RESUMEN
The design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry. In this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenvironment of most solid tumors has attracted considerable attention. This review summarizes the major progresses that have been realized in this field over the past ten years. This includes the new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of ß-glucuronidase-responsive albumin binding prodrugs.
Asunto(s)
Antineoplásicos/farmacología , Glucuronidasa/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Profármacos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Profármacos/uso terapéuticoRESUMEN
The rise of chemical biology has led to the development of sophisticated molecular devices designed to explore and manipulate biological processes. Within this framework, we developed the first chemical system programmed for the selective internalization and subsequent enzyme-catalyzed double release of bioactive compounds inside a targeted population of cells. This system is composed of five distinct units including a targeting ligand, an enzymatic trigger, a self-immolative linker and two active compounds articulated around a chemical amplifier. Designed as such, this molecular assembly is capable in an autonomous manner to recognize a selected population of cells, penetrate into the intracellular medium through endocytosis and transform a single enzymatic activation step into the release of two active units. Demonstrating that an enzyme-catalyzed amplification process can occur spontaneously under the conditions prevailing within the cells could be an important step toward the development of innovative molecular systems for a diverse range of applications spanning drug delivery, biological sensors and diagnostics.
Asunto(s)
Antineoplásicos/farmacología , Galactósidos/farmacología , beta-Galactosidasa/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Biocatálisis , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Galactósidos/biosíntesis , Galactósidos/química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas , beta-Galactosidasa/químicaRESUMEN
We developed a glucuronide prodrug of the potent monomethylauristatin E (MMAE). This prodrug is significantly less toxic than the parent drug. However, in the presence of ß-glucuronidase the prodrug leads to the efficient release of MMAE thereby triggering a subnanomolar cytotoxic activity against several cancer cell lines. Preliminary in vivo experiments conducted in C57BL/6 mice bearing a subcutaneous murine Lewis Lung Carcinoma (LLC) demonstrated the potential of this targeting system for the selective treatment of solid tumors.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Glucurónidos/farmacología , Oligopéptidos/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Animales , Antineoplásicos/química , Carcinoma Pulmonar de Lewis/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glucurónidos/síntesis química , Glucurónidos/química , Humanos , Células KB , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , Profármacos/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Cytarabine combined with an anthracycline or an anthracenedione represents the usual intensive induction therapy for the treatment of AML. However, this protocol induces severe side effects and treatment-related mortality due to the lack of selectivity of these cytotoxic agents. In this paper, we present the study of the first galactosidase-responsive molecular "Trojan Horse" programmed for the delivery of doxorubicin exclusively inside AML blasts over-expressing the folate receptor (FR). This targeting system allows the selective killing of AML blasts without affecting normal endothelial, cardiac or hematologic cells from healthy donors suggesting that FDC could reduce adverse events usually recorded with anthracyclines.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Células Madre Neoplásicas/efectos de los fármacos , beta-Galactosidasa/metabolismo , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/metabolismo , Crisis Blástica/patología , Línea Celular Tumoral , Células Cultivadas , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Sistemas de Liberación de Medicamentos/métodos , Femenino , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Receptor 2 de Folato/genética , Receptor 2 de Folato/metabolismo , Ácido Fólico/química , Células HEK293 , Células HL-60 , Humanos , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/genética , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Adulto JovenRESUMEN
Massive attack: Galactoside prodrugs have been designed that can be selectively activated by lysosomal ß-galactosidase located inside cancer cells expressing a specific tumor-associated receptor. This efficient enzymatic process triggers a potent cytotoxic effect, releasing the potent antimitotic agent MMAE and allowing the destruction of both receptor-positive and surrounding receptor-negative tumor cells.