Abstract
Globally, breast cancer is the foremost cause of mortality among women detected with cancer, with 21% diagnosed in India alone. Etoposide loaded gelatin nanoparticles (EGNP) were prepared and its physical characterization (size:150nm±0.241; zeta potential −29.32 mV) was done along with in-vitro studies to assess biotoxicity, intracellular ROS, cell cycle arrest and death caused by EGNPs. We report the molecular pathways induced by EGNP in-vitro, pharmacokinetics, biodistribution and tumor regression in-vivo in Balb/c mice.Gene expression profiling of Bax, Bcl2, p53, Caspase-3, RIPK1, RIPK3 and ß-actin as internal control were done by RT-PCR wherein Etoposide and EGNP treated MCF-7 cells showed higher expressions of apoptotic genes-Bax, p53, caspase-3, lower expression of anti-apoptotic gene-Bcl2 when compared to control. Enhanced expression of necroptosis-RIPK1 were observed, while RIPK3 was insignificant. Since, RIPK1 regulates necroptosis and apoptosis, expression of apoptotic markers confirmed apoptotic molecular mechanisms. Negligible hemolysis of Gelatin nanoparticles (GNP), and EGNP at selected dosages confirmed biocompatibility. In vivo pharmacokinetics and biodistribution were done by 99Tc-labelled nanoparticles indicating increased circulation of EGNPs, allowing accumulation at the tumor site by Enhanced permeability and retention (EPR) phenomena. Tumor regression indicates the efficacy of EGNP by reducing the tumor burden when compared to void GNP and Etop per se, resulting in increased life span. High biocompatibility and bio-efficacy of EGNPs prove their therapeutic potential in cancer treatment.
Highlights
Cancer is a global life-threatening problem, only second to cardiovascular disease
We report the bio-efficacy, ROS generation and cell cycle analysis induced by Etoposide loaded gelatin nanoparticles (EGNP) in MCF-7 breast cancer cell line and HEK-293 cells and compared these results with etoposide per se
We report preparation of Gelatin nanoparticles (GNP) in the size range of ∼150nm with PDI of 0.257; Physical characterization specified a spherical morphology and a size that was in unison with the NTA data
Summary
Cancer is a global life-threatening problem, only second to cardiovascular disease. Past few decades have witnessed an exponential rise in incidence of cancer, by about 33%. There is a 43% increase in cancer incidence as a result of aging (contributing 13%) and burst in population growth (15%) (Fitzmaurice et al, 2017). Etop administration is challenging due to its lipophilic nature and short half-life in serum. It further prevents cancer cell growth and DNA replication by inducing apoptosis in cancer cell. Necroptosis is a caspase-independent death program that may be mediated by receptor interacting protein kinase-3 (RIPK3) (Moriwaki and Chan, 2013). The cellular inhibitor of apoptosis proteins (cIAPs) get depleted, tumor necrosis factor (TNF) receptor-1 stimulates a cascade that terminates by binding RIPK3 with its upstream molecule-RIPK1 via the RIP homotypic interaction motif (RHIM). Mixed lineage kinase domain-like (MLKL) a substrate of RIPK3 is recruited by stimulated, RIPK3 (Sun et al, 2012), and gets phosphorylated to form oligomers that gets transported to the intracellular membranes as well as the plasma membrane, which ruptures the membrane (Cai et al, 2014; Chen et al, 2014; Dondelinger et al, 2014; Wang et al, 2014)
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