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| Author(s): |
Paula Aboud Barbugli
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2010-05-05 |
| Examining board members: |
Antonio Claudio Tedesco;
Marcelo Dias Baruffi;
Rose Maria Carlos;
Andréia Machado Leopoldino;
Antonio Eduardo da Hora Machado
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| Advisor: | Antonio Claudio Tedesco |
| Abstract | |
Melanoma is the type of skin cancer with poor prognosis due to its high probability of suffering metastases. Currently there are few effective treatments for the this, and the survival of patients with metastases is very low, around 8 months, with cure rates of these conditions do not exceed 1%. Photodynamic therapy (PDT) is a therapeutic modality selective and non-invasive, it has shown excellent clinical results in the treatment of non-melanoma skin cancers such as squamous and basal cell carcinoma. This work discusses the effectiveness of PDT in human melanoma cell lines in different stages of tumor progression, from the early stages of the disease (radial growth phase cells - RGP), to the metastatic stage, not only in cell culture in monolayer (2D), but also through the development of three-dimensional cellular models (3D), mixed or not with human fibroblasts, which aims to mimic in vitro, the real conditions existing in in vivo tumorigenesis, such as cell-cell contact between cancer cell lines and fibroblasts of the dermis, the contact cell-extracellular matrix (collagen matrix), as well as futher the growth of the tumor cells free from the substrate adhesion, which is characteristic of malignant processes. In a first step, the photosensitizer Cloroaluminum Phthalocyanine (AlClPc) was chosen to be used in the studies, which is encapsulated in liposomal vesicles, allowing the solubility of the drug in water, optimizing its intracellular incorporation. Furthermore, the photochemical and photophysical properties of the liposomal formulation were evaluated, ensuring that the encapsulation does not interfere with its photodynamic activity. As a second step, the formulation was tested in cellular models 2D and 3D above described, performing not only toxicity, but assays of cell death (apoptosis versus necrosis), intracellular drug incorporation (uptake), both quantitative and also qualitative, showing the main intracellular localization of the photosensitizer. Both in 2D cultures and 3D cultures, the liposomal AlClPc showed better pharmacological activity than the current applied PDT protocols, already described in the literature, and this is an open field for in vivo studies with animals with good prospects for responses to the treatment of human melanoma with possibilities for future clinical applications. (AU) | |