RESUMEN
Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates. In vitro cytotoxicity of these molecules was evaluated using the MTT assay. Based on the assay results, we selected the conjugate which showed cytotoxic potential close to unmodified docetaxel. At the same time, the molar solubility of the resulting compound increased up to 20 times in comparison with the drug itself. In vivo evaluation on 22Rv1 (PSMA+) xenograft model demonstrated a good potency of the synthesized conjugate to inhibit tumor growth: the inhibition turned out to be more than 80% at a dose of 30 mg/kg. Pharmacokinetic parameters of conjugate distribution were analyzed. Also, it was found that PSMA-targeted docetaxel conjugate is less toxic than docetaxel itself, the decrease of molar acute toxicity in comparison with free docetaxel was up to 20%. Obtained conjugate PSMA-DOC is a good candidate for further expanded preclinical trials because of high antitumor activity, fewer side toxic effects and better solubility.
Asunto(s)
Antineoplásicos/farmacología , Docetaxel/farmacología , Antígeno Prostático Específico/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Docetaxel/síntesis química , Docetaxel/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/metabolismo , Conejos , Ratas , Ratas Wistar , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
This review presents data on dual conjugates of therapeutic and diagnostic action for targeted delivery to prostate cancer cells. The works of the last ten years on this topic were analyzed. The mail attention focuses on low-molecular-weight conjugates directed to the prostate-specific membrane antigen (PSMA); the comparison of high and low molecular weight PSMA-targeted conjugates was made. The considered conjugates were divided in the review into two main classes: diagnostic bimodal conjugates (which are containing two fragments for different types of diagnostics), theranostic conjugates (containing both therapeutic and diagnostic agents); also bimodal high molecular weight therapeutic conjugates containing two therapeutic agents are briefly discussed. The data of in vitro and in vivo studies for PSMA-targeted double conjugates available by the beginning of 2021 have been analyzed.
Asunto(s)
Antígenos de Superficie/química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Citostáticos/química , Glutamato Carboxipeptidasa II/química , Neoplasias de la Próstata/diagnóstico , Antígenos de Superficie/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Citostáticos/farmacología , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Humanos , Masculino , Estructura Molecular , Peso Molecular , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
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.