Distribution and Estimation of Imatinib Loaded Pegylated PPI Dendrimeron BDF<sub>1</sub> Hybrid Mice-Bearing K-563 Acute Lymphoblastic Leukemia

Research Article

Austin J Nanomed Nanotechnol. 2016; 4(1): 1044.

Distribution and Estimation of Imatinib Loaded Pegylated PPI Dendrimeron BDF1 Hybrid Mice-Bearing K-563 Acute Lymphoblastic Leukemia

Karthikeyan R¹*, Sai Koushik O¹ and Vijayraj Kumar P²

¹Department of Biotechnology, Acharya Nagarjuna University, India

²Department of Pharmaceutical Sciences, Vignan Pharmacy College, India

3Faulty of Pharmaceutical Sciences, UCSI University, Malaysia

*Corresponding author: Ramadoss Karthikeyan, Department of Biotechnology, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur-522510, India

Received: May 25, 2016; Accepted: June 30, 2016; Published: July 05, 2016


The Pharmacokinetics (PK) and Bio Distribution (BD) of Imatinib loaded PEGylated PPI dendrimer formulations with different drug release rates were studied on BDF1 hybrid mice-bearing k-563 acute lymphoblastic leukemia. Imatinib is an efficacious anticancer drug with a spectrum of potential antitumor applications limited by poor bio distribution at therapeutic concentrations, so Imatinib loaded PEGylated PPI dendrimer was assessed for pharmacokinetic distribution profile of PEGylated PPI dendrimer holding Imatinib. Its single dose (6.25 mg kg-1) was administered i.v. to male micebearing k-563 acute lymphoblastic leukemia. Imatinib concentration was measured in spleen, liver, kidney and lung using a HPLC assay. These findings encourage the development of novel Imatinib formulations to treat other cancers.Estimated the bio-distribution of Imatinib in different vital organ was carriedout by HPLC method and the study was promising the distribution of drug candidate.

Keywords: PEGylated dendrimers; Imatinib; Bio-distribution; Chromatographic method


An effective anticancer drug, currently approved by the FDA is Imatinib used inthe treatment of gastrointestinal stromal tumours (GIST), post-surgical removal of GIST and chronic myelogenous leukaemia. Imatinib competitively binds to the ATP binding site in the Abl domain of the BCR-ABL and it is a sensibly designed inhibitor of signal transduction. Due to its ability to inhibit the tyrosine kinase c-Kit it is effective in GIST [1-3]. For a large spectrum of antitumor applicationsImatinib is employed due to its high target selectivity. Imatinib has shown to inhibit small-cell lung cancer proliferation and to decrease PDGFR-β phosphorylation in nonsmall- celllung cancer. To a-1-acid glycoprotein it has high binding affinity which significantly affects its pharmacokinetics. Because of the protein binding, P450 mediated metabolism and P-glycoprotein affinity features, Imatinib presents drug-drug interactions with a variety of drugs [4-6]. These interactions affect the systemic exposure due to changes in bioavailability, clearance and plasma free fraction and may need dose monitoring. Overall, these studies point out the potential that Imatinib presents but also its limitations: firstly, to penetrate effectively into tissues secondly, to reach sufficient exposure and residence time in the tissue; and third, the complex drug-drug interactions. In order to explore the pharmacokinetics and tissue distribution, Imatinib was formulated in PEGylated PPI dendrimers, which have been shown to alter the pharmacokinetics and toxicology of drugs. Therefore, the current study aims to assess the distribution profile and tissue distribution of PEGylated PPI dendrimers loaded Imatinib in a dendrimeric formulation after administration to on BDF1 hybrid mice-bearing k-563 acute lymphoblastic leukemia [7-9].

Materials and Methods


PEG4000, Reney Nickel was obtained from Sigma, Germany, Raney Nickel was procured from Merck pharmaceuticals private Ltd., Mumbai, India, Triethylamine, dioxan, ethylene diamine, N, N dicyclohexylcarbodiimide (DCC), Cellulose dialysis bag MWCO 12- 14 Kda, Himediaprivate Ltd., India, 4 dimethyl amino pyridine SDfine chemicals private Ltd., Mumbai, India, Imatinib was gifted from Shasunpharmaceuticalsprivate Ltd, Chennai, India.

Synthesis of 5.0 G PPI Dendrimers

Double Michael addiction reaction occurs between acrylonitrile and aqueous solution of ethylenediamine which leads to the half generation EDA-dendrimer-(CN) 4n was synthesized. Next to the exothermic initial phase, the mixture was heated for 1 h at 80°C to complete the addition reaction. By vacuum distillation excess of acrylonitrile was removed. Later, use of Reney Nickel as catalyst, the hydrogenation in methanolfor 1 h at 70°C and 40 atm hydrogen pressures the EDA-dendrimer-(NH2) 4n of full generation was synthesized. Then the reaction mixture was cooled and filtered. Under reduced pressure the solvent was evaporated [7]. The product was then dried under vacuum. By repetition of all the above steps consecutively, EDA-PPI dendrimers up to 5.0G were prepared with acrylonitrile in increasing quantity. The scheme of the synthesis is shown in Figure 1.