Ongoing clinical trials are exploring anticancer approaches based on signaling by TRAIL, a ligand for the cell death receptors DR4 and DR5. In this study, we report on the selective apoptotic effects of multivalent DR5 binding peptides (TRAIL mim/DR5 ) on cancer cells in vitro and in vivo. Surface plasmon resonance revealed up to several thousand-fold increased affinities of TRAIL mim/DR5 -receptor complexes on generation of divalent and trivalent molecules, the latter of which was achieved with a conformationally restricted adamantane core. Notably, only multivalent molecules triggered a substantial DR5-dependent apoptotic response in vitro. In tumor models derived from human embryonic kidney cells or primary foreskin fibroblasts, TRAIL mim/DR5peptides exerted a cancer cell-selective action that could synergize with resveratrol in a manner independent of p53. In a xenograft model of human colon cancer, a divalent TRAIL mim/DR5 peptide inhibited tumor growth.Our results offer a proof-of-principle for the development of synthetic small molecules to trigger the TRAIL apoptosis pathway for cancer therapy.
Small-molecule ligands specific for prostate-specific membrane antigen (PSMA) have the potential to improve prostate cancer imaging. However, highly charged ligands are difficult to label with 99m Tc and to purify. In this study, we present an adamantanetrimerized small molecule that has nanomolar binding to PSMA and also has 12 negative charges. Methods: To convert this molecule into a clinically viable SPECT diagnostic, we have developed a simple, cartridge-based, solid-phase prelabeling strategy that, within 25 min, converts readily available and inexpensive 99m Tc-pertechnetate into a chemically pure complex, with a reactive N-hydroxysuccinimide (NHS) ester, in neat organic solvent. This stable intermediate can label any aminecontaining small molecule or peptide with 99m Tc in 1 step, with high specific activity and without the need for high-performance liquid chromatography (HPLC). Results: Solid-phase conversion of 99m Tc-pertechnetate to 99m Tc-MAS 3 -NHS (MAS3 is S-acetylmercaptoacetyltriserine) could be completed in 25 min, with .99% radiochemical purity and with no coligands present. This intermediate was then conjugated to adamantane-trimerized GPI (2[(3-amino-3-carboxypropyl)(hydroxy)(phosphinyl)-methyl]pentane-1,5-dioic acid) in 1 step with .95% yield and no need for HPLC purification. The final molecule bound specifically to living human tumor cells expressing PSMA on their surface. Quantitative comparison was made among GPI monomer, GPI trimer, and their 99m Tc-derivatives. Conclusion: Our study describes a simple cartridge-based conversion of 99m Tcpertechnetate to a useful, preloaded NHS ester intermediate that takes only 25 min to prepare and results in .99% radiochemical purity. Using this chemistry, we produced a highspecific-activity, 99m Tc-labeled, PSMA-targeted small molecule and demonstrate g-ray radioscintigraphic imaging of living human prostate cancer cells.
Adamantane scaffolds for affinity maturation of prostate cancer specific ligands of low molecular mass are described. These scaffolds are modular and can be used for conjugation of up to three ligands and an additional effector molecule by standard peptide coupling techniques. The potential of the scaffolds is demonstrated with the multimerization of GPI 1, a prostate cancer specific small molecule. A detailed study of multimerized GPI conjugates with NIR-fluorophores and their binding properties to different prostate cancer cell lines shows the specific binding of these conjugates to cell types positive for prostate specific membrane antigen (PSMA). We demonstrate that these conjugates allow the sensitive imaging of prostate cancer cells with NIR methodology and suggest that our adamantane scaffolds might be generally useful for affinity maturation of small molecules targeting cell surface epitopes.
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