Top

Published in:

Open Access 01-12-2021 | Photodynamic Therapy | Research article

Novel meso-substituted porphyrin derivatives and its potential use in photodynamic therapy of cancer

Authors: Pablo Vallecorsa, Gabriela Di Venosa, M. Belén Ballatore, Dario Ferreyra, Leandro Mamone, Daniel Sáenz, Gustavo Calvo, Edgardo Durantini, Adriana Casas

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

Photodynamic therapy (PDT) is an anticancer treatment that utilizes the interaction of light and a photosensitiser (PS), promoting tumour cell death mediated by generation of reactive oxygen species. In this study, we evaluated the in vitro photoactivity of four meso-substituted porphyrins and a porphyrin coupled to a fullerene.

Methods

The cell line employed was the LM3 mammary adenocarcinoma, and the PS with the best photokilling activity was administered to mice bearing the LM3 subcutaneously implanted adenocarcinoma. The TEMCP⁴⁺ porphyrin and its analogue TEMCC⁴⁺ chlorine contain four identical carbazoyl substituents at the meso positions of the tetrapyrrolic macrocycle and have A₄ symmetry. The TAPP derivative also has A₄ symmetry, and it is substituted at the meso positions by aminopropoxy groups. The DAPP molecule has ABAB symmetry with aminopropoxy and the trifluoromethyl substituents in trans positions. The TCP-C₆₀⁴⁺ dyad is formed by a porphyrin unit covalently attached to the fullerene C₆₀.

Results

The PSs are taken up by the cells with the following efficiency: TAPP> TEMCP⁴⁺ = TEMCC⁴⁺ > DAPP >TCP-C₆₀⁴⁺, and the amount of intracellular PS correlates fairly with the photodamage degree, but also the quantum yields of singlet oxygen influence the PDT outcome. TAPP, DAPP, TEMCC⁴⁺ and TEMCP⁴⁺ exhibit high photoactivity against LM3 mammary carcinoma cells, being TAPP the most active. After topical application of TAPP on the skin of mice bearing LM3 tumours, the molecule is localized mainly in the stratum corneum, and at a lower extent in hair follicles and sebaceous glands. Systemic administration of TAPP produces a tumour: normal skin ratio of 31.4, and high accumulation in intestine and lung.

Conclusion

The results suggest a potential use of topical TAPP for the treatment of actinic keratosis and skin adnexal neoplasms. In addition, selectivity for tumour tissue after systemic administration highlights the selectivity of and potentiality of TAPP as a new PS.

Available only for authorised users

Weishaupt KR, Gomer CJDT. Identification of singlet oxygen as the cytotoxic agent in photoinactivation of a murine tumor. Cancer Res. 1976;36(7 PT 1):2326–9.PubMed

Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, et al. Photodynamic therapy. J Natl Cancer Inst. 1998;90(12):889–905. https://doi.org/10.1093/jnci/90.12.889.CrossRefPubMedPubMedCentral

Tampa M, Sarbu MI, Matei C, Mitran CI, Mitran MI, Caruntu C, et al. Photodynamic therapy: a hot topic in dermato-oncology (review). Oncol Lett. 2019;17(5):4085–93. https://doi.org/10.3892/ol.2019.9939.CrossRefPubMedPubMedCentral

Celli JP, Spring BQ, Rizvi I, Evans CL, Samkoe KS, Verma S, et al. Imaging and photodynamic therapy: mechanisms, monitoring, and optimization. Chem Rev. 2010;110(5):2795–838. https://doi.org/10.1021/cr900300p.CrossRefPubMedPubMedCentral

Josefsen LB, Boyle RW. Photodynamic therapy: novel third-generation photosensitizers one step closer? Br J Pharmacol. 2008;154(1):1–3. https://doi.org/10.1038/bjp.2008.98.CrossRefPubMedPubMedCentral

Bonnett R. Chemical aspects of photodynamic therapy; 2000. https://doi.org/10.1201/9781482296952.CrossRef

Lazzeri D, Durantini EN. Synthesis of meso-substituted cationic porphyrins as potential photodynamic agents. Arkivoc. 2003;2003(10):227–39. https://doi.org/10.3998/ark.5550190.0004.a23.CrossRef

Couto GK, Pacheco BS, Borba VM, Junior JCR, Oliveira TL, Segatto NV, et al. Tetra-cationic platinum(II) porphyrins like a candidate photosensitizers to bind, selective and drug delivery for metastatic melanoma. J Photochem Photobiol B Biol. 2020;202:111725. https://doi.org/10.1016/j.jphotobiol.2019.111725.CrossRef

Bakry R, Vallant RM, Najam-ul-Haq M, Rainer M, Szabo Z, Huck CW, et al. Medicinal applications of fullerenes. Int J Nanomedicine. 2007;2(4):639–49.PubMedPubMedCentral

10.

Milanesio M, Alvarez M, Rivarola V, Silber J, Durantini E. Porphyrin-fullerene C60 dyads with high ability to form photoinduced charge-separated state as novel sensitizers for photodynamic therapy. Photochem Photobiol. 2005;81(4):891–7. https://doi.org/10.1562/2005-01-24-RA-426R.1.CrossRefPubMed

11.

Durantini J, Otero L, Funes M, Durantini E, Fungo F, Gervaldo M. Electrochemical oxidation-induced polymerization of 5,10,15,20-tetrakis[3-(N-ethylcarbazoyl)]porphyrin. Formation and characterization of a novel electroactive porphyrin thin film. Electrochim Acta. 2011;56(11):4126–34. https://doi.org/10.1016/j.electacta.2011.01.111.CrossRef

12.

Ferreyra DD, Spesia MB, Milanesio ME, Durantini EN. Synthesis and photodynamic properties of 5,10,15,20-tetrakis[3-(N-ethyl-N- methylcarbazoyl)]chlorin and its analogous porphyrin in solution and in human red blood cells. J Photochem Photobiol A Chem. 2014;282:16–24. https://doi.org/10.1016/j.jphotochem.2014.02.004.CrossRef

13.

Ferreyra DD, Reynoso E, Cordero P, Spesia MB, Alvarez MG, Milanesio ME, et al. Synthesis and properties of 5,10,15,20-tetrakis[4-(3-N,N-dimethylaminopropoxy)phenyl] chlorin as potential broad-spectrum antimicrobial photosensitizers. J Photochem Photobiol B Biol. 2016;158:243–51. https://doi.org/10.1016/j.jphotobiol.2016.02.021.CrossRef

14.

Quiroga ED, Mora SJ, Alvarez MG, Durantini EN. Photodynamic inactivation of Candida albicans by a tetracationic tentacle porphyrin and its analogue without intrinsic charges in presence of fluconazole. Photodiagn Photodyn Ther. 2016;13:334–40. https://doi.org/10.1016/j.pdpdt.2015.10.005.CrossRef

15.

Caminos DA, Durantini EN. Synthesis of asymmetrically meso-substituted porphyrins bearing amino groups as potential cationic photodynamic agents. J Porphyr Phthalocyanines. 2005;9(05):334–42. https://doi.org/10.1142/S1088424605000423.CrossRef

16.

Ballatore MB, Spesia MB, Milanesio ME, Durantini EN. Synthesis, spectroscopic properties and photodynamic activity of porphyrin-fullerene C60 dyads with application in the photodynamic inactivation of Staphylococcus aureus. Eur J Med Chem. 2014;83:685–94. https://doi.org/10.1016/j.ejmech.2014.06.077.CrossRefPubMed

17.

Mora SJ, Milanesio ME, Durantini EN. Spectroscopic and photodynamic properties of 5,10,15, 20-tetrakis[4-(3-n,n- dimethylaminopropoxy)phenyl]porphyrin and its tetracationic derivative in different media. J Photochem Photobiol A Chem. 2013;270:75–84. https://doi.org/10.1016/j.jphotochem.2013.07.013.CrossRef

18.

Urtreger AJ, Ladeda VE, Puricelli LI, Rivelli A, Del Carmen VM, De Lustig ES, et al. Modulation of fibronectin expression and proteolytic activity associated with the invasive and metastatic phenotype in two new murine mammary tumor cell lines. Int J Oncol. 1997;11(3):489–96. https://doi.org/10.3892/ijo.11.3.489.CrossRefPubMed

19.

Denizot F, Lang R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods. 1986;89(2):271–7. https://doi.org/10.1016/0022-1759(86)90368-6.CrossRefPubMed

20.

Taylor R. Interpretation of the correlation coefficient: a basic review. J Diagn Med Sonogr. 1990;6(1):35–9. https://doi.org/10.1177/875647939000600106.CrossRef

21.

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: An open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82. https://doi.org/10.1038/nmeth.2019.

22.

Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ, et al. Guidelines for the welfare and use of animals in cancer research. Br J Cancer. 2010;102(11):1555–77. https://doi.org/10.1038/sj.bjc.6605642.CrossRefPubMedPubMedCentral

23.

Smith A, Morgan WT. Hemopexin-mediated transport of heme into isolated rat hepatocytes. J Biol Chem. 1981;256(21):10902–109. https://doi.org/10.1016/S0021-9258(19)68530-3.CrossRefPubMed

24.

Hall HK. Correlation of the base strengths of amines. J Am Chem Soc. 1957;79(20):5441–4. https://doi.org/10.1021/ja01577a030.CrossRef

25.

Rodriguez L, Vallecorsa P, Battah S, Di Venosa G, Calvo G, Mamone L, et al. Aminolevulinic acid dendrimers in photodynamic treatment of cancer and atheromatous disease. In: Photochemical and Photobiological Sciences; 2015. p. 1617–27.

26.

Liu JH, Cao L, Luo PG, Yang ST, Lu F, Wang H, et al. Fullerene-conjugated doxorubicin in cells. ACS Appl Mater Interfaces. 2010;2(5):1384–9. https://doi.org/10.1021/am100037y.CrossRefPubMed

27.

Mamone L, Ferreyra DD, Gándara L, Di Venosa G, Vallecorsa P, Sáenz D, et al. Photodynamic inactivation of planktonic and biofilm growing bacteria mediated by a meso-substituted porphyrin bearing four basic amino groups. J Photochem Photobiol B Biol. 2016;161:222–9. https://doi.org/10.1016/j.jphotobiol.2016.05.026.CrossRef

28.

Berg K, Selbo P. Macromolecular therapeutics. The cellular membrane as a barrier o therapeutic effectiveness. In: Kadish K, Smith K, Guilard R, editors. Handbook Of Porphyrin Science: With Applications To Chemistry, Physics, Material Sciences, Engineering, Biology and Medicine. London: World Scientific Publishing Co. Pte. Ltd; 2016. p. 249–50.

29.

Fontanelli R, Papadia A, Martinelli F, Lorusso D, Grijuela B, Merola M, et al. Photodynamic therapy with M-ALA as non surgical treatment option in patients with primary extramammary Paget’s disease. Gynecol Oncol. 2013;130(1):90–4. https://doi.org/10.1016/j.ygyno.2013.04.008.CrossRefPubMed

30.

Gold MH, Bradshaw VL, Boring MM, Bridges TM, Biron JA, Lewis TL. Treatment of sebaceous gland hyperplasia by photodynamic therapy with 5-aminolevulinic acid and a blue light source or intense pulsed light source. J Drugs Dermatol. 2004;3(6 Suppl). PMID: 15624735.

Title: Novel meso-substituted porphyrin derivatives and its potential use in photodynamic therapy of cancer
Authors: Pablo Vallecorsa
Gabriela Di Venosa
M. Belén Ballatore
Dario Ferreyra
Leandro Mamone
Daniel Sáenz
Gustavo Calvo
Edgardo Durantini
Adriana Casas
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Photodynamic Therapy
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08286-6

2024 ASCO Annual Meeting Coverage

Highlights of the Day: Breast cancer – metastatic

Breast Cancer Video

In this session, Dr. Wolff provides his key takeaways from the data presented in the metastatic breast cancer oral abstract session at ASCO 2024.

Watch now

Highlights of the Day: Gynecologic cancer

Gynecologic Cancer Video

Highlights of the Day: Breast Cancer – local/regional/adjuvant

Breast Cancer Video

Neoadjuvant dual immunotherapy improves melanoma outcomes

04-06-2024 Melanoma News

» View more highlights on the ASCO 2024 congress hub page

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Image Credits

ASCO 2024 | Highlights of the Day: Breast cancer – metastatic/© 2024 American Society of Clinical Oncology, all rights reserved., ASCO 2024 | Highlights of the Day: Gynecologic Cancer/© 2024 American Society of Clinical Oncology, all rights reserved., ASCO 2024 | Highlights of the Day: Breast Cancer – local/regional/adjuvant/© 2024 American Society of Clinical Oncology, all rights reserved., Melanoma/© selvanegra / Getty Images / iStock, Antibody drug conjugated with cytotoxic payload/© Love Employee / Getty images / iStock

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

The PRO-ACTIVE trial protocol: a randomized study comparing the effectiveness of PROphylACTic swallow InterVEntion for patients receiving radiotherapy for head and neck cancer

Tumor response as defined by iRECIST in gastrointestinal malignancies treated with PD-1 and PD-L1 inhibitors and correlation with survival

A nomogram based on pretreatment levels of serum bilirubin and total bile acid levels predicts survival in colorectal cancer patients

Clinical features associated with the efficacy of chemotherapy in patients with glioblastoma (GBM): a surveillance, epidemiology, and end results (SEER) analysis

Topical estrogen, testosterone, and vaginal dilator in the prevention of vaginal stenosis after radiotherapy in women with cervical cancer: a randomized clinical trial