BackgroundCancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin.Methodology/Principal FindingsApotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano) have diameters of 25–50 ηm, which increase to 60–80 ηm upon direct loading of drug (direct-nano), and showed further increase in dimension (75–95 ηm) in conjugated nanoparticles (conj-nano). The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a) localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus) (b) pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c) the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in regression of hepatocellular carcinoma with negligible toxicity to kidney and liver.ConclusionsThe present study thus demonstrates that the direct-nano is highly efficacious in delivery of drug in a target specific manner with lower toxicity to heart, liver and kidney.
Eukaryotic Topoisomerase II (Topo II) is present in two isoforms alpha and beta. The alpha isoform is predominantly localized in proliferative tissue, while beta isoform is present in all tissues. In the present study we report the activity and protein levels of Topoisomerase II alpha and beta in rat brains of different age groups viz.: E11 (Embryo day 11), E18 (Embryo day 18), post-natal day 1, young (<10 days), adult (<6 months) and old (>2 years). Topoisomerase II beta isoform is found to be the predominant form in brain tissue but Topoisomerase II alpha is found in embryos up to post-natal day 1. The studies to examine the regional distribution of Topoisomerase II beta in brain showed highest activity in cerebellar region and that too only neuronal cell fraction. There was a significant age-dependent decline in this activity. Hence, Topoisomerase II beta may have some unknown function in cerebellum and the low levels of Topoisomerase II beta activity in ageing cerebellum may contribute to the genomic instability in cerebellar region of ageing brain.
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