Pharmaceutical NanotechnologySynthesis, characterization of chitosan–tripolyphosphate conjugated chloroquine nanoparticle and its in vivo anti-malarial efficacy against rodent parasite: A dose and duration dependent approach
Graphical abstract
Introduction
Pharmaceuticals and pharmaceutical carriers represent currently an important and still growing area of biomedical research by the help of the basic property of any multifunctional nanocarrier. Nanotechnology is a multidisciplinary field covering the design, manipulation, characterization, production and application of structures, devices and systems at nanometer scale (1–500 nm size range) which at this size range present with unique or superior physicochemical properties (Bawa et al., 2005). Chitin is an interesting biopolymer to prepare nano sized particle, owing to its unique polymeric cationic character, good biocompatibility, biodegradability, its mucoadhesivity, and absorption-enhancing effects. Additionally, the use of a natural polymer as the carrier material avoids any potentially toxic effects of nanoparticles (Wang et al., 2012). Chitosan, a natural linear biopolyaminosaccharide obtained by alkaline deacetylation of chitin (Fig. 1a), and second abundant polysaccharide next to cellulose. Rendering amino (NH2) and hydroxyl (OH) groups, CS enables a high degree of chemical modification. Chitin is a straight chain homopolymer composed of (1,4)-linked N-acetyl glucosamine units, while CS comprises of copolymers of glucosamine and N-acetyl glucosamine. CS has one primary amino group and two free hydroxyl groups for each C6 building unit. Due to the availability of free amino groups, it carries a positive charge and reacts with many negatively charged surfaces such as the cell membrane, mucus lining (due to negatively charged sialic acid residues), and also with other anionic polymers (Paliwal et al., 2012, Chakraborty et al., 2010). CS is a weak base, insoluble in water and organic solvents, however, it is soluble in dilute aqueous acidic solution (pH < 6.5), which can convert the glucosamine units into a soluble form of protonated amine (RNH3+) (Lam et al., 2006). As such nanomedicine drug delivery system can reduce the drug dosage frequency, treatment time and toxicity (Swai et al., 2008). Thus nanodrug delivery systems seem to be a promising and viable strategy for improving malaria treatment.
Both passive and active nanotechnology-based drug delivery systems for malaria have been evaluated and they are able to deliver the drug to the specific target in the human body where the malaria parasite is located. In passive targeting, conventional nanocarriers or surface-modified long-circulating nanocarriers can be used (Kato et al., 2003, Soma et al., 2000). Although it is true that the pharmacokinetics of drugs differ between humans and mice, it is also true that all mammalian plasmodium species have comparable life cycles and are sensitive to the same drugs. The increasing resistance of malaria parasites to available drugs increases the burden of disease and the need to develop new and effective anti-malarial agents (Guinovart et al., 2006). The outbreed albino mouse inoculated with Plasmodium berghei is generally considered to be a valid model for the primary and large scale screening of drugs for eventual use against human malaria. The use of strains of rodent malaria parasites can yield additional information concerning both its potential value against strains of human malaria, and the mode of action of a compound. Therefore, a credible in vivo screening system needs to be established for testing the efficacy of these drugs against malaria (Peters et al., 1975).
The antimalarial drug policy states that all Plasmodium vivax cases, undiagnosed fever cases, and clinical malaria cases should be treated with chloroquine in full therapeutic doses. Chloroquine, an effective drug on all five species of parasites, including some strains of Plasmodium falciparum, therefore, remains the main drug for the treatment of all malarias in India except in PHCs with 10% or more cases found resistant to it (Sharma, 2007). CQ acts against the intraerythrocytic stage of the human malaria parasite, and is thought to exert its toxic effect in the parasite's acidic digestive vacuole (DV). Once inside the acidic DV, CQ becomes protonated (mostly diprotonated), which renders it less membrane-permeant and results in its accumulation to high concentrations but CQ become ineffective due to efflux out of the DV, away from its primary site of accumulation and action (Lehane and Kirk, 2010). In this fact, nano drug carrier may overcome the efflux of CQ from DV and as well as may reduce the resistant zone of the age old CQ.
This study seeks to synthesize, characterize the CS–TPP nanoparticle conjugated chloroquine and to determine whether the initial number of parasites inoculated and/or the medication after inoculation influence the anti-malarial efficacy of nanoconjugated chloroquine against P. berghei NK65 infection in Swiss mice as models, in order to ascertain the true value of its use in the treatment of malaria.
Section snippets
Parasites
The NK65 strain of P. berghei, used in this study was supplied from Dr. Pralhad Ghosh's Research Laboratory, Department of Biotechnology, Delhi University, South Campus, Delhi, India and maintained into sex and age-matched wild type mice by weekly passage by intraperitoneal injection (Joshi et al., 2008) and blood stage parasites were stored at −80 °C.
Animals
Swiss male mice (6–8 weeks old, weight 20–25 g) were used to full fill the experiments. Animals were maintained in accordance with the guidelines
Results and discussion
Nanomedicine has the potential to restore the use of old and toxic drugs by modifying their biodistribution, improve bioavailability and reducing toxicity (Peters et al., 1975), so we have synthesized and characterized by conjugating the chloroquine with CS–TPP NPs and it has been treated 100 mg/kg bw/day, 250 mg/kg bw/day and 500 mg/kg bw/day in P. berghei infected Swiss mice to evaluate the effective dose. To determine the effective duration, we have charged the evaluated effective dose for 5
Conclusion
The study demonstrate that, ionically cross-linked CS–TPP nanoparticles act as drug delivery vehicles against rodent parasite and CS–TPP NP containing chloroquine, potentially eliminate parasite and protects the lymphocytes, serum and RBC against P. berghei infection at the dose of 250 mg/kg bw/day for 15 days maximally by decreasing free radical generation, lipid and protein damage, and also by increasing the antioxidant status. Hence, the nanoconjugated chloroquine may be used as a potential
Conflicts of interest
The authors declare that there are no conflicts of interest.
Acknowledgements
The authors express gratitude to the Indian Institute of Technology, Kharagpur and Vidyasagar University, Midnapore for providing the facilities to execute these studies.
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