Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo

Abstract

Artemether (ATM) is an effective antimalarial drug that also has a short half-life in the blood. Furthermore, ATM is also cardiotoxic and is associated with pro-arrhythmogenic risks. We aimed to develop a delivery system enabling the prolonged release of ATM into the blood coupled with reduced cardiotoxicity. To achieve this, we prepared polymeric nanocapsules (NCs) from different biodegradable polyesters, namely poly(D,L-lactide) (PLA), poly-ε-caprolactone (PCL), and surface-modified NCs, using a monomethoxi-polyethylene glycol-block-poly(D,L-lactide) (PEG5kDa-PLA45kDa) polymer. Using this approach, we were able to encapsulate high yields of ATM (>85%, 0–4 mg/mL) within the oily core of the NCs. The PCL-NCs exhibited the highest percentage of ATM loading as well as a slow release rate. Atomic force microscopy showed nanometric and spherical particles with a narrow size dispersion. We used the PCL NCs loaded with ATM for biological evaluation following IV administration. As with free-ATM, the ATM-PCL-NCs formulation exhibited potent antimalarial efficacy using either the “Four-day test” protocol (ATM total at the end of the 4 daily doses: 40 and 80 mg/kg) in Swiss mice infected with P. berghei or a single low dose (20 mg/kg) of ATM in mice with higher parasitemia (15%). In healthy rats, IV administration of single doses of free-ATM (40 or 80 mg/kg) prolonged cardiac QT and QTc intervals and induced both bradycardia and hypotension. Repeated IV administration of free-ATM (four IV doses at 20 mg/kg every 12 h for 48 h) also prolonged the QT and QTc intervals but, paradoxically, induced tachycardia and hypertension. Remarkably, the incorporation of ATM in ATM-PCL-NCs reduced all adverse effects. In conclusion, the encapsulation of ATM in biodegradable polyester NCs reduces its cardiovascular toxicity without affecting its antimalarial efficacy.

Mechanisms of artemether toxicity on single cardiomyocytes and protective effect of nanoencapsulation

“…The mean hydrodynamic diameter, polydispersity index (PDI), and ζ potential of NCs were determined using Zetasizer NanoZS equipment (Malvern Instruments, UK), dynamic light scattering technique (DLS), and DLS coupled with microelectrophoresis for size and ζ potential measurements, respectively. NC‐ATM were developed previously and characterized in detail by our group, and more than 90% of artemether was encapsulated in NCs (Vidal‐Diniz, 2014). Free artemether was prepared as suspension mixing 0.09 g of artemether with 0.3 g of carboxymethylcellulose and 2.0 ml of sorbitol dispersed in 15 ml of MilliQ water.…”

Nanotherapeutics against malaria: A decade of advancements in experimental models

“…berghei ‐infected mice, reducing animal mortality when administered orally, even at the highest tested dose (120 mg/kg; Souza et al, 2018). Similarly, Vidal‐Diniz et al encapsulated different amounts of ARM in the biodegradable polyesters poly( d,l ‐lactide) (ARM‐PLA) and PCL (ARM‐PCL; Vidal‐Diniz et al, 2022; Table 1). PCL nanocapsules exhibited the highest drug loading efficiencies and the lowest release rates.…”

Polymeric Nanoparticles for Biomedical Applications

“…In turn, Vidal-Diniz et al [ 5 ] prepared artemether-loaded polymeric nanocapsules (NCs) for malaria treatment. Three distinct formulations, composed of poly(D,L-lactide) (PLA), poly-ε-caprolactone (PCL), or PEG-PLA, were prepared via the polymer deposition method following solvent displacement with the aim of finding the formulation with the best physicochemical properties.…”