Skip to main content
SpringerLink
Log in

In vitro and in vivo antitumor activity of a novel porphyrin-based photosensitizer for photodynamic therapy

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Photodynamic therapy (PDT) is a promising treatment in cancer therapy, based on the use of a photosensitizer activated by visible light in the presence of oxygen. Nowadays significant research efforts have been focused on finding a new photosensitizer. In the present paper, the antitumor effects of a novel porphyrin-based photosensitizer, {Carboxymethyl-[2-(carboxymethyl-{[4-(10,15,20-triphenylporphyrin-5-yl)-phenylcarbamoyl]-methyl}-amino)-ethyl]-amino}-acetic acid (ATPP-EDTA) on two types of human malignant tumor cells in vitro and a gastric cancer model in nude mice, were evaluated.

Methods

The PDT efficacy with ATPP-EDTA in vitro was assessed by MTT assay. The intracellular accumulation was detected with fluorescence spectrometer, and the intracellular distribution was determined by laser scanning confocal microscopy. The mode of cell death was investigated by Hoechst 33342 staining and flow cytometer. BGC823-derived xenograft tumor model was established to explore the in vivo antitumor effects of ATPP-EDTA.

Results

ATPP-EDTA exhibited intense phototoxicity on both cell lines in vitro in concentration- and light dose-dependent manners meanwhile imposing minimal dark cytotoxicity. The accumulation of ATPP-EDTA in two malignant cell lines was time-dependent and prior compared to normal cells. It was mainly localized at lysosomes, but induced cell death by apoptotic pathway. ATPP-EDTA significantly inhibited the growth of BGC823 tumors in nude mice (160 mW/cm2, 100 J/cm2).

Conclusions

Present studies suggest that ATPP-EDTA is an effective photosensitizer for PDT to tumors. It distributed in lysosomes and caused cell apoptosis. ATPP-EDTA, as a novel photosensitizer, has a great potential for human gastric cancer treatment in PDT and deserves further investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Adams JM, Cory S (2007) Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol 19(5):488–496

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Almeida RD, Manadas BJ, Carvalho AP, Duarte CB (2004) Intracellular signaling mechanisms in photodynamic therapy. Biochim Biophys Acta 1704(2):59–86

    CAS  PubMed  Google Scholar 

  • Antignani A, Youle RJ (2006) How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane? Curr Opin Cell Biol 18(6):685–689

    Article  CAS  PubMed  Google Scholar 

  • Bhowmick R, Girotti AW (2009) Signaling events in apoptotic photokilling of 5-aminolevulinic acid-treated tumor cells: inhibitory effects of nitric oxide. Free Radic Biol Med 47(6):731–740

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Buytaert E, Callewaert G, Hendrickx N, Scorrano L, Hartmann D, Missiaen L, Vandenheede JR, Heirman I, Grooten J, Agostinis P (2006) Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin-mediated photodynamic therapy. FASEB J 20(6):756–758

    CAS  PubMed  Google Scholar 

  • Buytaert E, Dewaele M, Agostinis P (2007) Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. Biochim Biophys Acta 1776(1):86–107

    CAS  PubMed  Google Scholar 

  • Celli JP, Spring BQ, Rizvi I, Evans CL, Samkoe KS, Verma S, Pogue BW, Hasan T (2010) Imaging and photodynamic therapy: mechanisms, monitoring, and optimization. Chem Rev 110(5):2795–2838. doi:10.1021/cr900300p

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chin W, Lau W, Cheng C, Olivo M (2004) Evaluation of Hypocrellin B in a human bladder tumor model in experimental photodynamic therapy: biodistribution, light dose and drug-light interval effects. Int J Oncol 25(3):623–629

    CAS  PubMed  Google Scholar 

  • Chiu SM, Xue LY, Lam M, Rodriguez ME, Zhang P, Kenney ME, Nieminen AL, Oleinick NL (2010) A requirement for bid for induction of apoptosis by photodynamic therapy with a lysosome—but not a mitochondrion-targeted photosensitizer. Photochem Photobiol 86(5):1161–1173. doi:10.1111/j.1751-2010.00766.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dewaele M, Verfaillie T, Martinet W, Agostinis P (2010) Death and survival signals in photodynamic therapy. Methods Mol Biol 635:7–33. doi:10.1007/978-1-60761-697-9_2

    Article  CAS  PubMed  Google Scholar 

  • Garg AD, Nowis D, Golab J, Agostinis P (2010) Photodynamic therapy: illuminating the road from cell death towards anti-tumor immunity. Apoptosis 15(9):1050–1071. doi:10.1007/s10495-010-0479-7

    Article  CAS  PubMed  Google Scholar 

  • Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305(5684):626–629

    Article  CAS  PubMed  Google Scholar 

  • Grimm S, Mvondo D, Grune T, Breusing N (2011) The outcome of 5-ALA-mediated photodynamic treatment in melanoma cells is influenced by vitamin C and heme oxygenase-1. BioFactors 37(1):17–24. doi:10.1002/biof.129

    Article  CAS  PubMed  Google Scholar 

  • Juzeniene A, Moan J (2007) The history of PDT in Norway: part one: identification of basic mechanisms of general PDT. Photodiagnosis Photodyn Ther 4(1):3–11. doi:10.1016/j.pdpdt.2006.11.002

    Article  CAS  PubMed  Google Scholar 

  • Kessel D, Poretz RD (2000) Sites of photodamage induced by photodynamic therapy with a chlorin e6 triacetoxymethyl ester (CAME). Photochem Photobiol 71(1):94–96

    Article  CAS  PubMed  Google Scholar 

  • Kessel D, Sun HH (1999) Enhanced responsiveness to photodynamic therapy induced apoptosis after mitochondrial DNA depletion. Photochem Photobiol 70(6):937–940

    Article  CAS  PubMed  Google Scholar 

  • Kessel D, Luo Y, Mathieu P, Reiners JJ Jr (2000) Determination of the apoptotic response to lysosomal photodamage. Photochem Photobiol 71(2):196–200

    Article  CAS  PubMed  Google Scholar 

  • Kessel D, Luguya R, Vicente MG (2003) Localization and photodynamic efficacy of two cationic porphyrins varying in charge distributions. Photochem Photobiol 78(5):431–435

    Article  CAS  PubMed  Google Scholar 

  • Konan YN, Gurny R, Alle´mann E (2002) State of the art in the delivery of photosensitizers for photodynamic therapy. J Photochem Photobiol 66(22):89–106

    Article  CAS  Google Scholar 

  • Liu TJ, Chen JJ, Cao B, Wu L (2010) Diethylene triamine pentaacetic acid, or ethylene diamine tetraacetic acid, or amine triacetate-modified porphyrins and metalloporphyrins, their preparation and application. Chin Pat 201010184331:7

    Google Scholar 

  • Liu L, Zhang Z, Xing D (2011) Cell death via mitochondrial apoptotic pathway due to activation of Bax by lysosomal photodamage. Free Radic Biol Med 51(1):53–68. doi:10.1016/j.freeradbiomed.03.042

    Article  CAS  PubMed  Google Scholar 

  • Liu XT, Wang YR, Zhang M (2013) Mitochondria-mediated apoptosis: a review of recent studies. J Environ Health 30(2):182–184

    CAS  Google Scholar 

  • Luguya R, Jaquinod L, Fronczek FR, Vicente MG, Smith KM (2004) Synthesis and reactions of meso-(p-nitrophenyl)porphyrins. Tetrahedron 60(12):2757–2763

    Article  CAS  Google Scholar 

  • Moon YH, Park JH, Kim SA, Lee JB, Ahn SG, Yoon JH (2010) Anticancer effect of photodynamic therapy with hexenyl ester of 5-aminolevulinic acid in oral squamous cell carcinoma. Head Neck 32(9):1136–1142. doi:10.1002/hed.21301

    Article  PubMed  Google Scholar 

  • Morgan J, Oseroff AR (2001) Mitochondria-based photodynamic anti-cancer therapy. Adv Drug Deliv Rev 49(1–2):71–86

    Article  CAS  PubMed  Google Scholar 

  • Nagata S, Obana A, Gohto Y, Nakajima S (2003) Necrotic and apoptotic cell death of human malignant melanoma cells following photodynamic therapy using an amphiphilic photosensitizer ATX-S10 (Na). Lasers Surg Med 33(1):64–70

    Article  PubMed  Google Scholar 

  • Oleinick NL, Morris RL, Belichenko I (2002) The role of apoptosis in response to photodynamic therapy: what, where, why, and how. Photochem Photobiol Sci 1(1):1–21

    Article  CAS  PubMed  Google Scholar 

  • Pandey RK, Goswami LN, Chen Y, Gryshuk A, Missert JR, Oseroff A, Dougherty TJ (2006) A rich source for developing multifunctional agents. Tumor imaging and photodynamic therapy. Lasers Surg Med 38(5):445–467

    Article  PubMed  Google Scholar 

  • Pazos MDC, Nader HB (2007) Effect of photodynamic therapy on the extracellular matrix and associated components. Braz J Med Biol Res 40(8):1025–1035

    Article  CAS  PubMed  Google Scholar 

  • Runnels JM, Chen N, Ortel B, Kato D, Hasan T (1999) BPD-MA-mediated photosensitization in vitro and in vivo: cellular adhesion and beta1 integrin expression in ovarian cancer cells. Br J Cancer 80(7):946–953

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Selbo PK, Hogset A, Prasmickaite L, Berg K (2002) Photochemical internalisation: a novel drug delivery system. Tumour Biol 23(2):103–112

    Article  CAS  PubMed  Google Scholar 

  • Shi L, Wang X, Wang H (2012) Application of nanoparticle vectors in photodynamic therapy of tumors. Int Oncol 39(3):193–196

    CAS  Google Scholar 

  • Vrouenraets MB, Visser GW, Snow GB, van Dongen GA (2003) Basic principles, applications in oncology and improved selectivity of photodynamic therapy. Anticancer Res 23(1B):505–522

    CAS  PubMed  Google Scholar 

  • Yan YJ, Zheng MZ, Chen ZL, Yu XH, Yang XX, Ding ZL, Xu L (2010) Studies on preparation and photodynamic mechanism of chlorin P6-13,15-N-(cyclohexyl) cycloimide (Chlorin-H) and its antitumor effect for photodynamic therapy in vitro and in vivo. Bioorg Med Chem 18(17):6282–6291. doi:10.1016/j.bmc.2010.07.027

    Article  CAS  PubMed  Google Scholar 

  • Zuluaga MF, Lange N (2008) Combination of photodynamic therapy with anti-cancer agents. Curr Med Chem 15(17):1655–1673

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Tianjin Municipal Science and Technology Support Key Projects (12ZCDZSY11900) and Science and Technology Innovation Project of Higher Education of Shanxi Province (2013139).

Conflict of interest

We declare that we have no conflict of interest in relation to this article exists.

Author information

Authors and Affiliations

  1. Central Laboratory of Heping Hospital, Changzhi Medical College, Changzhi City, 046000, Shanxi Province, People’s Republic of China

    Jing-Jing Chen & Wen-Jun Cao

  2. Institute of Biomedical Engineering, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin City, 300192, People’s Republic of China

    Ge Hong & Tian-Jun Liu

  3. Department of Physiology of Changzhi Medical College, Changzhi City, 046000, Shanxi Province, People’s Republic of China

    Li-Jing Gao

Authors
  1. Jing-Jing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ge Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li-Jing Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tian-Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-Jun Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tian-Jun Liu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, JJ., Hong, G., Gao, LJ. et al. In vitro and in vivo antitumor activity of a novel porphyrin-based photosensitizer for photodynamic therapy. J Cancer Res Clin Oncol 141, 1553–1561 (2015). https://doi.org/10.1007/s00432-015-1918-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-015-1918-1

Keywords

Search

Navigation