Galactose-Anchored Gelatin Nanoparticles for Primaquine Delivery and Improved Pharmacokinetics: A Biodegradable and Safe Approach for Effective Antiplasmodial Activity against P. falciparum 3D7 and in Vivo Hepatocyte Targeting

• Published in: Molecular pharmaceutics 2017-10, Vol.14 (10), p.3356-3369
• Main Authors: Kumar, Hitesh, Gothwal, Avinash, Khan, Iliyas, Nakhate, Kartik T, Alexander, Amit, Ajazuddin, Singh, Vineeta, Gupta, Umesh
• Format: Article
• Language: English
• Subjects: Animals; Antimalarials - pharmacology; Antimalarials - therapeutic use; Biological Availability; Delayed-Action Preparations - pharmacology; Delayed-Action Preparations - therapeutic use; Drug Design; Drug Liberation; Galactose - chemistry; Gelatin - chemistry; Half-Life; Hepatocytes - drug effects; Humans; Inhibitory Concentration 50; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Nanoconjugates - chemistry; Particle Size; Plasmodium falciparum - drug effects; Primaquine - pharmacology; Primaquine - therapeutic use; Rats; Rats, Sprague-Dawley; Tissue Distribution
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.7b00376

Primaquine phosphate (PQ) is mainly used as a radical cure therapy to eradicate relapse of malaria at the liver stage, which is particularly caused by P. falciparum and P. vivax. In the present study, PQ-loaded galactosylated gelatin nanoparticles (Gel–LA–PQ–NPs) were formulated using a one-step desolvation technique. The mean particle size of Gel–LA–PQ–NPs was found to be 93.48 ± 6.36 nm with a zeta potential of 4.80 ± 0.20 mV having 69.90 ± 1.53% encapsulation efficiency. Electron microscopy demonstrated that the NPs were spherical in shape and uniformly distributed without any cluster formation. The in vitro release of PQ from Gel–LA–PQ–NPs has been facilitated in sustained manner, and the release was three times slower than the naïve drug. The prepared nanoparticles (Gel–LA–PQ–NPs) were significantly (p < 0.0001) less hemolytic than the pure drug PQ. The hematological ex vivo study further supported that the developed Gel–LA–PQ–NPs were safer than PQ. The in vitro antiplasmodium assay revealed that the IC50 value against the blood stage of asexual P. falciparum 3D7 strains was significantly (p < 0.01) less (2.862 ± 0.103 μM) for Gel–LA–PQ–NPs than naïve PQ (3.879 ± 0.655 μM). In vivo pharmacokinetic parameters of Gel–LA–PQ–NPs such as half-life and AUC were significantly higher for Gel–LA–PQ–NPs, i.e., with higher bioavailability. Galactosylation of the NPs led to liver targeting of the PQ in animal studies. Approximately eight-fold higher accumulation of PQ was observed in liver compared to pure drug (i.e., PQ). Conclusively, the prepared galactosylated gelatin nanocarrier holds the promising potential and hepatic targetability of an antimalarial, maintaining its safety and biocompatibility.