RÉSUMÉ
Over the past few decades, photodynamic therapy (PDT) has evolved as a minimally invasive treatment modality offering precise control over cancer and various other diseases. To address inherent challenges associated with PDT, researchers have been exploring two promising avenues: the development of intelligent photosensitizers activated through light-induced energy transfers, charges, or electron transfers, and the disruption of photosensitive bonds. Moreover, there is a growing emphasis on the bioorthogonal delivery or activation of photosensitizers within tumors, enabling targeted deployment and activation of these intelligent photosensitive systems in specific tissues, thus achieving highly precise PDT. This concise review highlights advancements made over the last decade in the realm of light-activated or bioorthogonal photosensitizers, comparing their efficacy and shaping future directions in the advancement of photodynamic therapy.
RÉSUMÉ
In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e6 photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a ß-glucuronidase-responsive linker. Upon activation by ß-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells. This activation was accompanied by the recovery of its fluorescence and the generation of reactive oxygen species. Investigation of photodynamic and dark toxicity in vitro revealed that the novel conjugate had an excellent safety profile and was able to inhibit tumor cells proliferation at submicromolar concentrations. Additionally, combined therapy effects were also observed in 3D models of tumor growth, demonstrating synergistic suppression through the activation of both photodynamic and targeted therapy.
Sujet(s)
Nanoparticules , Photothérapie dynamique , Porphyrines , Tumeurs de la vessie urinaire , Humains , Glucuronidase , Photosensibilisants/pharmacologie , Photosensibilisants/usage thérapeutique , Tumeurs de la vessie urinaire/traitement médicamenteux , Porphyrines/pharmacologie , Lignée cellulaire tumorale , Nanoparticules/usage thérapeutiqueRÉSUMÉ
Photodynamic therapy (PDT) is a treatment modality where light-mediated activation of photosensitizers in a patient's body leads to the generation of cytotoxic reactive oxygen species (ROS), eliminating cancer cells. One direction that has been firmly established over past years is the conjugation of photosensitizers with various molecules that demonstrate their own cytotoxic activity. As a result, improved selectivity and treatment outcomes are observed compared to those of unconjugated drugs. The attractiveness of such an approach is due to the variability of cytotoxic warheads and specific linkers available for the construction of conjugates. In this review, we summarize and analyze data concerning these inventions with the ultimate goal to find a promising conjugation partner for a porphyrinoid-based photosensitizer. The current challenges toward successful conjugation are also outlined and discussed. We hope that this review will motivate researchers to pay closer attention to conjugates and possibilities hidden in these molecules for the PDT of cancer.
Sujet(s)
Antinéoplasiques/usage thérapeutique , Métalloporphyrines/usage thérapeutique , Tumeurs/traitement médicamenteux , Photosensibilisants/usage thérapeutique , Animaux , Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacologie , Antinéoplasiques/effets des radiations , Lignée cellulaire tumorale , Humains , Lumière , Métalloporphyrines/composition chimique , Métalloporphyrines/pharmacologie , Métalloporphyrines/effets des radiations , Photothérapie dynamique , Photosensibilisants/composition chimique , Photosensibilisants/pharmacologie , Photosensibilisants/effets des radiations , Espèces réactives de l'oxygène/métabolismeRÉSUMÉ
A new water-soluble conjugate, consisting of a chlorin-e6 photosensitizer part, a 4-arylaminoquinazoline moiety with affinity to epidermal growth factor receptors, and a hydrophilic ß-d-maltose fragment, was synthesized starting from methylpheophorbide-a in seven steps. The prepared conjugate exhibited low levels of dark cytotoxicity and pronounced photoinduced cytotoxicity at submicromolar concentrations in vitro, with an IC50(dark)/IC50(light) ratio of â¼368 and a singlet oxygen quantum yield of about 20%. In tumor-bearing Balb/c nude mice, conjugate 1 preferentially accumulates in the tumor tissue. Irradiation of the nude mice bearing A431 xenograft tumors after intravenous administration of the prepared conjugate with a relatively low light dose (50 J/cm2) produced an excellent therapeutic effect with profound tumor regression and low systemic toxicity.
Sujet(s)
Carcinome épidermoïde/traitement médicamenteux , Photothérapie dynamique , Photosensibilisants/pharmacologie , Porphyrines/composition chimique , Quinazolines/composition chimique , Animaux , Apoptose , Carcinome épidermoïde/métabolisme , Prolifération cellulaire , Femelle , Humains , Souris , Souris de lignée BALB C , Souris nude , Photosensibilisants/composition chimique , Photosensibilisants/pharmacocinétique , Solubilité , Distribution tissulaire , Cellules cancéreuses en culture , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
A new water-soluble conjugate, consisting of a chlorin-based photosensitizing part, and a 4-arylaminoquinazoline moiety with high potential affinity to an epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), suitable for photodynamic therapy (PDT), was synthesized starting from methylpheophorbide-a in seven steps. An increased accumulation of this compound in A431â¯cells with high level of EGFR expression, in comparison with CHO and HeLa cells with low EGFR expression was observed. The prepared conjugate exhibits dark and photoinduced cytotoxicity at micromolar concentrations with IC50dark/IC50light ratio of 11-18. In tumor-bearing mice, the conjugate preferentially accumulates in the tumor tissue.