Publicação
Polymeric nanoparticles for methotrexate delivery
| Resumo: | Cancer has one of the highest incidence rates worldwide and chemotherapy remains the main treatment option for most cancers. Chemotherapy has several limitations, such as systemic toxicity, severe side effects and limited efficacy. Nanoparticles (NPs) offer the possibility to encapsulate poorly soluble drugs, protect these therapeutic molecules and modify their blood circulation and tissue distribution profiles. The intravenous (IV) route is the most reliable route of entry for all drug delivery systems (DDS). However, there are multiple biological barriers after IV administration. Due to unique size and amenability to surface functionalization of NPs, they are particularly suitable to overcome these barriers. Body distribution and elimination of NPs depends on several characteristics, but size and surface characteristics are the most important, controlling the fate of the NPs. In general, NPs ranging between 10 and 100 nm, coated with hydrophilic molecules, such as poly(ethylene glycol) (PEG), and modified with a targeting agent at the surface, such as folic acid (FA), can overcome the drawbacks of chemotherapy, allowing an effective treatment for cancer. Methotrexate (MTX) is extensively used for the treatment of cancer and also for the treatment of rheumatoid arthritis (RA). The main objective of this thesis was the development of polymeric NPs as DDS for a specific delivery of MTX. For this, an exhaustive optimization was performed in order to encapsulate high concentrations of MTX in Poloxamer 407 (P407)-based nanoemulsions. P407-MTX conjugate and several MTX derivatives, such as MTX disodium salt (MTX-Na); MTX-dimethyldioctadecylammonium bromide (MTX-DODAB) complex and MTX diethylated (MTX-OEt), were developed and used for the production of the intended NPs. The physicochemical and biological characterization of the developed nanoemulsions demonstrated the production of effective nanoemulsions suitable for MTX delivery applications. Nanoemulsions prepared using a combination between the P407-MTX conjugate and the MTX-OEt derivative demonstrated a great biological effect against cancer cells (Caco-2 cell line). In addition, polymeric micelles were developed, using PEGylated MTX (MTX-PEG2000). Although further optimizations are needed, the preliminary results demonstrated that this conjugate is able to induce the formation of micelles. In conclusion, the work developed in this master thesis allowed the accomplishment of the objectives proposed and the development of promising DDS for therapeutic applications, mainly for cancer therapy. |
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| Autores principais: | Moura, Ana Sofia dos Santos |
| Ano: | 2018 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Cancer has one of the highest incidence rates worldwide and chemotherapy remains the main treatment option for most cancers. Chemotherapy has several limitations, such as systemic toxicity, severe side effects and limited efficacy. Nanoparticles (NPs) offer the possibility to encapsulate poorly soluble drugs, protect these therapeutic molecules and modify their blood circulation and tissue distribution profiles. The intravenous (IV) route is the most reliable route of entry for all drug delivery systems (DDS). However, there are multiple biological barriers after IV administration. Due to unique size and amenability to surface functionalization of NPs, they are particularly suitable to overcome these barriers. Body distribution and elimination of NPs depends on several characteristics, but size and surface characteristics are the most important, controlling the fate of the NPs. In general, NPs ranging between 10 and 100 nm, coated with hydrophilic molecules, such as poly(ethylene glycol) (PEG), and modified with a targeting agent at the surface, such as folic acid (FA), can overcome the drawbacks of chemotherapy, allowing an effective treatment for cancer. Methotrexate (MTX) is extensively used for the treatment of cancer and also for the treatment of rheumatoid arthritis (RA). The main objective of this thesis was the development of polymeric NPs as DDS for a specific delivery of MTX. For this, an exhaustive optimization was performed in order to encapsulate high concentrations of MTX in Poloxamer 407 (P407)-based nanoemulsions. P407-MTX conjugate and several MTX derivatives, such as MTX disodium salt (MTX-Na); MTX-dimethyldioctadecylammonium bromide (MTX-DODAB) complex and MTX diethylated (MTX-OEt), were developed and used for the production of the intended NPs. The physicochemical and biological characterization of the developed nanoemulsions demonstrated the production of effective nanoemulsions suitable for MTX delivery applications. Nanoemulsions prepared using a combination between the P407-MTX conjugate and the MTX-OEt derivative demonstrated a great biological effect against cancer cells (Caco-2 cell line). In addition, polymeric micelles were developed, using PEGylated MTX (MTX-PEG2000). Although further optimizations are needed, the preliminary results demonstrated that this conjugate is able to induce the formation of micelles. In conclusion, the work developed in this master thesis allowed the accomplishment of the objectives proposed and the development of promising DDS for therapeutic applications, mainly for cancer therapy. |
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