Receptor-mediated hepatocyte-targeted delivery of primaquine phosphate nanocarboplex using a carbohydrate ligand

Abstract

Primaquine phosphate is a drug of choice for the treatment of malarial relapse. However, poor drug concentration in the hepatocytes and dose-related toxicity pose severe limitations. We report a nanocarboplex of primaquine phosphate by a simple in situ process using dextran sulphate as a carbohydrate polymer and pullulan as an asialoglycoprotein receptor ligand. Our aim was to preferentially enhance accumulation of the nanocarboplex in the hepatocytes. The in situ pullulan-anchored primaquine nanocarboplex was prepared by simple addition of a solution of dextran sulphate and pullulan with stabilizer to a measured quantity of primaquine phosphate in a vial, followed by shaking to obtain the primaquine phosphate nanocarboplex ready for injection. The nanocarboplex was characterized and evaluated in vivo for pharmacokinetics and biodistribution in the rat model. Specific uptake by hepatocytes in the liver was also quantified. Increase in t ½ with significant uptake in the RES organ was observed. More importantly, anchoring pullulan favored high liver uptake and preferential accumulation in the hepatocytes with a hepatocytes/nonparenchymal cells ratio of 75:25. The in situ primaquine phosphate nanocarboplex anchored with pullulan provides both a significant technological advantage and the desired targeting to the hepatocytes.

Polyethylene sebacate doxorubicin nanoparticles: role of carbohydrate anchoring on in vitro and in vivo anticancer efficacy

“…Further the ligands exert no influence on the drug loading efficacy and release characteristics (Iden & Allen, 2001). Increase in the average size by about 28 nm (Jokerst et al, 2011) and in zeta potential from À27 mv for NPs to À22, À17, and À19 mv for Pul NPs, AGn NPs, and Pul-AGn NPs, respectively, due to shielding of the negative charge of the nanoparticles, confirmed anchoring of the carbohydrates (Lemarchand et al, 2004;Joshi & Devarajan, 2014). Importantly, negative zeta potential could favor reduced plasma protein adhesion and low non-specific cellular uptake (Zhang et al, 2012).…”

Infectious Diseases: Need for Targeted Drug Delivery

“…Joshi et al prepared in situ primaquine nanocarboplex of primaquine phosphate anchored with pullulan as the ASGPR ligand for specifi c targeting to hepatocytes. Signifi cantly, enhanced hepatic accumulation with preferential accumulation in the hepatocytes and a high hepatocytes/nonparenchymal cells ratio of 75:25 confi rmed hepatocyte targeting [ 244 ]. Transferrin (Tf)-anchored solid lipid nanoparticles (SLNs) were intravenously administered for targeting quinine dihydrochloride to the brain, in cerebral malaria.…”

Polymeric curcumin nanoparticles by a facile in situ method for macrophage targeted delivery

“…The nanocarboplex revealed an average size of ~250 nm with >70% complexation. Active targeting to hepatocytes was confirmed by enhanced hepatocyte accumulation coupled with a very high hepatocytes: parenchymal cells ratio of ~75:25 …”

“…In contrast, in situ nanotechnology presents a method wherein generation of NPs is achieved by simple addition of a monophasic preconcentrate comprising drug, carrier (polymer/lipid), and stabilizers to an aqueous phase. Our group has reported in situ nanotechnology as a facile method for instantaneous and on‐site generation of NPs to enable point of care application . A distinct advantage of in situ technology is total bypass of the technological hurdles and stability issues associated with conventional NP fabrication methods.…”

“…Our group has reported in situ nanotechnology as a facile method for instantaneous and on-site generation of NPs to enable point of care application. [20][21][22] A distinct advantage of in situ technology is total bypass of the technological hurdles and stability issues associated with conventional NP fabrication methods. First generation in situ nanotechnology relies on dilution of monophasic preconcentrates with an aqueous media like potable drinking water just prior to oral administration or dextrose/ dextrose saline injection just prior to intravenous injection.…”