high macrophage uptake, antitubercular efficacy against macrophage internalised M. tuberculosis was significantly higher with PL (1:2) MPs. This suggested great promise of the pH-sensitive PL (1:2) MPs for enhanced antitubercular efficacy.

Asialoglycoprotein receptor targeted delivery of doxorubicin nanoparticles for hepatocellular carcinoma.

We report asialoglycoprotein receptor (ASGPR)-targeted doxorubicin hydrochloride (Dox) nanoparticles (NPs) for hepatocellular carcinoma (HCC). Polyethylene sebacate (PES)-Gantrez® AN 119 Dox NPs of average size 220 nm with PDI < 0.62 and ∼20% Dox loading were prepared by modified nanoprecipitation. ASGPR ligands, pullulan (Pul), arabinogalactan (AGn), and the combination (Pul-AGn), were anchored by adsorption. Ligand anchoring enabled high liver uptake with a remarkable hepatocyte:nonparenchymal cell ratio of 85:15. Furthermore, Pul-AGn NPs exhibited an additive effect implying incredibly high hepatocyte accumulation. Galactose-mediated competitive inhibition confirmed ASGPR-mediated uptake of ligand-anchored NPs in HepG2 cell lines. Subacute toxicity in rats confirmed the safety of the NP groups. However, histopathological evaluation suggested mild renal toxicity of AGn. Pul NPs revealed sustained reduction in tumor volume in PLC/PRF/5 liver tumor-bearing Nod/Scid mice up to 46 days. Extensive tumor necrosis, reduced collagen content, reduction in the HCC biomarker serum α-fetoprotein (p < 0.05), a mitotic index of 1.135 (day 46), and tumor treated/tumor control (T/C) values of <0.42 signified superior efficacy of Pul NPs. Furthermore, weight gain in the NP groups, and no histopathological alterations indicated that they were well tolerated by the mice. The high efficacy coupled with greater safety portrayed Pul Dox NPs as a promising nanocarrier for improved therapy of HCC.

Polyethylene sebacate doxorubicin nanoparticles: role of carbohydrate anchoring on in vitro and in vivo anticancer efficacy.

We report carbohydrate-anchored polyethylene sebacate (PES)-Gantrez® AN 119 Doxorubicin hydrochloride (Dox) nanoparticles (NPs) for enhanced anticancer efficacy. The carbohydrates Arabinogalactan (AGn), an adjuvant in anticancer chemotherapy and pullulan (Pul) reported to promote collagen synthesis, were selected as ligands. PES Dox NPs of an average size around 200 nm, greater than 20% w/w Dox loading and negative zeta potential were anchored with Pul, AGn, and Pul-AGn combination by simple incubation. Increase in particle size and zeta potential confirmed carbohydrate anchoring. FTIR confirmed ionic complexation of Dox and Gantrez® AN 119. DSC and XRD demonstrated amorphization of Dox. Higher Dox release in pH 5.5 as compared with pH 7.4 is beneficial for reduced systemic toxicity and enhanced drug release in tumors. Good in vitro serum stability and low hemolysis revealed suitability for intravenous administration. All NPs revealed circulation longevity in normal rats. Pul NPs revealed superior anticancer efficacy in vitro and an 11-fold enhancement in uptake in MCF-7 breast cancer cells. The greater efficacy in vivo is attributed to possible pullulan-mediated integrin receptor uptake and interaction with tumor collagen. Histopathology confirmed safety and suggested promise of Pul NPs in improved anticancer efficacy.

Comparative evaluation of polymeric nanoparticles of rifampicin comprising Gantrez and poly(ethylene sebacate) on pharmacokinetics, biodistribution and lung uptake following oral administration.

The present study reports the comparative pharmacokinetic evaluation and biodistribution of rifampicin (RIF) following oral administration of nanoparticles of a bioadhesive polymer, Gantrez and a hydrophobic polymer poly(ethylene sebacate) (PES). A specific objective of the study was to evaluate lung uptake of the nanoparticles following oral administration. Nanoparticles were obtained in the size range 350-450 nm with rifampicin loading of 12-14% w/w. Zeta potential confirmed colloidal stability. PES nanoparticles revealed high macrophage uptake compared to Gantrez nanoparticles, and direct correlation was observed between hydrophobicity (contact angle) and macrophage uptake (r2 -0.940). Enhanced RIF uptake with folic acid anchoring suggested folate receptor mediated uptake. RIF nanoparticles exhibited significantly higher Cmax and AUC, delayed Tmax and sustained release compared to plain RIF. More importantly the plasma concentration of RIF with the nanoparticles was significantly greater than the MIC of RIF (0.25 microng/mL) over 24 h. While gamma scintigraphy revealed higher lung accumulation of nanoparticles, the concentration with Gantrez nanoparticles was significantly higher. HPLC evaluation of lung concentration correlated with scintigraphy data. The significantly higher bioavailability and lung accumulation with Gantrez nanoparticle over PES nanoparticles was attributed mucoadhesion and high affinity of Gantrez to the Peyer's patches. Our study suggests Gantrez nanoparticles as a promising carrier for enhancing lung accumulation of drugs.

Polyethylene sebacate-doxorubicin nanoparticles for hepatic targeting.

The present study discusses polyethylene sebacate (PES)-doxorubicin (DOX) nanoparticles (PES-DOX NP) using pullulan as asialoglycoprotein receptor (ASGPR) ligand for hepatic targeting. Pullulan, a hydrophilic polymer served as ligand and as stealth agent. PES-DOX NP were prepared by modified nanoprecipitation using PES and Gantrez AN 119 (Gantrez), as complexing agent in the organic phase, while DOX was dissolved in the aqueous phase. Pullulan was adsorbed on the formed nanoparticles (PES-DOX-PUL). Intimate association of PES and Gantrez, and ionic complexation of DOX with Gantrez (confirmed by FTIR), coupled with rapidity of nanoprecipitation resulted in nanoparticles with high entrapment efficiency and high drug loading. Nanoparticles were successfully freeze dried. Drug release from PES NP followed zero order kinetics. PES-DOX NP and PES-DOX-PUL exhibited low hemolytic potential and good serum stability. Comparative biodistribution study in rats using (99m)Tc labeled formulations revealed higher blood concentration and lower liver concentration of PES-DOX-PUL, confirming the long circulating nature of PES-DOX-PUL, and thereby the possibility of improved targeting to hepatocytes. Nanoparticles revealed lower DOX concentration in the heart suggestive of low cardiotoxicity. Our study presents a radically different yet simple approach for the design of PES-DOX nanoparticles with high drug loading for improved therapy in hepatic cancer.

Nanoparticles of polyethylene sebacate: a new biodegradable polymer.

The present study demonstrates feasibility of preparation of nanoparticles using a novel polymer, polyethylene sebacate (PES), and its application in the design of drug-loaded nanocarriers. Silymarin was selected as a model hydrophobic drug for the present study. Two methods of preparation, viz., nanoprecipitation and emulsion solvent diffusion, were evaluated for preparation of nanoparticles. Effect of surfactants polyvinyl alcohol (PVA), lutrol F 68, and Tween 80 on the preparation of blank and silymarin-loaded PES nanoparticles was evaluated. Nanoprecipitation resulted in the formation of nanoparticles with all the surfactants (<450 nm). Increase in surfactant concentration resulted in decrease in entrapment efficiency and particle size except with PVA. The type and concentration of surfactant was critical to achieve low size and adequate drug entrapment. While increase in concentration of PES resulted in larger nanoparticles, inclusion of acetone in the organic phase resulted in particles of smaller size. In case of emulsion solvent diffusion, nanoparticles were obtained only with lutrol F 68 as surfactant and high surfactant concentration. The study revealed nanoprecipitation as a more versatile method for preparation of PES nanoparticles. Scanning electron microscopy studies revealed spherical shape of nanoparticles. Freeze-dried nanoparticles exhibited ease of redispersion, with a marginal increase in size. Differential scanning calorimetry and X-ray diffraction analysis revealed amorphous nature of the drug. The study demonstrates successful design of PES nanoparticles as drug carriers.

Polyethylene sebacate: genotoxicity, mutagenicity evaluation and application in periodontal drug delivery system.

The objective of the present study is to evaluate Polyethylene sebacate (PES) for its toxicity profile including oral toxicity, genotoxicity and mutagenicity. PES was synthesised, and characterised by gel permeation chromatography, FTIR, (1)H-NMR, differential scanning calorimetry and X-ray diffraction. Oral toxicity studies revealed PES to be nontoxic up to 3000 mg/kg body weight with no significant changes in serum biochemistry. The standard battery of genotoxicity tests including micronucleus test, chromosomal aberration and comet assay revealed PES as nongenotoxic. Mutagenicity of PES was evaluated using the Ames microplate format mutagenicity assay sample kit using TA98 and TA100 strains of Salmonella typhimurium, both in presence and absence of Aroclor 1254 induced rat liver S9. Ames assay confirmed PES to be nonmutagenic. Periodontal implants of PES of varying roxithromycin/PES ratios and different diameter were prepared. A decrease in in vitro drug release was seen with increase in diameter of the implants. Release rates, however, increased with increase in PES concentration, and were attributed to decreased crystallinity of roxithromycin, confirmed by the DSC thermographs and XRD spectra. Roxithromycin release from the implants followed Higuchi kinetics and exhibited controlled release. The results suggest PES as a safe polymer for biomedical and pharmaceutical applications.