Polypeptide-Based Molecular Platform and Its Docetaxel/Sulfo-Cy5-Containing Conjugate for Targeted Delivery to Prostate Specific Membrane Antigen

Stanislav A Petrov,Elena K Beloglazkina,Nikolay V Zyk,Alexander G Majouga,Vitaly A Roznyatovsky,Aleksei E Machulkin,Anastasia A Uspenskaya,Yuri K Grishin,Nikolay Y Zyk,Anastasia S Garanina,Vladimir I Polshakov,Rostislav A Petrov,Ekaterina A Nimenko

doi:10.3390/molecules25245784

Abstract

A strategy for stereoselective synthesis of molecular platform for targeted delivery of bimodal therapeutic or theranostic agents to the prostate-specific membrane antigen (PSMA) receptor was developed. The proposed platform contains a urea-based, PSMA-targeting Glu-Urea-Lys (EuK) fragment as a vector moiety and tripeptide linker with terminal amide and azide groups for subsequent addition of two different therapeutic and diagnostic agents. The optimal method for this molecular platform synthesis includes (a) solid-phase assembly of the polypeptide linker, (b) coupling of this linker with the vector fragment, (c) attachment of 3-aminopropylazide, and (d) amide and carboxylic groups deprotection. A bimodal theranostic conjugate of the proposed platform with a cytostatic drug (docetaxel) and a fluorescent label (Sulfo-Cy5) was synthesized to demonstrate its possible sequential conjugation with different functional molecules.

Highlights

Prostate cancer (PCa) is one of the most commonly diagnosed men’s cancers and remains one of the leading causes of cancer death
1) was compound was PSMAfor ligands of structurally types, and it was shown that, for maximum affinity to the tested cytotoxic activity andrelated cell staining
To obtain the target prostate-specific membrane antigen (PSMA) ligand with peptide fragments, we developed the synthetic scheme, linker fragment for further stage-by-stage conjugation, with diagnostic and therapeutic moieties at including the following stages: (1) synthesis of EuK vector 6 with modified urea fragment

Summary

Introduction

Prostate cancer (PCa) is one of the most commonly diagnosed men’s cancers and remains one of the leading causes of cancer death. Depending on the stage of the cancer and its severity, various imaging techniques, such as computed tomography (CT), transrectal ultrasound, and relatively recent methods such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron. Molecules 2020, 25, 5784 emission tomography (PET) are used to assess prostate cancer [3]. The selected method for the treatment of PC usually depends on the stage of the disease. For localized PC, the options range from radical prostatectomy to radiation therapy. Metastatic PC is preferably treated with androgen deprivation therapy (ADT). When tumors develop resistance to androgens, the options are reduced to alternative hormone therapy or chemotherapy. No active treatment for PC showed superiority in survival rates

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Discussion

Conclusion