Rose Hayeshi

Nanomedicine: Past, present and future – A global perspective

Nanomedicine is an emerging and rapidly evolving field and includes the use of nanoparticles for diagnosis and therapy of a variety of diseases, as well as in regenerative medicine. In this mini-review, leaders in the field from around the globe provide a personal perspective on the development of nanomedicine. The focus lies on the translation from research to development and the innovation supply chain, as well as the current status of nanomedicine in industry. The role of academic professional societies and the importance of government funding are discussed. Nanomedicine to combat infectious diseases of poverty is highlighted along with other pertinent examples of recent breakthroughs in nanomedicine. Taken together, this review provides a unique and global perspective on the emerging field of nanomedicine.

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.

Curdlan-Conjugated PLGA Nanoparticles Possess Macrophage Stimulant Activity and Drug Delivery Capabilities

PurposeThere is significant interest in the application of nanoparticles to deliver immunostimulatory signals to cells. We hypothesized that curdlan (immune stimulating polymer) could be conjugated to PLGA and nanoparticles from this copolymer would possess immunostimulatory activity, be non-cytotoxic and function as an effective sustained drug release system.MethodsCarbodiimide chemistry was employed to conjugate curdlan to PLGA. The conjugate (C-PLGA) was characterized using 1H and 13C NMR, FTIR, DSC and TGA. Nanoparticles were synthesized using an emulsion-solvent evaporation technique. Immunostimulatory activity was characterized in THP-1 derived macrophages. MTT assay and real-time impedance measurements were used to characterize polymer and nanoparticle toxicity and uptake in macrophages. Drug delivery capability was assessed across Caco-2 cells using rifampicin as a model drug.ResultsSpectral characterization confirmed successful synthesis of C-PLGA. C-PLGA nanoparticles enhanced phosphorylated ERK production in macrophages indicating cell stimulation. Nanoparticles provided slow release of rifampicin across Caco-2 cells. Polymers but not nanoparticles altered the adhesion profiles of the macrophages. Impedance measurements suggested Ca2+ dependent uptake of nanoparticles by the macrophages.ConclusionsPLGA nanoparticles with macrophage stimulating and sustained drug delivery capabilities have been prepared. These nanoparticles can be used to stimulate macrophages and concurrently deliver drug in infectious disease therapy.

State of the art and future directions in nanomedicine for tuberculosis

Introduction: Tuberculosis (TB) ranks the second leading cause of death from an infectious disease worldwide. However, treatment of TB is affected by poor patient compliance due to the requirement for daily drug administration, for lengthy periods of time, often with severe drug-induced side effects. Nanomedicines have the potential to improve treatment outcomes by providing therapies with reduced drug doses, administered less frequently, under shortened treatment durations. Areas covered: In this article, we present the pathophysiology of the disease, focusing on pulmonary TB and the characteristics of drugs used in treatment and discuss the application of nanomedicines within this scope. We also discuss new formulation approaches for TB nanomedicines and directions for future research. Expert opinion: Nanomedicines have the potential to improve TB treatment outcomes. New approaches such as nanoparticle systems able to impact the immune response of macrophages and deliver drug intracellularly, as well as the use of polymer–drug conjugates for drug delivery, are likely to play an important role in TB nanomedicines in future. However, further research is required before TB nanomedicines can be translated to the clinic.

Permeation of PLGA nanoparticles across different in vitro models

Many drug delivery systems have indicated improvement in delivery of various drug molecules and among these biodegradable and biocompatible polymers such as poly(D,L-lactide-co-glycolide) (PLGA) have been shown to enhance intracellular uptake of drug candidates when formulated as nanoparticles. PLGA nanoparticles were prepared by means of a double emulsion solvent evaporation technique and evaluated in terms of size, encapsulation efficiency, surface charge, isoniazid release and in vitro transport. The nanoparticles have an average size of 237 nm and were previously shown to be distributed in several tissues after oral administration without triggering an immune response. This study focussed on the in vitro permeation of the PLGA nanoparticles across different membranes and showed that although Rhodamine 6G-labelled nanoparticles are efficiently delivered across the intestinal epithelium, its epithelial permeability changes when a drug such as isoniazid is encapsulated. Future studies should focus on ways to optimise PLGA nanoparticle delivery when a drug such as isoniazid is encapsulated for instance by coating with polymers such as polyethylene glycol.

Bioaccumulation and Subchronic Toxicity of 14 nm Gold Nanoparticles in Rats

Colloidal suspensions of 14 nm gold nanoparticles (AuNPs) were repeatedly administered intravenously at three dose levels (0.9, 9 and 90 µg) to male Sprague Dawley rats weekly for 7 weeks, followed by a 14-day washout period. After sacrificing, the amount of gold was quantified in the liver, lungs, spleen, skeleton and carcass using neutron activation analysis (NAA). During the study, pre- and post (24 h) administration blood samples were collected from both the test and control groups, the latter which received an equal injection volume of normal saline. General health indicators were monitored together with markers of kidney and liver damage for acute and subchronic toxicity assessment. Histopathological assessments were done on the heart, kidneys, liver, lungs and spleen to assess any morphological changes as a result of the exposure to AuNPs. The mass measurements of all the groups showed a steady increase with no signs of overt toxicity. The liver had the highest amount of gold (µg) per gram of tissue after 56 days followed by the spleen, lungs, skeleton and carcass. Markers of kidney and liver damage showed similar trends between the pre and post samples within each group and across groups. The histopathological examination also showed no hepatotoxicity and nephrotoxicity. There was accumulation of Au in tissues after repeated dosing, albeit with no observable overt toxicity, kidney or liver damage.

Potential of Improving the Treatment of Tuberculosis Through Nanomedicine

Current treatment of tuberculosis is inadequate due to lengthy treatment course and drug-related toxicity. To address these setbacks, we developed a nanotechnology drug delivery system that can be administered in a single dose that maintains an active level of drug for at least a week. Polymeric poly(lactic-co-glycolic acid) nanoparticles of 200–300 nm were synthesized, with a drug encapsulation efficiency of 50–65% for isoniazid and rifampicin. The particles were taken up in vitro and in vivo and a slow release profile was observed in mice over 5 days. This study illustrates the feasibility of a sustained release system for tuberculosis treatment.

Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice

Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity.

Nanomedicine in the Development of Drugs for Poverty-Related Diseases

The use of current treatments for poverty-related diseases (PRDs) is compromised due to factors such as toxicity and poor solubility leading to lowered bioavailability and thus reduced efficacy. In addition, there is lack of activity from the pharmaceutical industry due to the difficulty in refinancing the high development costs. Hence, new approaches have to be explored for the treatment of PRDs. Nanotechnology-based drug delivery systems (nanomedicine) offer a possible solution by presenting the ability to alter the pharmacokinetics of the conventional drugs to enhance bioavailability, increase the half-life of the drugs and reduce the toxicity. The advantages that nanomedicine-based drug delivery systems present in the treatment of PRDs and the progress of its application in Africa are summarised in this chapter. Nanodrug delivery systems seem to be a promising and viable strategy for improving treatment of PRDs and should urgently be considered in drug development programmes in Africa.