title: Dehydroascorbate-derivatized chitosan particles for targeting antimalarial agents to infected erythrocytes.
abstract: The mammalian glucose transporter GLUT-1 and Plasmodium falciparum hexose transporter PfHT1 are overexpressed on human RBC infected with the parasite (iRBC), presumably for enhanced glucose uptake. Dehydroascorbic acid (DHA) competes out glucose in GLUT-1 binding. We prepared particles containing chloroquine phosphate using novel derivatives of chitosan (CSN). CSN was either pre-derivatized with DHA (PRE) or particles made of CSN were derivatized by surface-grafting DHA (POST). The optimized formulations were analyzed for size (170-200nm) drug content (about 40%) entrapment efficiency (50-57%), in vitro drug release (80% in 72h, Higuchi's model), hemolysis on exposure to whole blood or RBC at 5% hematocrit, cytotoxicity towards cultured HEK 293T (kidney) and HepG2 (hepatic) cells, targeting iRBC and in vitro efficacy against P. falciparum. PRE particles were superior to POST CSN particles in terms of uptake and extent of preferential targeting to iRBCs than RBCs. Unlike starch particles reported earlier, dextrose did not competitively inhibit uptake of DHA-derivatized CSN particles. Both formulations significantly induced parasite inhibition at 1nM while free drug showed comparable activity at 100nM. Both PRE and POST particles were superior to free drug in efficacy. Targeting with high efficiency promises dose reduction and possibility of overcoming efflux-based drug resistance.
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India.
authors.forename: Hasham
authors.initials: H
authors.lastname: Shafi
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India; National Institute of Pharmaceutical Education and Research, ITI Compound, Rae Bareli 229010, UP, India.
authors.forename: D V Siva
authors.initials: DVS
authors.lastname: Reddy
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India.
authors.forename: Tabassum
authors.initials: T
authors.lastname: Khan
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Ranjan
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India.
authors.forename: Suniti
authors.initials: S
authors.lastname: Vaishya
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India.
authors.forename: Tanuj
authors.initials: T
authors.lastname: Sharma
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqui
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India.
authors.forename: Saman
authors.initials: S
authors.lastname: Habib
authors.affiliation: CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow 226031, UP, India. Electronic address: amit_misra@cdri.res.in.
authors.forename: Amit
authors.initials: A
authors.lastname: Misra
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage*; D048271:Chitosan / Q000737:chemistry*; D003683:Dehydroascorbic Acid / Q000737:chemistry*; D004912:Erythrocytes / Q000187:drug effects* / Q000469:parasitology; D057809:HEK293 Cells; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials; D048271:Chitosan; D003683:Dehydroascorbic Acid
keywords: Chitosan (PubChem CID: 71853); Chloroquine phosphate (PubChem CID: 83818); Chloroquine phosphate malaria; Competitive binding; Dehydroascorbate (PubChem CID: 210328); Flow cytometry; GLUT-1; Nanoparticles