Publicação
Development of PEGylated nanoparticles for delivery of methotrexate derivatives
| Resumo: | Cancer is one of the most devastating and life-threatening diseases, and conventional chemotherapeutic agents, such as methotrexate (MTX), present several limitations and adverse effects. The use of nanoparticles (NPs) enables an efficient alternative to conventional therapy as they can overcome these limitations. NPs may be engineered to have a prolonged circulation time, enhanced cellular uptake and targeting abilities. One widely used targeting approach is the development of NPs containing folic acid (FA) at the surface. Folate receptor (FR) is overexpressed in tumor cells and is not expressed or is present at low levels in normal cells. In this way, FA-tagged NPs allow a specific delivery of the drug. Although several types of NPs have been developed as drug delivery systems (DDS), this work focused on the polymeric micelles and liposomes. Thus, the main aim of this project was the development of PEGylated micelles and liposomes with suitable characteristics for intravenous (IV) administration and with the ability to delivery hydrophobic MTX derivatives to a target cell population. First of all, micelles and liposomes production methods were optimized. For the micelles production were tested two different methods, auxiliary solvent method and sonication, and the liposomes were produced using ethanol injection method. The full characterization of the developed NPs was performed, including the analysis of their physicochemical properties, stability, drug encapsulation efficiency (EE) and biological effect. The use of the auxiliary solvent method with evaporation at 30 ºC, a polyoxyethanyl-α-tocopheryl sebacate (PTS) concentration of 15 mg/mL and a PTS/MTX diethylated (MTX-OEt) mass ratio of 8:1 resulted in monodisperse micelles with small size. These PEGylated micelles revealed the expected biological effect against cancer cells (Caco-2 cells). In the case of liposomes, the ideal formulation was reached using a lipid concentration of 9 mM, water as aqueous phase, a MTXdimethyldioctadecylammonium bromide (MTX-DODAB) concentration of 2.91 mg/mL and an initial water/ethanol volume of 6/6 mL. The obtained liposomes also showed suitable characteristics including a monodisperse population of small and neutral particles and demonstrated a significant cytotoxicity against cancer cells, similar to free MTX. In sum, the developed PEGylated micelles and liposomes loaded with hydrophobic MTX derivatives demonstrated to be promising DDS for cancer therapy. |
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| Autores principais: | Cerqueira, Patrícia Alexandra Gomes |
| 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 is one of the most devastating and life-threatening diseases, and conventional chemotherapeutic agents, such as methotrexate (MTX), present several limitations and adverse effects. The use of nanoparticles (NPs) enables an efficient alternative to conventional therapy as they can overcome these limitations. NPs may be engineered to have a prolonged circulation time, enhanced cellular uptake and targeting abilities. One widely used targeting approach is the development of NPs containing folic acid (FA) at the surface. Folate receptor (FR) is overexpressed in tumor cells and is not expressed or is present at low levels in normal cells. In this way, FA-tagged NPs allow a specific delivery of the drug. Although several types of NPs have been developed as drug delivery systems (DDS), this work focused on the polymeric micelles and liposomes. Thus, the main aim of this project was the development of PEGylated micelles and liposomes with suitable characteristics for intravenous (IV) administration and with the ability to delivery hydrophobic MTX derivatives to a target cell population. First of all, micelles and liposomes production methods were optimized. For the micelles production were tested two different methods, auxiliary solvent method and sonication, and the liposomes were produced using ethanol injection method. The full characterization of the developed NPs was performed, including the analysis of their physicochemical properties, stability, drug encapsulation efficiency (EE) and biological effect. The use of the auxiliary solvent method with evaporation at 30 ºC, a polyoxyethanyl-α-tocopheryl sebacate (PTS) concentration of 15 mg/mL and a PTS/MTX diethylated (MTX-OEt) mass ratio of 8:1 resulted in monodisperse micelles with small size. These PEGylated micelles revealed the expected biological effect against cancer cells (Caco-2 cells). In the case of liposomes, the ideal formulation was reached using a lipid concentration of 9 mM, water as aqueous phase, a MTXdimethyldioctadecylammonium bromide (MTX-DODAB) concentration of 2.91 mg/mL and an initial water/ethanol volume of 6/6 mL. The obtained liposomes also showed suitable characteristics including a monodisperse population of small and neutral particles and demonstrated a significant cytotoxicity against cancer cells, similar to free MTX. In sum, the developed PEGylated micelles and liposomes loaded with hydrophobic MTX derivatives demonstrated to be promising DDS for cancer therapy. |
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