In 2015 malaria, an infectious disease caused by the protist Plasmodium spp., registered 212 million cases and claimed the lives of 429,000 people, mainly young African children in developing regions. Despite a significant reduction in the number of malaria-related deaths, there is still a need for new therapeutic strategies such as finding new antimalarial drugs or substantially improving old ones, through decreasing side effects and avoiding resistance evolution. Because malaria pathophysiology is so complex and the disease is so widespread, it is generally accepted that to achieve eradication a combination of tools targeting the parasite and/or mosquito will be needed. These include the improvement of existing approaches and the development of new ones, with drug therapy remaining the mainstay of treatment and prevention to target the parasite reservoir, and nanotechnology being able to provide innovative useful strategies. Encapsulation of drugs in targeted nanovectors (NVs) is a rapidly growing area with a clear applicability to infectious disease treatment, and pharmaceutical nanotechnology has been identified as a potentially essential tool in the future fight against malaria. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a NV for the targeted delivery of antimalarial compounds exclusively to Plasmodium-infected red blood cells (pRBCs), thus increasing drug efficacy and minimizing the induction of resistance to newly developed therapeutic agents. We have engineered polyamidoamine (PAA)-derived NVs combining into a single chemical structure drug encapsulating capacity, antimalarial activity, low unspecific toxicity, specific pRBC targeting, optimal in vivo activity, and affordable synthesis cost. Recent data suggest that the antiparasitic mechanism of PAAs consists on a coating of Plasmodium that has the effect of blocking the erythrocyte invasion of egressed parasites. The ensuing prolonged exposure of Plasmodium to the immune system might be applied to the design of new malaria prophylactic approaches where PAAs could play a dual role as carriers of antimalarial drugs, and as boosters of immunity. In addition to binding egressed merozoites, PAA-based nanoparticles are capable of penetrating late-stage pRBCs, and of adsorbing on intracellular merozoites of both human and murine malarias. Affinity chromatography assays indicate that the specific targeting of PAAs to pRBCs results from the presence of adhesive proteins exported by the parasite to parasitized erythrocyte membranes. The mechanism of pRBC entry by PAAs has not been elucidated yet but it seems to be related to the known increased permeability of parasitized cells to small nanostructures. Preliminary experiments where fluorescently labeled PAAs were administered to living Anopheles atroparvus mosquitoes revealed the presence of the polymers in the circulatory fluids of the insect, thus opening new possibilities for the application of PAAs to malaria therapeutics.
|Titolo:||Amphoteric polyamidoamines as innovative tools to selectively direct antimalarial drugs towards Plasmodium-infected red blood cells|
|Data di pubblicazione:||15-feb-2017|
|Parole Chiave:||Malaria; bioactive and biocompatible polymers; polymeric antimalarial agents|
|Settore Scientifico Disciplinare:||Settore CHIM/04 - Chimica Industriale|
|Enti collegati al convegno:||Università degli Studi di MIlano; CNR-ISMCA|
|Citazione:||Amphoteric polyamidoamines as innovative tools to selectively direct antimalarial drugs towards Plasmodium-infected red blood cells / Elisabet Martí, Krijn Paaijmans, Patricia Urbán, Amedea Manfredi, Arnau Biosca, Elena Lantero, Ernest Moles, Elisabetta Ranucci, Paolo Ferruti, Xavier Fernández-Busquets. ((Intervento presentato al convegno Milan Polymer Days tenutosi a Milano nel 2017.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|