ABSTRACT
Linear arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) peptide-nonsteroidal anti-inflammatory drug conjugates were synthesized to evaluate their anticancer effect. Two well-known targeting peptide sequences, RGD and NGR, were conjugated with naproxen and ibuprofen. It is expected that the RGD peptide selectively binds to αv -integrin receptors, which are highly expressed in cancer cells, and that the NGR peptide selectively targets aminopeptidase N (APN/CD13, EC 3.4.11.2), which is overexpressed in blood vessels of tumors. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon linker (hexanoic acid) was also used as a spacer. Cytotoxic effects of the synthesized compounds were evaluated against several cancer cell lines, including MCF-7, A2780 (αv ß3 positive), OVCAR3 (high αv ß3 ), HT-1-80, and SKOV-3 cells (CD13 positive). The NGR conjugate forms of both ibuprofen and naproxen showed better activity against the SKOV-3 tumor cell line. The improved binding of these conjugates to their receptors was confirmed by docking studies.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Drug Design , Oligopeptides/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Fibroblasts/drug effects , Humans , Molecular Docking Simulation , Molecular Structure , Oligopeptides/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
It is well known that Arginine-Glycine-Aspartic acid (RGD) and Asparagine-Glycine-Arginine (NGR) peptides preferentially bind to integrin receptors and aminopeptidase N respectively and these two receptors play important roles in angiogenesis. Therefore ketoprofen as a non-selective cox Inhibitor was conjugated with linear RGD and NGR to take advantage of targeting capability of these two motifs and delivering ketoprofen to these cancer cells with overexpression of integrin and aminopeptidase N. In order to investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six carbon (hexanoic acid) linker was also used as a spacer. Cytotoxic effect of the synthesized compounds was evaluated against a group of cancer cell lines, including MCF-7, A2780 (αvß3 positive), OVCAR3 (high αvß3), HT-1-80 (high CD13) and SKOV-3 (CD13 positive). Both NGR and RGD conjugated forms of ketoprofen showed higher cytotoxic activity against OVCAR3 and HT-1-80 respectively.
ABSTRACT
The introduction of 2-[18F] fluor-2-deoxy-D-glucose (18FDG) has provided a valuable tool for the study of glucose metabolism in both normal and diseased tissue in conjunction with positron emission tomography (PET). 18FDG is the most important radiopharmaceutical to be used in Nuclear Medicine for studying the brain, heart and tumor. The advancement in synthesis and quality control of 18FDG and its approval by US FDA are main reasons for increasing clinical application of 18FDG over the last 20 years. In this manuscript we explain the synthesis, quality control and stability studies of 18FDG (evaluate the physicochemical and microbiological stability of 18FDG, stored at room temperature (18 - 23 °C), and 35 - 40 °C, at different time intervals). We investigated how the influence of environmental factors in different lengths of time, alters the quality of this radiopharmaceutical. The pH, radionuclidic identity and purity, radiochemical identity and purity, chemical purity, bacterial endotoxins and sterility of 18FDG were evaluated according to the European Pharmacopoeia 7ed. analytical methods and acceptance criteria. The results suggest that under experimental conditions 18FDG has physicochemical and microbiological stability up to 10 h after the end of synthesis.
