RESUMO
Porphyrins and chlorins such as Foscan® have a natural proclivity to accumulate in cancer cells. This trait has made them good candidates for photosensitizers and as imaging agents in phototherapy. In order to improve on cellular selectivity to lower post-treatment photosensitivity bile acid porphyrin bioconjugates have been prepared and investigated in esophageal cancer cells. Bile acids which are known to selectively bind to, or be readily taken up by cancer cells were chosen as targeting moieties. Synthesis of the conjugates was achieved via selective nucleophilic monofunctionalization of 5,10,15,20-tetrahydroxyphenylporphyrins with propargyl bromide followed by Cu(I) mediated cycloaddition with bile acid azides in good yields. The compounds were readily taken up by esophageal cancer cells but showed no PDT activity.
Assuntos
Ácidos e Sais Biliares/química , Fármacos Fotossensibilizantes/síntese química , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste/síntese química , Meios de Contraste/toxicidade , Cobre/química , Reação de Cicloadição , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Humanos , Pargilina/análogos & derivados , Pargilina/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/toxicidade , Porfirinas/químicaRESUMO
Due to the ongoing development of clinical photodynamic therapy (PDT), the search continues for optimized photosensitizers that can overcome some of the side effects associated with this type of treatment modality. The main protagonists being: post-treatment photosensitivity, due to only limited cellular selectivity and post-treatment tumor regrowth, due to the up-regulation of pro-inflammatory agents within the tumor microenvironment. A photosensitizer that could overcome one or both of these drawbacks would be highly attractive to those engaged in clinical PDT. Certain non-steroidal anti-inflammatory drugs (NSAIDs) when used in combination with PDT have shown to increase the cytotoxicity of the treatment modality by targeting the tumor microenvironment. Temoporfin (m-THPC), the gold standard chlorin-based photosensitizer (PS) since its discovery in the 1980's, has successfully been conjugated to non-steroidal anti-inflammatory compounds, in an attempt to address the issue of post-treatment tumor regrowth. Using a modified Steglich esterification reaction, a library of "iPorphyrins" was successfully synthesized and evaluated for their PDT efficacy.
Assuntos
Anti-Inflamatórios/uso terapêutico , Mesoporfirinas/uso terapêutico , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Microambiente Tumoral , Humanos , Técnicas In Vitro , Neoplasias/patologiaRESUMO
Improved photosensitizers for use in photomedicine must possess good water-solubility and optimal photophysical properties. Phosphorus(V) porphyrins fulfill these criteria and are a class of porphyrins with significant potential applications in phototherapy. Five phosphorus(V) porphyrins bearing alkyl substituents have been synthesized. Reasonable to good yields were obtained for all P(V) insertions and all compounds underwent biological evaluation for their PDT activity on two esophageal cancer cell lines, OE33 and SKGT-4. Their cellular uptake was investigated using a high content screening method. Notably, three compounds displayed good uptake and using the MTS cell proliferation assay, two were shown to have photocytotoxicity comparable to mTHPC (Temoporfin(®)) with IC50 values of 6.5 and 5.5 µM.
Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Porfirinas/farmacocinética , Porfirinas/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Neoplasias Esofágicas/patologia , Humanos , Luz , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/síntese química , Solubilidade , Resultado do Tratamento , Água/químicaRESUMO
A novel single step assay approach to screen a library of photdynamic therapy (PDT) compounds was developed. Utilizing high content analysis (HCA) technologies several robust cellular parameters were identified, which can be used to determine the phototoxic effects of porphyrin compounds which have been developed as potential anticancer agents directed against esophageal carcinoma. To demonstrate the proof of principle of this approach a small detailed study on five porphyrin based compounds was performed utilizing two relevant esophageal cancer cell lines (OE21 and SKGT-4). The measurable outputs from these early studies were then evaluated by performing a pilot screen using a set of 22 compounds. These data were evaluated and validated by performing comparative studies using a traditional colorimetric assay (MTT). The studies demonstrated that the HCS assay offers significant advantages over and above the currently used methods (directly related to the intracellular presence of the compounds by analysis of their integrated intensity and area within the cells). A high correlation was found between the high content screening (HCS) and MTT data. However, the HCS approach provides additional information that allows a better understanding of the behavior of these compounds when interacting at the cellular level. This is the first step towards an automated high-throughput screening of photosensitizer drug candidates and the beginnings of an integrated and comprehensive quantitative structure action relationship (QSAR) study for photosensitizer libraries.
Assuntos
Ensaios de Triagem em Larga Escala , Fármacos Fotossensibilizantes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Imagem Molecular , Fotoquimioterapia , Porfirinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Bibliotecas de Moléculas PequenasRESUMO
Photodynamic therapy (PDT) is based on the delivery of photocytotoxic agents to a target tissue, followed by irradiation. In order to increase the efficiency of PDT in oesophageal cancer therapy, polyethylene glycol (PEG)-grafted, transferrin (Tf)-conjugated liposome formulations of 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (Foscan), a second-generation photosensitiser, were prepared. Expression of transferrin receptors (CD71) in the oesophageal cancer cell line, OE21, was confirmed by immunoblot and confocal laser scanning microscopy. The anti-proliferative effect of Foscan liposomes was evaluated and compared with plain formulations (i.e., without Tf) as well as with free drug. In addition, the intracellular accumulation was studied using high content analysis. Surprisingly, delivering Foscan by transferrin-conjugated PEG-liposomes to oesophageal cancer cells did not improve the photocytotoxicity or the intracellular accumulation of Foscan when compared to unmodified liposomes or indeed free photosensitiser. Tf-targeted drugs and drug delivery systems have shown improved the therapy of many cancers. Our study, however, did not corroborate these findings. If this is due to the tumour type, the choice of in vitro model or the delivery systems remains to be confirmed.
Assuntos
Antineoplásicos/administração & dosagem , Mesoporfirinas/administração & dosagem , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem , Transferrina/administração & dosagem , 1,2-Dipalmitoilfosfatidilcolina/análogos & derivados , 1,2-Dipalmitoilfosfatidilcolina/química , Antígenos CD/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Lipossomos , Fosfatidilgliceróis/química , Polietilenoglicóis/química , Receptores da Transferrina/metabolismo , Transferrina/químicaRESUMO
Photodynamic therapy (PDT) has developed over last century and is now becoming a more widely used medical tool having gained regulatory approval for the treatment of various diseases such as cancer and macular degeneration. It is a two-step technique in which the delivery of a photosensitizing drug is followed by the irradiation of light. Activated photosensitizers transfer energy to molecular oxygen which results in the generation of reactive oxygen species which in turn cause cells apoptosis or necrosis. Although this modality has significantly improved the quality of life and survival time for many cancer patients it still offers significant potential for further improvement. In addition to the development of new PDT drugs, the use of nanosized carriers for photosensitizers is a promising approach which might improve the efficiency of photodynamic activity and which can overcome many side effects associated with classic photodynamic therapy. This review aims at highlighting the different types of nanomedical approaches currently used in PDT and outlines future trends and limitations of nanodelivery of photosensitizers.