en
Doctoral thesis
English

Exploring Metabolic Alterations in Cancer for Photodynamic Purposes

ContributorsKiening, Martinorcid
Imprimatur date2022-12-16
Defense date2022-12-16
Abstract

Theranostics is a dedicated field that includes both identification (diagnostics) and therapy at once. Using a photosensitizer that accumulates selectively in cancer cells, photodynamic diagnosis (PDD) coupled with photodynamic therapy (PDT) allow precise localization of tumors by fluorescence imaging and their destruction by generating reactive oxygen species (ROS). 5-aminolevulinic acid (5-ALA) is a natural prodrug involved in the heme biosynthesis pathway. The administration of 5-ALA to a patient leads to the accumulation of the natural photosensitizer protoporphyrin IX (PpIX) selectively in cancer cells, allowing to perform PDD and PDT. Despite the selectivity of this mechanism seems to function in most cancer types, the question has barely been addressed in the context of breast cancer, which has become the most diagnosed cancer worldwide, with almost 2.3 million new cases in 2020. Unfortunately, the highly polar 5-ALA toughly cross the plasma membrane where it must be metabolized. In this thesis manuscript, we tested the efficacy of an enhanced 5-ALA derivative whose lipophilicity was increased with an hexylester chain and its stability improved thanks to a phosphate-self-immolative (PSI) group, leading to the PSI-ALA-Hex derivative. We tested the ability of this prodrug to induce a PpIX accumulation in two-dimension, spheroid and chick embryo breast cancer models representing various subtypes of breast cancer that expressed different levels of estrogen, progesterone and HER2 receptors. We also investigated changes of the cancer cell proteome upon 5-ALA treatment that could induce or be due to the selective accumulation of the PpIX in order to find new therapeutic approaches.

eng
Keywords
  • Breast cancer
  • Photodynamic therapy
  • Photodynamic diagnosis
  • Theranostics
  • Protoporphyrin IX
  • 5-aminolevulinic acid
  • Protoporphyrin IX
  • Proteomics
Citation (ISO format)
KIENING, Martin. Exploring Metabolic Alterations in Cancer for Photodynamic Purposes. 2022. doi: 10.13097/archive-ouverte/unige:166238
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Thesis
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