Synthesis and Biological Analysis of Prostate-Specific Membrane Antigen-Targeted Anticancer Prodrugs

Abstract

Ligand-targeted therapeutics have increased in prominence because of their potential for improved potency and reduced toxicity. However, with the advent of personalized medicine, a need for greater versatility in ligand-targeted drug design has emerged, where each tumor-targeting ligand should be capable of delivering a variety of therapeutic agents to the same tumor, each therapeutic agent being selected for its activity on a specific patient's cancer. In this report, we describe the use of a prostate-specific membrane antigen (PSMA)-targeting ligand to deliver multiple unrelated cytotoxic drugs to human prostate cancer (LNCaP) cells. We demonstrate that the PSMA-specific ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid, is capable of mediating the targeted killing of LNCaP cells with many different therapeutic warheads. These results suggest that flexibility can be designed into ligand-targeted therapeutics, enabling adaptation of a single targeting ligand for the treatment of patients with different sensitivities to different chemotherapies.

DUPA Conjugation of a Cytotoxic Indenoisoquinoline Topoisomerase I Inhibitor for Selective Prostate Cancer Cell Targeting

“…12 These properties make PSMA an excellent candidate for tumor-targeted drug delivery of anticancer agents. 13 −15 In 2009, the Post and Low groups at Purdue University reported the design of a 99m Tc-radioimaging derivative 2 of DUPA starting from the crystal structure of a PSMA−inhibitor 3 complex (PDB code 2C6C). 16 The radioimaging agent has potential applications in detecting prostate cancer recurrence, monitoring response to therapy, and selecting patients for PSMA-targeted therapy.…”

At the Interface of Chemical and Biological Synthesis: An Expanded Genetic Code

“…Similarly, bispecifics have been made that target CD33 and CLL1 for the treatment of acute myelogenous leukemia . Tumorspecific small molecules can also be used to recruit cytotoxic T cells to tumor cells (Murelli et al 2009;Kularatne et al 2010). For example, 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid, a small molecule that selectively binds PSMA, which is overexpressed in prostate cancer, was site-specifically conjugated to anti-CD3 to generate a PSMA-targeting small molecule-antibody conjugate (SMAC) (Fig.…”

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

“…Another advantage of ligand-targeted therapies is the ability to design a cognate imaging agent with the same targeting ligand [70,71]. Furthermore, ligand (2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid) (DUPA) can selectively bind to a cell surface glycoprotein and it is known as prostate-specific membrane antigen [72,73]. The efficiency of drug release from respective DUPA-conjugates with chemotherapeutics was assessed by treating the conjugate with either glutathione (GSH, tripeptide) or dithiothreitol (DTT) to reduce the disulfide bonds.…”