Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme
| Autor: | Cristina Soto-Sánchez, Pablo Botella, Eduardo Fernández, Elisa Checa-Chavarria, Gema Martinez Navarrete, Miguel Angel Sanchez Martos, Eva Rivero-Buceta |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Generalitat Valenciana |
| Rok vydání: | 2021 |
| Předmět: |
Male
endocrine system diseases Cell Pharmaceutical Science Apoptosis 02 engineering and technology 030226 pharmacology & pharmacy Stereotaxic Techniques 0302 clinical medicine Drug Discovery Cytotoxic T cell Prodrugs heterocyclic compounds U87 Cells Cultured Blood-brain barrier Cerebral Cortex Brain Neoplasms Chemistry Prodrug 021001 nanoscience & nanotechnology medicine.anatomical_structure 5-aminolevulinic acid Molecular Medicine Female 0210 nano-technology medicine.drug endocrine system Cell Survival Primary Cell Culture Antineoplastic Agents Glioblastoma multiforme Article blood−brain barrier 03 medical and health sciences In vivo Cell Line Tumor medicine Animals Humans neoplasms Targeting In vitro digestive system diseases Rats Disease Models Animal Solubility Cell culture Astrocytes Cancer research Camptothecin Drug Screening Assays Antitumor Glioblastoma |
| Zdroj: | RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia instname Digital.CSIC. Repositorio Institucional del CSIC Molecular Pharmaceutics |
| ISSN: | 1543-8392 |
| Popis: | A novel therapeutic approach for glioblastoma multiforme (GBM) therapy has been carried out through in vitro and in vivo testing by using the prodrug camptothecin-20-O-(5-aminolevulinate) (CPT-ALA). The incorporation of ALA to CPT may promote uptake of the cytotoxic molecule by glioblastoma cells where the heme synthesis pathway is active, improving the therapeutic action and reducing the side effects over healthy tissue. The antitumor properties of CPT-ALA have been tested on different GBM cell lines (U87, U251, and C6) as well as in an orthotopic GBM model in rat, where potential toxicity in central nervous system cells was analyzed. In vitro results indicated no significant differences in the cytotoxic effect over the different GBM cell lines for CPT and CPT-ALA, albeit cell mortality induced by CPT over normal cell lines was significantly higher than CPT-ALA. Moreover, intracranial GBM in rat was significantly reduced (30% volume) with 2 weeks of CPT-ALA treatment with no significant side effects or alterations to the well-being of the animals tested. 5-ALA moiety enhances CPT diffusion into tumors due to solubility improvement and its metabolic-based targeting, increasing the CPT cytotoxic effect on malignant cells while reducing CPT diffusion to other proliferative healthy tissue. We demonstrate that CPT-ALA blocks proliferation of GBM cells, reducing the infiltrative capacity of GBM and promoting the success of surgical removal, which improves life expectancy by reducing tumor recurrence. Financial support from Spanish Ministry of Economy and Competitiveness (Projects PID2019-111436RB-C21 and SEV-2016-0683) and the Generalitat Valenciana (Project PROMETEO/2017/060) is gratefully acknowledged. We thank Prof. Luis Fernández (Group of Structural Mechanics and Materials Modellings-GEMM, University of Zaragoza, Spain) for donation of human GBM cell lines. We are grateful to Dr. Lawrence Humphreys (CIBER-BBN) for critical reading of the manuscript. |
| Databáze: | OpenAIRE |
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