Browsing by Author "Keating, Kelly A."
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Item Pharmacokinetics, biodistribution, and anti-angiogenesis efficacy of diamino propane tetraiodothyroacetic acid-conjugated biodegradable polymeric nanoparticle(Nature, 2019-06-21) Li, Weikun; Bharali, Dhruba J.; Lin, Qishan; Godugu, Kavitha; Fujioka, Kazutoshi; Keating, Kelly A.; Mousa, Shaker A.; Yalçın, Murat; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734The anti-angiogenic agent, diamino propane tetraiodothyroacetic acid (DAT), is a thyro-integrin (integrin alpha v beta 3) antagonist anticancer agent that works via genetic and nongenetic actions. Tetraiodothyroacetic acid (tetrac) and DAT as thyroid hormone derivatives influence gene expression after they transport across cellular membranes. To restrict the action of DAT to the integrin alpha v beta 3 receptors on the cell surface, we used DAT-conjugated PLGA nanoparticles (NDAT) in an active targeting mode to bind to these receptors. Preparation and characterization of NDAT is described, and both in vitro and in vivo experiments were done to compare DAT to NDAT. Intracellular uptake and distribution of DAT and NDAT in U87 glioblastoma cells were evaluated using confocal microscopy and showed that DAT reached the nucleus, but NDAT was restricted from the nucleus. Pharmacokinetic studies using LC-MS/MS analysis in male C57BL/6 mice showed that administration of NDAT improved the area under the drug concentration curve AUC(()(0-)(48 h)) by 4-fold at a dose of 3 mg/kg when compared with DAT, and C-max of NDAT (4363 ng/mL) was 8-fold greater than that of DAT (548 ng/ mL). Biodistribution studies in the mice showed that the concentrations of NDAT were higher than DAT/Cremophor EL micelles in heart, lung, liver, spleen, and kidney. In another mouse model using female NCr nude homozygous mice with U87 xenografts, tumor growth was significantly decreased at doses of 1 and 3 mg/kg of NDAT. In the chick chorioallantoic membrane (CAM) assay used to measure angiogenesis, DAT (500 ng/CAM) resulted in 48% inhibition of angiogenesis levels. In comparison, NDAT at low dose (50 ng/CAM) showed 45% inhibition of angiogenesis levels. Our investigation of NDAT bridges the study of polymeric nanoparticles and anti-angiogenic agents and offers new insight for the rational design of anti-angiogenic agents.Item Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac(Dove Medical, 2017) Sudha, Thangirala; Bharali, Dhruba J.; Darwish, Noureldien H. E.; Keating, Kelly A.; Lin, Hung-Yun; Davis, Paul J.; Mousa, Shaker A. Shaker A.; Yalçın, Murat; Coşkun, Melis Debreli; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; AAF-3992-2020; 57192959734; 57193066146The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic-co-glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin alpha v beta 3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; P < 0.001) and 2.3-fold (doxorubicin; P < 0.01) higher than with conventional systemic drug administration. Tumor volume reductions reflected enhanced xenograft drug uptake. Cell viability was estimated by bioluminescent signaling in pancreatic tumors and confirmed an increased paclitaxel effect with drug delivery by NDAT. NDAT delivery of chemotherapy increases drug delivery to cancers and increases drug efficacy.