RESUMO
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.
Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Neoplasias da Bexiga Urinária , Humanos , Glucuronidase , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Porfirinas/farmacologia , Linhagem Celular Tumoral , Nanopartículas/uso terapêuticoRESUMO
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.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Quinazolinas/química , Animais , Apoptose , Carcinoma de Células Escamosas/metabolismo , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Solubilidade , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.