Solvent effects on host-guest residence time and kinetics: further insights from metadynamics simulation of Toussaintine-A unbiding from chitosan nanoparticle

This research article published by Springer Nature Switzerland AG., 2021Solvents play an important role in host-guest intermolecular interactions. The kinetics and residence time of Toussaintine-A (TouA) unbinding from chitosan was investigated by means of well-tempered metadynamics and thermodynamic integration using two solvents, polar aprotic (DMSO), and polar protic (water). The kinetic rates were found to be strongly dependent on the solvent polarity; hence, the unbinding rate proceeded much faster in DMSO compared to water. DMSO tends to participate less in a chemical reaction by weakening the intermolecular interaction between chitosan and TouA due to lack of acidic hydrogen resulting in a reduction of the transition state. On the other hand, water, which ought to donate hydrogen atoms, sustains a strong interaction and hence large barrier heights. Consequently, this reduces the unbinding rate and increases the residence time. Binding free energy from thermodynamic integration suggests a thermodynamic stable chitosan-TouA complex in water than in DMSO

Standardization of natural mycolic acid antigen composition and production for use in biomarker antibody detection to diagnose active tuberculosis

This research article published by Elsevier B.V., 2016Mycobacterium tuberculosis, the causative agent of tuberculosis, is characterized by the abundance of species specific, antigenic cell wall lipids called mycolic acids. These wax-like molecules all share an identical, amphiphilic mycolic motif, but have different functional groups in a long hydrophobic hydrocarbon mero-chain that divide them into three main classes: alpha-, keto- and methoxy-mycolic acids. Whereas alpha-mycolic acids constitutively maintain an abundance of around 50%, the ratio of methoxy- to keto-mycolic acid types may vary depending on, among other things, the growth stage of M. tuberculosis. In human patients, antibodies to mycolic acids have shown potential as diagnostic serum biomarkers for active TB. Variations in mycolic acid composition affect the antigenic properties and can potentially compromise the precision of detection of anti-mycolic acids antibodies in patient sera to natural mixtures. We demonstrate this here with combinations of synthetic mycolic acid antigens, tested against TB patient and control sera. Combinations of methoxy- and α-mycolic acids are more antigenic than combinations of keto- and α-mycolic acids, showing the former to give a more sensitive test for TB biomarker antibodies. Natural mixtures of mycolic acids isolated from mature cultures of M. tuberculosis H37Rv give the same sensitivity as that with synthetic methoxy- and α-mycolic acids in combination, in a surface plasmon resonance inhibition biosensor test. To ensure that the antigenic activity of isolates of natural mycolic acids is reproducible, we cultured M. tuberculosis H37Rv on Middlebrook 7H10 solid agar plates to stationary growth phase in a standardized, optimal way. The proportions of mycolic acid classes in various batches of the isolates prepared from these cultures were compared to a commercially available natural mycolic acid isolate. LC-MS/MS and NMR data for quantitation of mycolic acids class compositions show that the variation in batches is small, suggesting that the quality of the results for anti-mycolic acid antibody detection in the TB patients should not be affected by different batches of natural mycolic acid antigens if prepared in a standard way

Nanomedicine for drug delivery in South Africa: a protocol for systematic review

Background: The emergence of nanomedicine in the past decade has changed the landscape of disease diagnosis and treatment. Nanomedicine makes use of nanostructures for applications in different fields of medicine, including drug delivery, biosensors, neuro-electronic interfaces, in vivo imaging, and cell-specific molecular interactions. Despite its relative infancy, nanomedicine has generated a significant body of research as evidenced by peer reviewed literature and several patents. This proposed systematic review will focus specifically on drug delivery systems in which nanoparticles are used to enhance the pharmacological and therapeutic properties of drugs. The strength of nanoparticulate drug delivery systems is their ability to alter the pharmacokinetics and bio-distribution of drugs. Globally, the discourse on nanomedicine is dominated by research being done in the developed countries of Europe and in the United States of America. Less attention has been given to the applications of nanomedicine in developing countries, particularly Africa. There is dearth of information on the applications of nanomedicine in terms of drug delivery with particular reference to which diseases are being targeted generally in Africa. The review will describe the specific diseases that are being targeted and the progress being made in South Africa, with a view to determining whether the applications of nanomedicine are being appropriated to address the context-specific challenges in this country or if they mimic what is being done globally. Methods: Keywords related to nanomedicine and drug delivery will be combined to build a search strategy for each of the following databases: PubMed, Cochrane Library (including Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Cochrane Methodology Register), Google Scholar, NHS Health Technology Assessment Database and Web of Science. We will also check reference lists of included studies for other eligible reports and search unpublished data. To ensure that the search is comprehensive, grey literature will be searched extensively. Literature to be included will have nanomedicine in drug delivery as the primary application and report on the specific diseases that are targeted in South Africa. Two authors will independently screen the search output, select studies and extract data; discrepancies will be resolved by consensus and discussion. When no consensus is reached, the third author will be consulted. Discussion: The systematic review will inform the government, policy-makers, investors, health professionals, scientists, and engineers about the applications of nanomedicine in drug delivery. In particular, it will identify the diseases targeted by the application of nanomedicine for drug delivery and the progress being made in South Africa as the disease burden of this country differs from that of developed countries where nanomedicine has been widely used for drug delivery. Systematic review registration PROSPERO CRD4201705738

Preparation of rifampicin/poly(d,l-lactice) nanoparticles for sustained release by supercritical assisted atomization technique

Research Article published by Elsevier Volume 95In this work supercritical assisted atomization (SAA) process was used for the co-precipitation of poly(d,l-lactide) (PDLLA) and rifampicin (RIF) as nanoparticles for sustained release applications. The effect of the variation of PDLLA/RIF ratio on co-precipitate characteristics was mainly investigated. The precipitated particles were analyzed in terms of their morphological, thermodynamic and crystallographic properties. In addition, loading efficiency and in-vitro release studies were conducted. Spherical PDLLA/RIF nanoparticles with mean diameter ranging from 123 to 148 nm were prepared. Loading efficiency was greater than 100% resulting in RIF loadings of 28.8 to 50.5%. X-ray diffraction revealed that the encapsulated RIF is in an amorphous state, while NMR spectra indicated no structural modifications after the SAA process. In-vitro release studies showed an initial burst release of 80–87% of total RIF loaded, necessary to suppress the generation of resistance by the microorganism, followed by first-order sustained release between 0.4 and 0.8 mg/L RIF per day over a period of 17 days

Effects of protein binding on the biodistribution of PEGylated PLGA nanoparticles post oral administration

The surface of nanoparticles is often functionalised with polymeric surfactants, in order to increase systemic circulation time. This has been investigated mainly for intravenously administered nanoparticles. This study aims to elucidate the effect of surface coating with various concentrations of polymeric surfactants (PEG and Pluronics F127) on the in vitro protein binding as well as the tissue biodistribution, post oral administration, of PLGA nanoparticles. The in vitro protein binding varied depending on the polymeric surfactant used. However, in vivo, 1% PEG and 1% Pluronics F127 coated particles presented similar biodistribution profiles in various tissues over seven days. Furthermore, the percentage of PEG and Pluronics coated particles detected in plasma was higher than that of uncoated PLGA particles, indicating that systemic circulation time can also be increased with oral formulations. The difference in the in vitro protein binding as a result of the different poloxamers used versus similar in vivo profiles of these particles indicates that in vitro observations for nanoparticles cannot represent or be correlated to the in vivo behaviour of the nanoparticles. Our results therefore suggest that more studies have to be conducted for oral formulations to give a better understanding of the kinetics of the particles

Modifications of the hydrophilicity of heterocyclic methacrylate copolymers for protein release

Research Article published by Elsevier Volume 16, Issue 18, December 1995A series of copolymers comprising ethyl methacrylate (EM) and tetrahydrofurfuryl methacrylate (THFMA) gelled with either THFMA monomer or hydroxyethyl methacrylate (HEMA) monomer have been developed. In this paper, we examine the water uptake characteristics of the polymer systems and address the possibility of increasing the hydrophilicity of the systems by changing the ratios of the copolymers. We have investigated whether protein release from the polymers is related to the composition of the polymer systems. More protein was released from the polymers gelled with the more hydrophilic monomer (HEMA) than with THFMA. This was consistent with the calculated diffusion coefficients, which were 10 times greater for the polymers gelled with HEMA than those gelled with THFMA. Interestingly, the water uptake and protein release profiles were not dependent on the ratio of EM and THFMA in the copolymers. This is probably due to the conflicting roles of THFMA in the copolymer; it is both the more hydrophilic component as well as a cross-linking agent. In addition, it would appear that the structural and surface topography of these polymers had more significant effects on protein release than copolymer composition

Polyamidoamine Dendrimers for Enhanced Solubility of Small Molecules and Other Desirable Properties for Site Specific Delivery: Insights from Experimental and Computational Studies

Clinical applications of many small molecules are limited due to poor solubility and lack of controlled release besides lack of other desirable properties. Experimental and computational studies have reported on the therapeutic potential of polyamidoamine (PAMAM) dendrimers as solubility enhancers in pre-clinical and clinical settings. Besides formulation strategies, factors such as pH, PAMAM dendrimer generation, PAMAM dendrimer concentration, nature of the PAMAM core, special ligand and surface modifications of PAMAM dendrimer have an influence on drug solubility and other recommendable pharmacological properties. This review, therefore, compiles the recently reported applications of PAMAM dendrimers in pre-clinical and clinical uses as enhancers of solubility and other desirable properties such as sustained and controlled release, bioavailability, bio-distribution, toxicity reduction or enhancement, and targeted delivery of small molecules with emphasis on cancer treatment

In vivo evaluation of the biodistribution and safety of PLGA nanoparticles as drug delivery systems

The remarkable physicochemical properties of particles in the nanometer range have been proven to address many challenges in the field of science. However, the possible toxic effects of these particles have raised some concerns. The aim of this article is to evaluate the effects of poly(lactide-co-glycolide) (PLGA) nanoparticles in vitro and in vivo compared to industrial nanoparticles of a similar size range such as zinc oxide, ferrous oxide, and fumed silica. An in vitro cytotoxicity study was conducted to assess the cell viability following exposure to PLGA nanoparticles. Viability was determined by means of a WST assay, wherein cell viability of greater than 75% was observed for both PLGA and amorphous fumed silica particles and ferrous oxide, but was significantly reduced for zinc oxide particles. In vivo toxicity assays were performed via histopathological evaluation, and no specific anatomical pathological changes or tissue damage was observed in the tissues of Balb/C mice. The extent of tissue distribution and retention following oral administration of PLGA particles was analyzed for 7 days. After 7 days, the particles remained detectable in the brain, heart, kidney, liver, lungs, and spleen. The results show that a mean percentage (40.04%) of the particles were localized in the liver, 25.97% in the kidney, and 12.86% in the brain. The lowest percentage was observed in the spleen. Thus, based on these assays, it can be concluded that the toxic effects observed with various industrial nanoparticles will not be observed with particles made of synthetic polymers such as PLGA when applied in the field of nanomedicine. Furthermore, the biodistribution of the particles warrants surface modification of the particles to avoid higher particle localization in the liver