Abstract
The anti-angiogenic agent, diamino propane tetraiodothyroacetic acid (DAT), is a thyro-integrin (integrin αvβ3) 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 αvβ3 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 Cmax 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.
Highlights
Angiogenesis, the development of new blood vessels, is crucial for tumor growth
Folkman’s group pioneered the concept of angiogenesis modulation and its potential impact on cancer therapy. They found that angiogenesis inhibitor-copolymer conjugates did not cross the blood-brain barrier and they accumulated less in normal organs, resulting in lower neurotoxicity[10]. They demonstrated that conjugation of the potent, broad-spectrum angiogenesis inhibitor TNP-470 to monomethoxy-polyethylene glycol-polylactic acid to generate an oral formulation of nanopolymeric micelles improved TNP-470 inhibition of tumor angiogenesis in mice, and the conjugate did not cause neurotoxicity[11]
Further synthetic details for diamino propane tetraiodothyroacetic acid (DAT) and PLGA-DAT are provided in Supplementary Fig. S2
Summary
Angiogenesis, the development of new blood vessels, is crucial for tumor growth. An established tumor needs nutrients and oxygen from the blood in order to grow and spread, and several angiogenic factors are induced to promote the growth of new blood vessels. Many angiogenesis inhibitor candidates are low molecular weight compounds with poor solubility and permeability and have short plasma circulation times Folkman’s group pioneered the concept of angiogenesis modulation and its potential impact on cancer therapy In mice, they found that angiogenesis inhibitor-copolymer conjugates did not cross the blood-brain barrier and they accumulated less in normal organs, resulting in lower neurotoxicity[10]. Diamino propane tetraiodothyroacetic acid (tetrac), named DAT, is a thyroid hormone derivative It blocks the actions of agonist hormone analogs at both the T4/T3 receptor site and the T3-specific receptor site on integrin αvβ[3] and controls proliferation of tumor cells[19,20,21,22,23]. DAT at the thyroid hormone receptor differentially regulates expression of several hundred specific genes relevant to cell division, anti-apoptosis, and angiogenesis, including VEGF, bFGF, PDGF, EGF, EGR17,24,25
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