An innovative in situ method of creating hybrid dendrimer nano-assembly: An efficient next generation dendritic platform for drug delivery.

Dendrimers have proven to be effective for drug delivery and their biodisposition varies with change on their surface, generation and core. In an effort to understand the role of critical nanoscale design parameters, we developed a novel hybrid dendrimer approach to harness unique features of individual dendrimers and create a nano-assembly. We report an easy in situ method of creating hybrid dendrimer nano-assembly by mixing G4.0 PAMAM (-NH2) and G3.5 PAMAM (-COONa) dendrimers with a chemotherapeutic drug docetaxel (DTX). Zeta potential, HR-TEM, 1H-NMR proved the formation of nano-assembly. In vitro dissolution, release studies revealed pH dependent dissolution and sustained drug release. Cellular uptake, cytotoxicity, and flow cytometric analysis in human/mouse glioblastoma cells indicated the effectiveness of hybrid dendrimers. The oral administration of the hybrid dendrimers showed pharmacokinetic equivalence to intravenous injection of commercially available Taxotere®. Hybrid dendrimer concept provides much needed fine-tuning to create multistage next-generation dendritic platform in nanomedicine.

Fabrication of surfactant-stabilized nanosuspension of naringenin to surpass its poor physiochemical properties and low oral bioavailability.

BACKGROUND: Nanosuspension is a biphasic system consisting of native drug particles dispersed in an aqueous surfactant or polymeric solution with a particle size between 10 to 1000 nm. In contrast to other drug delivery systems, nanosuspension offer the unique advantage of increasing solubility of the native drug resulting into faster drug absorption and hence achieving faster maximum plasma concentration. HYPOTHESIS/PURPOSE: The present study aims to evaluate surfactants/polymer stabilized nanosuspensions of naringenin (NN), a phytomedicine, to surpass its poor physiochemical properties and low oral bioavailability. STUDY DESIGN: Optimization and characterization (DLS, SEM, PXRD and DSC) of nanosuspensions followed by in-vitro drug dissolution studies and pharmacokinetic study in male Sprague-Dawley rats were performed. METHODS: Nanosuspensions were prepared by precipitation-ultrasonication method with varying concentrations of different surfactants and polymer such as sodium cholate (SC), sodium lauryl sulphate (SLS), poly ethylene glycol 4000 (PEG), polysorbate 80 (Tween® 80), poloxomer-188 and D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS or Vitamin E-TPGS). RESULTS: Nanosuspension prepared with 0.5% w/v d-α-Tocopherol polyethylene glycol 1000 succinate (TPNS) and 7.5 mg NN, showed the smallest size of 118.1 ±â€¯2.7 nm. TPNS showed increase in drug dissolution in simulated gastric fluid pH 1.2 (SGF) and phosphate buffer pH 6.8 (PB). TPNS demonstrated an improved pharmacokinetic profile compared to pure NN resulting 2.14 and 3.76 folds increase in Cmax and AUC, respectively. In addition, TPNS were stable over a period of six months. CONCLUSION: The developed formulation strategy of nanosuspension could be exploited to improve the solubility and bio-availability of poorly soluble NN and other phytomedicines.

Poly (amidoamine) dendrimer-mediated hybrid formulation for combination therapy of ramipril and hydrochlorothiazide.

We present a dendrimer-based hybrid formulation strategy to explore the potential of poly (amidoamine) PAMAM dendrimers to be used as drug carriers for combination therapy of an anti-hypertensive drug ramipril (RAPL) and a diuretic hydrochlorothiazide (HCTZ). The drug-dendrimer complexes were prepared by phase-equilibration method. The results showed that the solubility of RAPL and HCTZ was dependent on dendrimer concentration and pH of dendrimer solution. The solubility profile of both RAPL and HCTZ dendrimer complexes illustrated a non-linear relationship with dendrimer concentration. At 0.8% (w/v) dendrimer concentration, solubility of RAPL was increased 4.91 folds with amine-terminated while for HCTZ, solubility enhancement was highest (3.72 folds) with carboxy-terminated. The complexes were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance analysis and high performance liquid chromatography. In-vitro drug dissolution performance of pure drugs, individual drug loaded dendrimer formulations and hybrid formulations was studied in USP dissolution medium (pH7.0) and in simulated gastric fluid (pH1.2). Dendrimer mediated formulations showed faster and complete dissolution compared to pure RAPL or HCTZ. Surprisingly, similar pattern of dissolution profile was established with hybrid formulations as compared to individual drug loaded dendrimers. The dendrimer-based hybrid formulations were found to be stable at dark and refrigerated conditions up to 5weeks. Conclusively, the proposed formulation strategy establishes a novel multitasking platform using dendrimer for simultaneous loading and delivery of multiple drugs for pharmaceutical applications.

The use of an oral brush biopsy without computer-assisted analysis in the evaluation of oral lesions: a study of 94 patients.

OBJECTIVE: The objective of this study was to evaluate the sensitivity and specificity of modified brush biopsy without computer-assisted analysis in the detection of oral premalignant and malignant lesions. STUDY DESIGN: Ninety-four patients attending outpatient clinics who exhibited oral lesions suspicious of premalignancy or malignancy were enrolled. All patients underwent an oral brush biopsy using a baby toothbrush followed by a scalpel biopsy. The specimens were analyzed manually in a double-blinded fashion. Sensitivity and specificity were used for the statistical analysis of the samples. Statistical significance was determined using the normal approximation to the binomial distribution of matched results, approximated by the Student t distribution mean test (paired t test). RESULTS: Seventy-nine patients with adequate transepithelial brush biopsy samples were included in the study group. When compared to scalpel biopsy, the statistical sensitivity of the brush biopsy was greater than 76.8% (P < .05) while the statistical specificity was greater than 93.3% (P < .05). There were 4 false negative brush biopsy cases. The 4 false negative patients turned out to be dysplasia/ malignancy on histopathology. All 4 were patients with clinical oral submucous fibrosis. CONCLUSION: The oral brush biopsy without computer-assisted analysis was found to be a painless, noninvasive test for evaluating oral lesions. The toothbrush brush biopsy with manual analysis had much [corrected] lower sensitivity and specificity than the commercially available oral brush biopsy with computer-assisted analysis. The results demonstrate that by using a toothbrush to obtain an oral brush biopsy sample, oral lesions can be easily evaluated in a resource challenged settings to rule out dysplasia and carcinoma.

Prevalence of H. pylori in patients with gastric cancer.

The present study was taken with an aim to assess the prevalence of H. pylori in patients with gastric carcinoma and correlate it with gross appearance and histological type. Endoscopic biopsies from 54 patients with gastric carcinoma and 50 age and sex matched controls were taken after thorough upper gastrointestinal examination. Gross appearance of the tumour was noted and two biopsies each from the site of malignancy and from normal appearing areas were taken. Sections were stained with Haematoxylin & Eosin and Loeffler's methylene blue for histopathological details and presence of H. pylori. Prevalence of H. pylori in controls was slightly higher than the patients group (80% Vs 78%). Ulcerated type of gross appearance had maximum prevalence of H. pylori (88%). Prevalence of H. pylori was more in diffuse type of gastric cancer than intestinal type (86% Vs 68%). A significant association between H. pylori and grades of gastritis was noted (P < 0.01) in controls as well as in patient group but it failed to show a significant association with tumour grades, intestinal metaplasia, site of the tumour and age of the patients. So, it can be inferred that prevalence of H. pylori infection is not directly associated with pathogenesis of gastric cancer but it may act as a co-carcinogen by damaging the mucosa and thereby making it more susceptible to effects of carcinogen.