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Radiolabelled porphyrinic metalla-assemblies linked to cellulose nanocrystals as PDT and imaging agents

Abstract : Cancer is one of the biggest set of diseases in our society, and although there are some very interesting treatments and drugs used in pratice, one of the biggest challenges of anticancer treatment is the specific delivery of drugs to the target cells in order to avoid deleterious effects on normal cells. In fact, most of the anticancer drugs have potent effects also on normal cells due to the strong similarity of the mechanisms of growth regulation of normal cells as compared to their transformed counterparts. Photodynamic therapy (PDT) imposes itself as one of the most preponderant voices to tackle cancer and provide solutions for the problems encountered with traditional therapies. With the combination of a photosensitizer, light and oxygen, PDT achieves a unique selectivity by the production of localized reactive oxygen species (ROS) inside cancerous cells, which leads to their destruction with limited side effects. Alongside treatment, early diagnosis undertakes a critical role for the outcome. In particular, imaging is an extremely intriguing tool since it allows not only for diagnosis but to follow treatment as well. This study aims to use cellulose nanocrystals to transport and deliver photo-responsive molecules to biological targets and create a new generation of theranostic agents. For that, porphyrins and phthalocyanines were synthesized,1 with the aim of exploring their peculiar set of absorption bands for PDT treatment. These were then used as panels to construct metalla-assemblies through coordination with ruthenium dimers, with the goal of enhancing not only their solubility but also helping with aggregation.2 The ruthenium metalla-clips also offer stability and inherent cytotoxicity through reduction in the cancer site.3 These complexes were subsequently linked to cellulose nanocrystals (CNCs)4 for better targeting. This is achieved through the increase of their size, making them interesting EPR (enhanced permeation retention) effect enhancers. This delivery strategy is based upon the particular structure of tumor neoangiogenic vessels that allow the passive targeting. Another advantage of grafting these compounds to CNCs is that they ensure biological compatibility and prolonged blood circulation time. From the resulting photo-responsive compounds, the ones that were considered to have the best characteristics were then radiolabeled with either technetium-99m or indium-111 through direct radiolabelling, allowing them to also be used as imaging probes. After synthesis, in vitro assays were performed to determine the IC50 and whether the PDT agents were selective towards cancer cells. At the same time, it allowed to determine the optimal concentration for in vivo experiments. Their cytotoxicity and potential therapeutic effects were evaluated on two ovarian cancer (A2780 and A2780cis) and one normal hepatic cell lines (HEK293T) through a metabolic activity assay. Their cellular uptake was determined as well. Finally, the radiolabeled compounds that showed the best in vitro results were used for scintigraphic imaging in Severe Combined Immunodeficiency (SCID) mice at several timepoints (1, 2, 4 and 24 h) with the intent of studying their biodistribution, which showed preferential accumulation mainly in the liver, but also in the bladder. The hypothesis is therefore that through consecutive modifications of the initial photosensitizers in order to ameliorate their biophysical characteristics (through coordination with organometallic compounds and cellulose nanocrystals) and later their radiolabelling, we will be able to achieve novel PDT theranostic agents. The present work, therefore, deals with the synthesis, characterization, in vitro and in vivo evaluation of a small family of novel PDT theranostic agents.
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Submitted on : Tuesday, April 12, 2022 - 11:57:26 AM
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João Carlos Salgueiro Simões. Radiolabelled porphyrinic metalla-assemblies linked to cellulose nanocrystals as PDT and imaging agents. Other. Université de Limoges; Université de Neuchâtel (Suisse). Faculté de sciences, 2021. English. ⟨NNT : 2021LIMO0115⟩. ⟨tel-03638616⟩

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