Low generation degradable dendrimer nanoclusters for delivery of anti-cancer drug

• Autor(a) principal: Shekar, Akudari Raja
• 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/10400.13/1533
• topic: Dendrimers; Nanoclusters; Doxorubicin; Drug delivery; Dendrímeros; Nanoagregados; Doxorubicina; Entrega de fármacos; 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

Although doxorubicin (DOX) has been widely investigated for treatment of different types of cancer, its poor cellular uptake and intracellular release still limit its further clinical applications (1). Due to their favourable characteristics, including the well-defined architecture, multivalency, and modifiable surface functionality, poly(amidoamine) (PAMAM) dendrimers have been extensively investigated for biomedical applications (2). However, most of the dendrimers are nondegradable, consequently resulting in high toxicity and uncontrollable drug release with limited release efficiency, which limits their further application in delivery of therapeutic agents (3). Low generation dendrimers are less expensive, possess a low number of defects and are more biocompatible than those of high generation. In this work degradable dendrimer nanoclusters were prepared by crosslinking of low generation PAMAM dendrimers (Generation 3, G3) using N, N’- cystamine-bis-acrylamide (CBA) as a disulphide containing cross linker. The synthesized G3-CBA was then PEGylated using methoxyl poly(ethylene glycol) carboxylic acid (m-PEG-COOH) (MW 2000 g/mol) for further improvement of the colloidal stability, which can be also helpful for prolonging the circulation period as well as reducing their toxicity, immunogenicity and antigenicity. The resulting G3-CBA-PEG dendrimers were characterised using Nuclear Magnetic Resonance (NMR), Fourier Transform Infra-Red Spectroscopy (FTIR), and Dynamic Light Scattering (DLS) to confirm the structure of G3-CBA and their PEGylated form (G3-CBAPEG). UV-Visible Spectroscopy technique was also performed to study the encapsulation of drug in the synthesized dendrimer nanoclusters. DOX, as a model drug was loaded into the resulting G3-CBA-PEG to obtain drug-loaded nanosystems (G3-CBA-PEG/DOX), which have been tested for anticancer drug delivery, concerning their drug release properties and anticancer cytotoxicity and cellular uptake through evaluation against CAL-72 cells (an osteosarcoma cell line). The results indicate that G3-CBA-PEG/DOX presented a pH and redox sensitive drug release in a sustainable way. The G3-CBA-PEG showed a reduced cytotoxicity than G3 dendrimers. G3-CBA-PEG/DOX presented a comparable anticancer cytotoxicity as compared with G3/DOX. The merits of the low generation PAMAM dendrimers, such as good cytocompatibility, sustained pH- and redox- dual cell responsive release properties, and improved anticancer activity, make them a promising platform for the delivery of other therapeutic agents beyond DOX.