Portal de investigação
Nanoparticles targeting Sialyl-Tn for efficient tyrosine kinase inhibitor delivery in gastric cancer
Data de publicação:
Data Ahead of Print:
Autores da FMUP
Participantes de fora da FMUP
- Diniz, F
- Lamas, S
- Osório, H
- Aguiar, P
- Freitas, D
- Gärtner, F
- Sarmento, B
- Gomes, J
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide and, therefore, it is urgent to develop new and more efficient therapeutic approaches. Foretinib (FRT) is an oral multikinase inhibitor targeting MET (hepatocyte growth factor receptor) and RON (recepteur d'origine nantais) re-ceptor tyrosine kinases (RTKs) that has been used in clinical trials for several solid tumors. Targeted uptake of therapeutic polymeric nanoparticles (NPs) represents a powerful approach in cancer cell drug delivery. Previously, a nanodelivery system composed of polymeric NPs functionalized with B72.3 anti-body, which targets the tumor-associated antigen Sialyl-Tn (STn), has been developed. Herein, these NPs were loaded with FRT to evaluate its capacity in delivering the drug to multicellular tumors spheroids (MCTS) and mouse models. The data indicated that B72.3 functionalized FRT-loaded PLGA-PEG-COOH NPs (NFB72.3) specifically target gastric MCTS expressing the STn glycan (MKN45 SimpleCell (SC) cells), lead-ing to a decrease in phospho-RTKs activation and reduced cell viability. In vivo evaluation using MKN45 SC xenograft mice revealed that NFB72.3 were able to decrease tumor growth, reduce cell proliferation and tumor necrosis. NFB72.3-treated tumors also showed inactivation of phospho-MET and phospho-RON. This study demonstrates the value of using NPs targeting STn for FRT delivery, highlighting its potential as a therapeutic application in GC. Statement of significance Despite the advances in gastric cancer therapeutics, it remains one of the diseases with the highest in-cidence and mortality in the world. Combining targeted therapies with a controlled drug release is an attractive strategy to reduce drug cytotoxic effects and improve specific drug delivery efficiency to the cancer cells. Thus, we developed nanoparticles loaded with a tyrosine kinase inhibitor and targeting a specific tumor glycan exclusive of cancer cells. In in vivo gastric cancer xenograft mice models, these nanoparticles efficiently reduced tumor growth, cell proliferation and tumor necrosis area and inactivated phosphorylation of targeting receptors. This approach represents an innovative therapeutic strategy with high impact in gastric cancer. (c) 2023 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )
Dados da publicação
- ISSN/ISSNe:
- 1742-7061, 1878-7568
- Tipo:
- Article
- Páginas:
- 142-154
Acta Biomaterialia Elsevier BV
Citações Recebidas na Web of Science: 3
Documentos
- Não há documentos
Filiações
Keywords
- Polymeric nanoparticles; Tyrosine kinase inhibitor; Foretinib; Sialyl-Tn antigen; Cancer therapy
Financiamento
Proyectos asociados
Expression of Thomsen-Friedenreich Antigen in colorectal cancer and association with microsatellite instability
Investigador Principal: Celso Albuquerque Reis
Estudo Clínico Académico . 2021
Citar a publicação
Diniz F,Lamas S,Osório H,Aguiar P,Freitas D,Gärtner F,Sarmento B,Reis CA,Gomes J. Nanoparticles targeting Sialyl-Tn for efficient tyrosine kinase inhibitor delivery in gastric cancer. Acta Biomater. 2023. 170. p. 142-154. IF:9,700. (1).
