RGD-Modified dendrimers for drug encapsulation and targeted inhibition of tumor cells

• Autor(a) principal: Xuedan, He
• Data de Publicação: 2014
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.13/1532
• topic: Dendrimers; RGD peptide; Doxorubicin; Targeted cancer therapy; Dendrímeros; Péptidos RGD; Doxorubicina; Terapia do cancro dirigida; Nanochemistry and Nanomaterials; .; Faculdade de Ciências Exatas e da Engenharia; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia dos Materiais; Domínio/Área Científica::Ciências Médicas::Biotecnologia Médica

In this study, cyclic arginine-glycine-aspartic acid (RGD) peptide-modified amine-terminated generation 5 poly(amidoamine) (G5.NH2 PAMAM) dendrimers were prepared for the encapsulation of the anticancer drug doxorubicin (DOX) for targeted delivery to cancer cells overexpressing αvβ3 integrin cell surface receptors. First, the thiolated RGD peptide was linked to polyethylene glycol (PEG) via the bifunctional cross-linking reagent 6-maleimidohexanoic acid N-hydroxysuccinimide ester (MHS). Then a dendrimer modification process was performed in which the PEGylated RGD peptide and fluorescein isothiocyanate (FI) were covalently attached to the G5 dendrimers. This process was finally followed by acetylation of the remaining dendrimer terminal amines. The experimental results show that each G5.NHAc-FI-PEG-RGD dendrimer approximately encapsulated six DOX molecules. This formed complex is water soluble and stable. In vitro release studies proved that the multifunctional dendrimers facilitate a sustained release of DOX. More interesting, one-dimensional NMR and two-dimensional NMR were applied to investigate the interactions between dendrimers and DOX. Here, the impact of the environmental pH on the release rate of DOX from G5.NHAc-FI-PEG-RGD/DOX was fully studied. Furthermore, cell biological studies demonstrated that G5.NHAc-FI-PEG-RGD dendrimers have no cytotoxicity towards U87-MG cancer cells but that G5.NHAc-FI-PEG-RGD/DOX complexes have almost the same cytotoxicity as DOX alone. Moreover, due to the targeting ability of RGD, this dendrimer/drug system can also specifically target and display therapeutic efficacy to cancer cells overexpressing αvβ3 integrins. The cellular internalization of the multifunctionalized dendrimer was shown to be receptor mediated to an important extent. According to this study, we can say that G5.NHAc-FI-PEG-RGD is a promising system for the targeted therapy of different types of cancer.