Purpose The purpose of this study was to investigate the albumin-binding compound 111 In-C4-DTPA as an imaging agent for the detection of endogenous albumin accumulation in tumors. Methods 111 In-C4-DTPA was injected in healthy nude mice for pharmacokinetic and biodistribution studies (10 min, 1, 6, 24, and 48 h, n = 4) and subsequently in tumor-bearing mice for single-photon emission computed tomography/X-ray-computed tomography (SPECT/CT) imaging studies. Four different human tumor xenograft models (LXFL529, OVXF899, MAXFTN401, and CXF2081) were implanted subcutaneously unilaterally or bilaterally (n = 4-8). After intravenous administration of 111 In-C4-DTPA, SPECT/CT images were collected over 72 h at 4-6 time points. Additionally, gamma counting was performed for the blood, plasma, lungs, heart, liver, spleen, kidneys, muscle, and tumors at 72 h post-injection. Results 111 In-C4-DTPA bound rapidly to circulating albumin upon injection, and the radiolabeled albumin conjugate thus formed was stable in murine and human serum. SPECT/CT images demonstrated a time-dependent uptake with a maximum of 2.7-3.8% ID/cm 3 in the tumors at approximately 24 h post-injection and mean tumor/muscle ratios in the range of 3.2-6.2 between 24 and 72 h post-injection. The kidneys and bladder were the predominant elimination organs. Gamma counting at 72 h postinjection showed 1.3-2.5% ID/g in the tumors and mean tumor/muscle ratios in the range of 4.9-9.4. Conclusion 111 In-C4-DTPA bound rapidly to circulating albumin upon injection and showed time-dependent uptake in the tumors demonstrating a potential for clinical application as a companion imaging diagnostic for albumin-binding anticancer drugs.Keywords Albumin . Drug carrier . Imaging agent . SPECT/CT imaging . Tumor accumulation . 111 In S. Daum and J. P. Magnusson contributed equally to this work.
Conformationally restricted amino acids are important components in peptidomimetics and drug design. Herein, we describe the synthesis of a novel, non-proteinogenic constrained delta amino acid containing a cyclobutane ring, cis-3(aminomethyl)cyclobutane carboxylic acid (ACCA). The synthesis of the target amino acid was achieved in seven steps, with the key reaction being a base induced intramolecular nucleophilic substitution. A small library of dipeptides was prepared through the coupling of ACCA with proteinogenic amino acids.
Background: Low pulmonary retinol levels and disrupted retinoid signaling pathway (RSP) have been implicated in the pathogenesis of congenital diaphragmatic hernia (CDH) and associated pulmonary hypoplasia (PH). It has been demonstrated that nitrofen disturbs the main retinol-binding protein (RBP)-dependent trophoblastic retinol transport. Several studies have demonstrated that prenatal treatment with retinoic acid (RA) can reverse PH in the nitrofen-induced CDH model. We hypothesized that maternal administration of RA can increase trophoblastic RBP-dependent retinol transport in a nitrofen model of CDH. Methods: Pregnant rats were treated with nitrofen or vehicle on gestational day 9 (D9) and sacrificed on D21. RA was given i.p. on D18, D19, and D20. Retinol and RA levels were measured using high-performance liquid chromatography. Immunohistochemistry was performed to evaluate trophoblastic expression of RBP. Expression levels of the primary RSP genes were determined using quantitative real-time PCR and immunohistochemistry. results: Markedly increased trophoblastic RBP immunoreactivity was observed in CDH+RA compared to CDH. Significantly increased serum and pulmonary retinol and RA levels were detected in CDH+RA compared to CDH. Pulmonary expression of RSP genes and proteins were increased in CDH+RA compared to CDH. conclusion: Increased trophoblastic RBP expression and retinol transport after antenatal administration of RA suggest that retinol-triggered RSP activation may attenuate CDHassociated PH by elevating serum and pulmonary retinol levels. t he mortality rate of infants born with congenital diaphragmatic hernia (CDH) remains high despite prenatal diagnosis and improved postnatal treatment strategies (1). The high morbidity and mortality is mainly attributed to pulmonary hypoplasia (PH) and associated persistent pulmonary hypertension (2). Much of the current understanding of the pathogenesis of PH in CDH originates from experimental animal studies. Maternal exposure to nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether) in rodents during midgestation results in a high rate of CDH and associated PH in their fetuses, which is strikingly similar to the human condition (3).It is well understood that retinoids-vitamin A and its derivatives-are essential for the morphogenesis of most developing organs and tissues, including the lungs (4). The placenta has a major role in retinol homeostasis in fetal life (5). As the fetus cannot synthesize retinol, it relies on circulating maternal retinol, which reaches the fetus by crossing the maternal-fetal barrier in the placenta (6). Although retinol-binding protein (RBP) is essential for retinol transport within the circulation (7), maternal RBP does not cross the placenta (8). Therefore, in order to enter the fetal circulation, maternal retinol bound to maternal RBP must be released at the maternal-fetal interface. Fetal RBP is produced by the trophoblast and then forms a complex with retinol to be subsequently released into the fetal circulation and delivered to the ...
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