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Synthesis and in vitro PDT evaluation of new porphyrins containing meso-epoxymethylaryl cationic groups.

ABSTRACT: OBJECTIVES:Photodynamic therapy (PDT) is an effective cancer treatment that uses photosensitizers, light, and oxygen to destroy malignant cells. Porphyrins, and in particular the cationic derivatives, are the most investigated photosensitizers for PDT. In this context, it is important to study new methodologies to develop efficient cationic photosensitizers for use in PDT. MATERIALS AND METHODS:New porphyrins bearing cationic epoxymethylaryl groups were synthesized and characterized. Their cellular uptake, intracellular localization, and phototoxicity were evaluated in human HEp2 cells, and compared with their methylated analogs. RESULTS:All cationic porphyrins were efficient generators of singlet oxygen, with quantum yields in the range 0.35-0.61. The two methylated derivatives (3 and 4) accumulated the most within cells at all times investigated, up to 24?hours. Of these two porphyrins, 4 was the most phototoxic to the cells (LD50 ?=?2.4??M at 1.5?J/cm2 ); however, porphyrin 3 also showed high phototoxicity (LD50 ?=?7.4??M at 1.5?J/cm2 ). The epoxymethyl-containing porphyrins were found to be less phototoxic than the methylated derivatives, with LD50? >? 38??M. The neutral porphyrins showed no phototoxicity up to the 100??M concentrations investigated, and had the lowest singlet oxygen quantum yields. All cationic porphyrins localized mainly in the cell ER, Golgi apparatus, and lysosomes. CONCLUSION:Our results suggest that cationic methylated porphyrin derivatives are promising PDT photosensitizing agents. The epoxymethyl-containing derivatives showed increased efficacy relative to the neutral analogs, and are good candidates for further investigation. Lasers Surg. Med. 50:566-575, 2018. © 2018 Wiley Periodicals, Inc.

SUBMITTER: Carneiro J

PROVIDER: S-EPMC6693339 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Synthesis and in vitro PDT evaluation of new porphyrins containing meso-epoxymethylaryl cationic groups.

Carneiro Jaqueline J Gonçalves Alan A Zhou Zehua Z Griffin Kaitlin E KE Kaufman Nichole E M NEM Vicente Maria da Graça Henriques MDGH

Lasers in surgery and medicine 20180425 5

<h4>Objectives</h4>Photodynamic therapy (PDT) is an effective cancer treatment that uses photosensitizers, light, and oxygen to destroy malignant cells. Porphyrins, and in particular the cationic derivatives, are the most investigated photosensitizers for PDT. In this context, it is important to study new methodologies to develop efficient cationic photosensitizers for use in PDT.<h4>Materials and methods</h4>New porphyrins bearing cationic epoxymethylaryl groups were synthesized and characteriz ...[more]

PMID: 29691890

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Project description:BACKGROUND: Porphyrin TMPyP4 (P4) and its C14H28-alkyl derivative (C14) are G-quadruplex binders and singlet oxygen (1O2) generators. In contrast, TMPyP2 (P2) produces 1O2 but it is not a G-quadruplex binder. As their photosensitizing activity is currently undefined, we report in this study their efficacy against a melanoma skin tumour and describe an in vitro mechanistic study which gives insights into their anticancer activity. METHODS: Uptake and antiproliferative activity of photoactivated P2, P4 and C14 have been investigated in murine melanoma B78-H1 cells by FACS, clonogenic and migration assays. Apoptosis was investigated by PARP-1 cleavage and annexin-propidium iodide assays. Biodistribution and in vivo anticancer activity were tested in melanoma tumour-bearing mice. Porphyrin binding and photocleavage of G-rich mRNA regions were investigated by electrophoresis and RT-PCR. Porphyrin effect on ERK pathway was explored by Western blots. RESULTS: Thanks to its higher lipophylicity C14 was taken up by murine melanoma B78-H1 cells up to 30-fold more efficiently than P4. When photoactivated (7.2 J/cm2) in B78-H1 melanoma cells, P4 and C14, but not control P2, caused a strong inhibition of metabolic activity, clonogenic growth and cell migration. Biodistribution studies on melanoma tumour-bearing mice showed that P4 and C14 localize in the tumour. Upon irradiation (660 nm, 193 J/cm2), P4 and C14 retarded tumour growth and increased the median survival time of the treated mice by ~50% (P <0.01 by ANOVA), whereas porphyrin P2 did not. The light-dependent mechanism mediated by P4 and C14 is likely due to the binding to and photocleavage of G-rich quadruplex-forming sequences within the 5'-untranslated regions of the mitogenic ras genes. This causes a decrease of RAS protein and inhibition of downstream ERK pathway, which stimulates proliferation. Annexin V/propidium iodide and PARP-1 cleavage assays showed that the porphyrins arrested tumour growth by apoptosis and necrosis. C14 also showed an intrinsic light-independent anticancer activity, as recently reported for G4-RNA binders. CONCLUSIONS: Porphyrins P4 and C14 impair the clonogenic growth and migration of B78-H1 melanoma cells and inhibit melanoma tumour growth in vivo. Evidence is provided that C14 acts through light-dependent (mRNA photocleavage) and light-independent (translation inhibition) mechanisms.

Dataset Information

Synthesis and in vitro PDT evaluation of new porphyrins containing meso-epoxymethylaryl cationic groups.

Publications

Synthesis and in vitro PDT evaluation of new porphyrins containing meso-epoxymethylaryl cationic groups.

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