Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme
Por:
Checa-Chavarria, E, Rivero-Buceta, E, Martos, M, Navarrete, G, Soto-Sanchez, C, Botella, P and Fernandez, E
Publicada:
5 abr 2021
Ahead of Print:
1 mar 2021
Resumen:
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.
Filiaciones:
Checa-Chavarria, E:
Univ Miguel Hernandez, Inst Bioengn, Elche, Spain
Ctr Network Biomed Res CIBER BBN, Elche 03202, Spain
Rivero-Buceta, E:
Univ Politecn Varencia, Consejo Super Invest Cientcas, Inst Tecnol Quim, Valencia 46022, Spain
Martos, M:
Univ Miguel Hernandez, Inst Bioengn, Elche, Spain
Ctr Network Biomed Res CIBER BBN, Elche 03202, Spain
Navarrete, G:
Univ Miguel Hernandez, Inst Bioengn, Elche, Spain
Ctr Network Biomed Res CIBER BBN, Elche 03202, Spain
Soto-Sanchez, C:
Univ Miguel Hernandez, Inst Bioengn, Elche, Spain
Ctr Network Biomed Res CIBER BBN, Elche 03202, Spain
Botella, P:
Univ Politecn Varencia, Consejo Super Invest Cientcas, Inst Tecnol Quim, Valencia 46022, Spain
:
Univ Miguel Hernandez, Inst Bioengn, Elche, Spain
Ctr Network Biomed Res CIBER BBN, Elche 03202, Spain
hybrid, Green Published
|