Coarse-grained modeling study of nonpeptide RGD ligand density and PEG molecular weight on the conformation of poly(γ-glutamyl-glutamate) paclitaxel conjugates

Molecular shape, flexibility, and surface hydrophilicity are thought to influence the ability of nanoparticles to cross biological barriers during drug delivery. In this study, coarse-grained (CG) molecular dynamics (MD) simulations were used to study these properties of a polymer-drug construct in potential clinical development: poly(γ-glutamyl-glutamate)-paclitaxel-poly(ethylene glycol) nonpeptide RGD (PGG-PTX-PEG-npRGD), a linear glutamyl-glutamate polymer with paclitaxel and poly(ethylene glycol)-nonpeptide RGD side groups. It was hypothesized that the PEG molecular weight (MW) (500 Da; 1,000 Da; and 2,000 Da) and nonpeptide RGD ligand density (4, 8, 12, and 16 per molecule), respectively, may have advantageous effects on the shape, flexibility, and surface hydrophilicity of PGG-PTX-PEG-npRGD. Circular dichroism spectroscopy was used to suggest initial structures for the all-atom (AA) models of PGG-PTX-PEG-npRGD, which were further converted to CG models using a commercially available mapping algorithm. Due to its semi-flexibility, PGG-PTX-PEG-npRGD is not limited to one specific conformation. Thus, CG MD simulations were run until statistical equilibrium, at which PGG-PTX-PEG-npRGD is represented as an ensemble of statistically similar conformations. The size of a PGG-PTX-PEG-npRGD molecule is not affected by the PEG MW or the nonpeptide RGD density, but higher PEG MW results in increased surface density of a PGG-PTX-PEG-npRGD molecule. Most PGG-PTX-PEG-npRGD shapes are globular, although filamentous shapes were also observed in the PEG500 and PEG1000 molecules. PEG500 and PEG1000 molecules are more flexible than PEG2000 systems. A higher presence of npRGD ligands results in decrease surface hydrophilicity of PGG-PTX-PEG-npRGD. These results indicate that the PGG-PTX-PEG1000-npRGD4 and PGG-PTX-PEG1000-npRGD8 molecules are the most efficacious candidates and are further recommended for experimental preclinical studies

Preclinical evaluation of antihyperglycemic activity of Clerodendron infortunatum leaf against streptozotocin-induced diabetic rats

© The Author(s) 2011. This article is published with open access at Springerlink.com Introduction: Clerodendron infortunatum Linn. (Verbenaceae), commonly known as Bhant in Hindi, is a small shrub occurring throughout the plains of India, which is traditionally used for several medicinal purposes. The aim of the present stud

Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)- paclitaxel nanoconjugate

The purpose of this study was to develop a novel, highly water-soluble poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate (PGG-PTX) that would improve the therapeutic index of paclitaxel (PTX). PGG-PTX is a modification of poly(L-glutamic acid)- paclitaxel conjugate (PGA-PTX) in which an additional glutamic acid has been added to each glutamic side chain in the polymer. PGG-PTX has higher water-solubility and faster dissolution than PGA-PTX. Unlike PGA-PTX, PGG-PTX self-assembles into nanoparticles, whose size remains in the range of 12–15 nm over the concentration range from 25 to 2,000 μg/mL in saline. Its critical micellar concentration in saline was found to be ~25 μg/mL. The potency of PGG-PTX when tested in vitro against the human lung cancer H460 cell line was comparable to other known polymer-PTX conjugates. However, PGG-PTX possesses lower toxicity compared with PGA-PTX in mice. The maximum tolerated dose of PGG-PTX was found to be 350 mg PTX/kg, which is 2.2-fold higher than the maximum tolerated dose of 160 mg PTX/kg reported for the PGA-PTX. This result indicates that PGG-PTX was substantially less toxic in vivo than PGA-PTX

The Impact, Emerging Needs, and New Research Questions Arising from 12 Years of the Center for the Study of Complex Malaria in India

The Center for the Study of Complex Malaria in India (CSCMi) was launched in 2010 with the overall goal of addressing major gaps in our understanding of "complex malaria" in India through projects on the epidemiology, transmission, and pathogenesis of the disease. The Center was mandated to adopt an integrated approach to malaria research, including building capacity, developing infrastructure, and nurturing future malaria leaders while conducting relevant and impactful studies to assist India as it moves from control to elimination. Here, we will outline some of the interactions and impacts the Center has had with malaria policy and control counterparts in India, as well as describe emerging needs and new research questions that have become apparent over the past 12 years

Chemistry of potent anti-cancer compounds, amphidinolides

Amphidinolides A-V represent a family of cytotoxic marine natural products with diverse structural features and pronounced biological activities. Kobayashi and his research group have been reporting over the years the discoveries of these remarkable molecules, one after another, since 1986 when the first report of the series appeared. Thanks to their perseverance and painstaking research, the family is still expanding. The unique structural features and biological activity profiles of these macrolides have obviously attracted the attention of organic chemists worldwide. The total syntheses of three members of the family, amphidinolides J, K and P, have already been achieved. This review tries to chronicle the fascinating chemistries of amphidinolides, studies on the syntheses of some of these molecules and their biological activity profiles

Efficacy of Simultaneous Application of Repetitive Transcranial Magnetic Stimulation and Virtual Reality Training on Sensory-motor and Cognitive Deficits among Stroke Patients: A Protocol for a Randomised Controlled Trial

Introduction: Stroke is a significant contributor to chronic impairment on a global scale, impacting millions of individuals each year. Despite the progress made in the field of stroke management, individuals frequently experience enduring sensorimotor and cognitive impairments that have a substantial influence on their quality of life and ability to live independently. Need of the study: Virtual Reality Training (VRT) consists of rigorous, repetitive sessions that promote cerebral-hemispheric integration through the creation of a stimulating environment that combines sensory and motor functions. It is anticipated that VRT and Transcranial Magnetic Stimulation (TMS) will stimulate the affected hemisphere while inhibiting the unaffected hemisphere. Voluntary movement is also crucial for interhemispheric interaction; therefore, the present research employs VRT for physical movements while stimulating across multiple regions of the brain. Aim: To investigate the combined efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) and Virtual Reality Training for sensorimotor and cognitive deficits among stroke patients. Materials and Methods: The present study will be a single-blind, prospective, randomised controlled trial recruiting 69 patients with unilateral stroke from Jaypee Hospital Noida, Uttar Pradesh, India for a continuous period of one year from July 2023 to June 2024 and will be allocated through block randomisation to one of the three treatment groups as per the inclusion and exclusion criteria. Group 1- Simultaneous repetitive TMS (rTMS) and VRT, Group 2- rTMS combined with Sham VRT, and Group 3- VRT protocol combined with Sham Stimulation. Fugl Meyer Assessment (FMA), Montreal Cognitive Assessment (MOCA), National Institutes of Health Stroke Scale (NIHSS), and Addenbrooke’s Cognitive Examination III (ACE III) will be measured at baseline and at the end of the fourth week

Studies directed toward the syntheses of amphidinolides: formal total synthesis of (-)-amphidinolide P

A formal total synthesis of (-)-amphidinolide P (1) has been achieved via an efficient convergent strategy for the stereoselective construction of the two advanced intermediates 2 and 3, used recently by Williams et al. in their synthesis of the same molecule