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Chlorin E6

Description of Chlorin E6: Chlorin E6 is a natural product, and usually can be made from Live chlorella. Chlorin E6 is a promising photosensitizer  for photodynamic therapy because of their high absorption in the red spectral region.  Chlorin E6 exhibits advantageous photophysical properties for PDT such as having long lifetimes in their photoexcited triplet states and high molar absorption in the red region of the visible spectrum. Moreover, a 664-nm laser light can penetrate tissue deeper that the 630-nm laser light used for Photofrin. Chlorin E6 is also an important starting material for making PDT drug Talaporfin sodium (mono-L-aspartyl chlorin e6, NPe6).

Photodynamic therapy (PDT) is currently being used as an alternative therapeutic modality for a variety of malignant tumors. This study was performed to show an efficient preparation of second generation of photosensitizer chlorin e6 (Ce6) with high yield and purity, and to test antitumor activity of Ce6-induced PDT (Ce6-PDT) both in vitro and in vivo using a rat tumor model. Three-week-old male Sprague-Dawley (SD) rats were inoculated s.c. on the right flank with 5x106 RK3E-ras cells. The animals were admin-istered i.v. with Ce6 (10 mg/kg) and 24 h later, PDT was performed using a laser diode at a light dose of 100 J/cm2. Ce6-PDT generated reactive oxygen species and led to significant growth inhibition in RK3E-ras cell. In addition, Ce6-PDT induced apoptosis through the activation of caspase-3 and its downstream target, PARP cleavage. The protein level of anti-apoptotic bcl-2 was also reduced by Ce6-PDT in RK3E-ras cells. In in vivo experiments, application of Ce6-PDT led to a significant reduction of tumor size. PCNA immunostaining and TUNEL assay revealed that Ce6-PDT inhibited tumor cell proliferation and increased apoptosis. These findings suggest that the newly purified Ce6-PDT can effectively arrest tumor growth by inhibiting cell proliferation and inducing apoptosis.  (source: Oncology Reports, 2009, 22(5). 1085-1091. Doi: 10.3892/or_00000540. Efficient preparation of highly pure chlorin e6 and its photodynamic anti-cancer activity in a rat tumor model. Authors: Yeon-Hee Moon, Seong-Min Kwon, Hyo-Jun Kim, Kwan-Young Jung, Jong-Hwan Park, Soo-A Kim, Yong-Chul Kim, Sang-Gun Ahn, Jung-Hoon Yoon. Affiliations: Department of Pathology, School of Dentistry, Chosun University, Gwangju 500-759, Korea, http://www.spandidos-publications.com/or/22/5/1085).

Methods to make Chlorin E6

Chlorin E6 is a natural product, and usually can be made from Live chlorella (Chlorella ellipsoidea, see the following pictures)

The following procedure was reported in Oncology Reports, 2009, 22(5). 1085-1091 by Korean scientists Yeon-Hee Moon et al.   Live chlorella (Chlorella ellipsoidea) 100 g (dried weight) was sequentially washed with 500 ml of water and 300 ml of 50% ethanol in water to remove polar materials and the residue was extracted twice with 500 ml of 100% ethanol to obtain chlorophyll a rich fraction (extraction yield 4.3%). Stirring the combined ethanol solution of chlorophyll a in 1 N HCl (pH 2.5) for 3 h at room temperature afforded pheophytin in the form of precipitates. The precipitate was dissolved in dichloromethane washed with distilled water, dried with anhydrous sodium sulfate, and rotary-evaporated to dryness. The residue was purified by a chromatography using neutral alumina (Aldrich, Brockmann, ~150 mesh) with a gradient elution from 30% dichloromethane in n-hexane to 100% dichloromethane. The main green band was collected and evaporated to dryness. The crystalline powder was dissolved in acetone, adjusted pH 12.0 with 1 N NaOH, and stirred for 12 h. The precipitated Ce6 was filtered, washed with acetone and dissolved in 100 ml of water, and filtered to remove insoluble impurity. After lyophilization of the filtered water solution, a fine black powder of Ce6 was obtained. The purity of Ce6 is 93-98% (yield of Ce6: 1% from dried weight of chlorella).

1: Saboktakin MR, Tabatabaie RM, Amini FS, Maharramov A, Ramazanov MA. Synthesis and In-Vitro Photodynamic Studies of the Superparamagnetic Chitosan Hydrogel/Chlorin E6 Nanocarriers. Med Chem. 2012 Jul 3. [Epub ahead of print] PubMed PMID: 22762166.

2: Park JH, Ahn MY, Kim YC, Kim SA, Moon YH, Ahn SG, Yoon JH. In vitro and in vivo antimicrobial effect of photodynamic therapy using a highly pure chlorin e6 against Staphylococcus aureus Xen29. Biol Pharm Bull. 2012;35(4):509-14. PubMed PMID: 22466554.

3: Li P, Zhou G, Zhu X, Li G, Yan P, Shen L, Xu Q, Hamblin MR. Photodynamic therapy with hyperbranched poly(ether-ester) chlorin(e6) nanoparticles on human tongue carcinoma CAL-27 cells. Photodiagnosis Photodyn Ther. 2012 Mar;9(1):76-82. Epub 2011 Oct 4. PubMed PMID: 22369732; PubMed Central PMCID: PMC3292741.

4: Bauer D, Montforts FP, Losi A, Görner H. Photoprocesses of chlorin e6 glucose derivatives. Photochem Photobiol Sci. 2012 Jun;11(6):925-30. Epub 2012 Jan 4. PubMed PMID: 22215185.

5: Shim G, Lee S, Kim YB, Kim CW, Oh YK. Enhanced tumor localization and retention of chlorin e6 in cationic nanolipoplexes potentiate the tumor ablation effects of photodynamic therapy. Nanotechnology. 2011 Sep 7;22(36):365101. Epub 2011 Aug 12. PubMed PMID: 21841215.

6: Shi H, Liu Q, Qin X, Wang P, Wang X. Pharmacokinetic study of a novel sonosensitizer chlorin-e6 and its sonodynamic anti-cancer activity in hepatoma-22 tumor-bearing mice. Biopharm Drug Dispos. 2011 Sep;32(6):319-32. doi: 10.1002/bdd.761. Epub 2011 Aug 3. PubMed PMID: 21815170.

7: Tu C, Zhu L, Li P, Chen Y, Su Y, Yan D, Zhu X, Zhou G. Supramolecular polymeric micelles by the host-guest interaction of star-like calix[4]arene and chlorin e6 for photodynamic therapy. Chem Commun (Camb). 2011 Jun 7;47(21):6063-5. Epub 2011 Apr 26. PubMed PMID: 21519601.

8: Huang L, Zhiyentayev T, Xuan Y, Azhibek D, Kharkwal GB, Hamblin MR. Photodynamic inactivation of bacteria using polyethylenimine-chlorin(e6) conjugates: Effect of polymer molecular weight, substitution ratio of chlorin(e6) and pH. Lasers Surg Med. 2011 Apr;43(4):313-23. doi: 10.1002/lsm.21056. PubMed PMID: 21500226.

9: Li F, Na K. Self-assembled chlorin e6 conjugated chondroitin sulfate nanodrug for photodynamic therapy. Biomacromolecules. 2011 May 9;12(5):1724-30. Epub 2011 Mar 18. PubMed PMID: 21417397.

10: Yumita N, Iwase Y, Nishi K, Ikeda T, Komatsu H, Fukai T, Onodera K, Nishi H, Takeda K, Umemura S, Okudaira K, Momose Y. Sonodynamically-induced antitumor effect of mono-l-aspartyl chlorin e6 (NPe6). Anticancer Res. 2011 Feb;31(2):501-6. PubMed PMID: 21378330.

11: Horibe S, Nagai J, Yumoto R, Tawa R, Takano M. Accumulation and photodynamic activity of chlorin e6 in cisplatin-resistant human lung cancer cells. J Pharm Sci. 2011 Jul;100(7):3010-7. doi: 10.1002/jps.22501. Epub 2011 Jan 27. PubMed PMID: 21274848.

12: Waidelich R. Comment on "Chlorin e6-polyvinylpyrrolidone mediated photodynamic therapy--A potential bladder sparing option for high risk non-muscle-invasive bladder cancer" by Lui Shiong Lee et al. [Photodiagn Photodyn Ther 2010;7:213-20]. Photodiagnosis Photodyn Ther. 2010 Dec;7(4):221. Epub 2010 Oct 23. PubMed PMID: 21112543.

13: Lee LS, Thong PS, Olivo M, Chin WW, Ramaswamy B, Kho KW, Lim PL, Lau WK. Chlorin e6-polyvinylpyrrolidone mediated photodynamic therapy--A potential bladder sparing option for high risk non-muscle invasive bladder cancer. Photodiagnosis Photodyn Ther. 2010 Dec;7(4):213-20. Epub 2010 Sep 29. PubMed PMID: 21112542.

14: Gao HJ, Zhang WM, Wang XH, Zheng RN. [Adriamycin enhances the sonodynamic effect of chlorin e6 against the proliferation of human breast cancer MDA-MB-231 cells in vitro]. Nan Fang Yi Ke Da Xue Xue Bao. 2010 Oct;30(10):2291-4. Chinese. PubMed PMID: 20965828.

15: Zheng R, Zhang W, Wang X, Gao H. [The sonodynamic effects of Chlorin e6 on the proliferation of human lung adenocarcinoma cell SPCA-1]. Zhongguo Fei Ai Za Zhi. 2010 Mar;13(3):201-5. Chinese. PubMed PMID: 20673516.

16: Chin WW, Praveen T, Heng PW, Olivo M. Effect of polyvinylpyrrolidone on the interaction of chlorin e6 with plasma proteins and its subcellular localization. Eur J Pharm Biopharm. 2010 Oct;76(2):245-52. Epub 2010 Jun 15. PubMed PMID: 20558287.

17: Vermathen M, Marzorati M, Vermathen P, Bigler P. pH-dependent distribution of chlorin e6 derivatives across phospholipid bilayers probed by NMR spectroscopy. Langmuir. 2010 Jul 6;26(13):11085-94. PubMed PMID: 20420428.

18: Park JH, Moon YH, Bang IS, Kim YC, Kim SA, Ahn SG, Yoon JH. Antimicrobial effect of photodynamic therapy using a highly pure chlorin e6. Lasers Med Sci. 2010 Sep;25(5):705-10. Epub 2010 Apr 23. PubMed PMID: 20414708.

19: Nikolaeva IA, Misharin AY, Ponomarev GV, Timofeev VP, Tkachev YV. Chlorin e6-cholesterol conjugate and its copper complex. Simple synthesis and entrapping in phospholipid vesicles. Bioorg Med Chem Lett. 2010 May 1;20(9):2872-5. Epub 2010 Mar 11. PubMed PMID: 20356740.

20: Wawrzyńska M, Kałas W, Biały D, Zioło E, Arkowski J, Mazurek W, Strzadała L. In vitro photodynamic therapy with chlorin e6 leads to apoptosis of human vascular smooth muscle cells. Arch Immunol Ther Exp (Warsz). 2010 Feb;58(1):67-75. PubMed PMID: 20077143; PubMed Central PMCID: PMC2816260.

21: Moon YH, Kwon SM, Kim HJ, Jung KY, Park JH, Kim SA, Kim YC, Ahn SG, Yoon JH. Efficient preparation of highly pure chlorin e6 and its photodynamic anti-cancer activity in a rat tumor model. Oncol Rep. 2009 Nov;22(5):1085-91. PubMed PMID: 19787225.

22: Juzeniene A. Chlorin e6-based photosensitizers for photodynamic therapy and photodiagnosis. Photodiagnosis Photodyn Ther. 2009 Jun;6(2):94-6. Epub 2009 Jul 2. PubMed PMID: 19683209.

23: Chin WW, Heng PW, Lim PL, Lau WK, Olivo M. Membrane transport enhancement of chlorin e6-polyvinylpyrrolidone and its photodynamic efficacy on the chick chorioallantoic model. J Biophotonics. 2008 Oct;1(5):395-407. PubMed PMID: 19343663.

24: Balem F, Yanamala N, Klein-Seetharaman J. Additive effects of chlorin e6 and metal ion binding on the thermal stability of rhodopsin in vitro. Photochem Photobiol. 2009 Mar-Apr;85(2):471-8. PubMed PMID: 19267872.

25: Chin WW, Thong PS, Bhuvaneswari R, Soo KC, Heng PW, Olivo M. In-vivo optical detection of cancer using chlorin e6--polyvinylpyrrolidone induced fluorescence imaging and spectroscopy. BMC Med Imaging. 2009 Jan 8;9:1. PubMed PMID: 19133127; PubMed Central PMCID: PMC2628892.

26: Ol'shevskaya VA, Nikitina RG, Savchenko AN, Malshakova MV, Vinogradov AM, Golovina GV, Belykh DV, Kutchin AV, Kaplan MA, Kalinin VN, Kuzmin VA, Shtil AA. Novel boronated chlorin e6-based photosensitizers: synthesis, binding to albumin and antitumour efficacy. Bioorg Med Chem. 2009 Feb 1;17(3):1297-306. Epub 2008 Dec 24. PubMed PMID: 19121946.

27: Vermathen M, Vermathen P, Simonis U, Bigler P. Time-dependent interactions of the two porphyrinic compounds chlorin e6 and mono-L-aspartyl-chlorin e6 with phospholipid vesicles probed by NMR spectroscopy. Langmuir. 2008 Nov 4;24(21):12521-33. Epub 2008 Sep 30. PubMed PMID: 18823137.

28: Isakau HA, Parkhats MV, Knyukshto VN, Dzhagarov BM, Petrov EP, Petrov PT. Toward understanding the high PDT efficacy of chlorin e6-polyvinylpyrrolidone formulations: photophysical and molecular aspects of photosensitizer-polymer interaction in vitro. J Photochem Photobiol B. 2008 Sep 18;92(3):165-74. Epub 2008 Jun 24. PubMed PMID: 18656379.

29: Chin WW, Heng PW, Thong PS, Bhuvaneswari R, Hirt W, Kuenzel S, Soo KC, Olivo M. Improved formulation of photosensitizer chlorin e6 polyvinylpyrrolidone for fluorescence diagnostic imaging and photodynamic therapy of human cancer. Eur J Pharm Biopharm. 2008 Aug;69(3):1083-93. Epub 2008 Mar 10. PubMed PMID: 18396019.

30: Chin WW, Heng PW, Olivo M. Chlorin e6 - polyvinylpyrrolidone mediated photosensitization is effective against human non-small cell lung carcinoma compared to small cell lung carcinoma xenografts. BMC Pharmacol. 2007 Dec 1;7:15. PubMed PMID: 18053148; PubMed Central PMCID: PMC2212622.

31: Yumita N, Han QS, Kitazumi I, Umemura S. Sonodynamically-induced apoptosis, necrosis, and active oxygen generation by mono-l-aspartyl chlorin e6. Cancer Sci. 2008 Jan;99(1):166-72. Epub 2007 Oct 29. PubMed PMID: 17970784.

32: Copley L, van der Watt P, Wirtz KW, Parker MI, Leaner VD. Photolon, a chlorin e6 derivative, triggers ROS production and light-dependent cell death via necrosis. Int J Biochem Cell Biol. 2008;40(2):227-35. Epub 2007 Aug 1. PubMed PMID: 17822943.

33: Mojzisova H, Bonneau S, Vever-Bizet C, Brault D. Cellular uptake and subcellular distribution of chlorin e6 as functions of pH and interactions with membranes and lipoproteins. Biochim Biophys Acta. 2007 Nov;1768(11):2748-56. Epub 2007 Jul 13. PubMed PMID: 17692283.

34: Isakau HA, Trukhacheva TV, Petrov PT. Isolation and identification of impurities in chlorin e6. J Pharm Biomed Anal. 2007 Sep 21;45(1):20-9. Epub 2007 May 21. PubMed PMID: 17614233.

35: Mori K, Kanai K, Peyman GA, Yoneya S. Intraocular biodistribution of mono-L-aspartyl chlorin e6 in a primate choroidal neovascularization model. Ophthalmic Surg Lasers Imaging. 2007 Mar-Apr;38(2):142-7. PubMed PMID: 17396695.

36: Istoin YP, Laptsevich TP, Bizyuk SA, Alexandrova EN. Photodynamic efficacy of topical application of chlorin e6--polyvinyl pyrrolidone complex in tumor-bearing rats. Exp Oncol. 2006 Dec;28(4):299-302. PubMed PMID: 17285114.

37: Ohmori S, Masuda K, Arai T. Characteristics of Photocytotoxicity with high peak power pulsed irradiation: Comparison of Photodynamic Therapy with two photosensitizers, Photofrin® and mono-L-aspartyl chlorin e6 on prostate cancer cell in vitro. Conf Proc IEEE Eng Med Biol Soc. 2005;1:217-9. PubMed PMID: 17282151.

38: Nakagawa H, Matsumiya T, Sakaki H, Imaizumi T, Kubota K, Kusumi A, Kobayashi W, Kimura H. Expression of vascular endothelial growth factor by photodynamic therapy with mono-L-aspartyl chlorin e6 (NPe6) in oral squamous cell carcinoma. Oral Oncol. 2007 Jul;43(6):544-50. Epub 2007 Jan 25. PubMed PMID: 17257889.

39: Isakau HA, Trukhacheva TV, Zhebentyaev AI, Petrov PT. HPLC study of chlorin e6 and its molecular complex with polyvinylpyrrolidone. Biomed Chromatogr. 2007 Mar;21(3):318-25. PubMed PMID: 17236242.

40: Mojzisova H, Bonneau S, Vever-Bizet C, Brault D. The pH-dependent distribution of the photosensitizer chlorin e6 among plasma proteins and membranes: a physico-chemical approach. Biochim Biophys Acta. 2007 Feb;1768(2):366-74. Epub 2006 Oct 25. PubMed PMID: 17141733.

41: Chin WW, Heng PW, Bhuvaneswari R, Lau WK, Olivo M. The potential application of chlorin e6-polyvinylpyrrolidone formulation in photodynamic therapy. Photochem Photobiol Sci. 2006 Nov;5(11):1031-7. Epub 2006 Sep 21. PubMed PMID: 17077899.

42: Radestock A, Elsner P, Gitter B, Hipler UC. Induction of apoptosis in HaCaT cells by photodynamic therapy with chlorin e6 or pheophorbide a. Skin Pharmacol Physiol. 2007;20(1):3-9. Epub 2006 Oct 11. PubMed PMID: 17035716.

43: Choi Y, Weissleder R, Tung CH. Protease-mediated phototoxicity of a polylysine-chlorin(E6) conjugate. ChemMedChem. 2006 Jul;1(7):698-701. PubMed PMID: 16902920.

44: Tawakol A, Castano AP, Anatelli F, Bashian G, Stern J, Zahra T, Gad F, Chirico S, Ahmadi A, Fischman AJ, Muller JE, Hamblin MR. Photosensitizer delivery to vulnerable atherosclerotic plaque: comparison of macrophage-targeted conjugate versus free chlorin(e6). J Biomed Opt. 2006 Mar-Apr;11(2):021008. PubMed PMID: 16674183; PubMed Central PMCID: PMC2936819.

45: Tarragó-Trani MT, Jiang S, Harich KC, Storrie B. Shiga-like toxin subunit B (SLTB)-enhanced delivery of chlorin e6 (Ce6) improves cell killing. Photochem Photobiol. 2006 Mar-Apr;82(2):527-37. PubMed PMID: 16613509.

46: Drulis-Kawa Z, Bednarkiewicz A, Bugla-Płoskonska G, Strek W, Doroszkiewicz W. The susceptibility of anaerobic bacteria isolated from periodontal diseases to photodynamic inactivation with Fotolon (chlorin e6). Pol J Microbiol. 2005;54(4):305-10. PubMed PMID: 16599302.

47: Tegos GP, Anbe M, Yang C, Demidova TN, Satti M, Mroz P, Janjua S, Gad F, Hamblin MR. Protease-stable polycationic photosensitizer conjugates between polyethyleneimine and chlorin(e6) for broad-spectrum antimicrobial photoinactivation. Antimicrob Agents Chemother. 2006 Apr;50(4):1402-10. PubMed PMID: 16569858; PubMed Central PMCID: PMC1426948.

48: Chin WW, Lau WK, Heng PW, Bhuvaneswari R, Olivo M. Fluorescence imaging and phototoxicity effects of new formulation of chlorin e6-polyvinylpyrrolidone. J Photochem Photobiol B. 2006 Aug 1;84(2):103-10. Epub 2006 Mar 20. PubMed PMID: 16542848.

49: Chin WW, Lau WK, Bhuvaneswari R, Heng PW, Olivo M. Chlorin e6-polyvinylpyrrolidone as a fluorescent marker for fluorescence diagnosis of human bladder cancer implanted on the chick chorioallantoic membrane model. Cancer Lett. 2007 Jan 8;245(1-2):127-33. Epub 2006 Mar 3. PubMed PMID: 16516376.

50: Kobayashi W, Liu Q, Nakagawa H, Sakaki H, Teh B, Matsumiya T, Yoshida H, Imaizumi T, Satoh K, Kimura H. Photodynamic therapy with mono-L-aspartyl chlorin e6 can cause necrosis of squamous cell carcinoma of tongue: experimental study on an animal model of nude mouse. Oral Oncol. 2006 Jan;42(1):46-50. Epub 2005 Nov 2. PubMed PMID: 16266818.

51: Pegaz B, Debefve E, Borle F, Ballini JP, Wagnières G, Spaniol S, Albrecht V, Scheglmann D, Nifantiev NE, van den Bergh H, Konan YN. Preclinical evaluation of a novel water-soluble chlorin E6 derivative (BLC 1010) as photosensitizer for the closure of the neovessels. Photochem Photobiol. 2005 Nov-Dec;81(6):1505-10. PubMed PMID: 15960590.

52: Pellerito C, D'Agati P, Fiore T, Mansueto C, Mansueto V, Stocco G, Nagy L, Pellerito L. Synthesis, structural investigations on organotin(IV) chlorin-e6 complexes, their effect on sea urchin embryonic development and induced apoptosis. J Inorg Biochem. 2005 Jun;99(6):1294-305. PubMed PMID: 15917083.

53: Ramaswamy B, Manivasager V, Chin WW, Soo KC, Olivo M. Photodynamic diagnosis of a human nasopharyngeal carcinoma xenograft model using the novel Chlorin e6 photosensitizer Fotolon. Int J Oncol. 2005 Jun;26(6):1501-6. PubMed PMID: 15870862.

54: Chan AL, Juarez M, Allen R, Volz W, Albertson T. Pharmacokinetics and clinical effects of mono-L-aspartyl chlorin e6 (NPe6) photodynamic therapy in adult patients with primary or secondary cancer of the skin and mucosal surfaces. Photodermatol Photoimmunol Photomed. 2005 Apr;21(2):72-8. PubMed PMID: 15752124.

55: Webber J, Leeson B, Fromm D, Kessel D. Effects of photodynamic therapy using a fractionated dosing of mono-L-aspartyl chlorin e6 in a murine tumor. J Photochem Photobiol B. 2005 Feb 1;78(2):135-40. PubMed PMID: 15664500.

56: Kikuchi T, Asakura T, Aihara H, Shiraki M, Takagi S, Kinouchi Y, Aizawa K, Shimosegawa T. Photodynamic therapy of intestinal tumors with mono-L-aspartyl chlorin e6 (NPe6): a basic study. Anticancer Res. 2003 Nov-Dec;23(6C):4897-900. PubMed PMID: 14981942.

57: Uzdensky AB, Dergacheva OY, Zhavoronkova AA, Reshetnikov AV, Ponomarev GV. Photodynamic effect of novel chlorin e6 derivatives on a single nerve cell. Life Sci. 2004 Mar 12;74(17):2185-97. PubMed PMID: 14969720.

58: Biały D, Derkacz A, Wawrzyńska M, Bednarkiewicz A, Ziółkowski P, Nowosad H, Strek W. In vitro photodynamic diagnosis of atherosclerotic wall changes with the use of mono-l-aspartyl chlorin e6. A preliminary report. Kardiol Pol. 2003 Oct;59(10):293-301. PubMed PMID: 14618213.

59: Wong TW, Aizawa K, Sheyhedin I, Wushur C, Kato H. Pilot study of topical delivery of mono-L-aspartyl chlorin e6 (NPe6): implication of topical NPe6-photodynamic therapy. J Pharmacol Sci. 2003 Oct;93(2):136-42. PubMed PMID: 14578580.

60: Kato H, Furukawa K, Sato M, Okunaka T, Kusunoki Y, Kawahara M, Fukuoka M, Miyazawa T, Yana T, Matsui K, Shiraishi T, Horinouchi H. Phase II clinical study of photodynamic therapy using mono-L-aspartyl chlorin e6 and diode laser for early superficial squamous cell carcinoma of the lung. Lung Cancer. 2003 Oct;42(1):103-11. PubMed PMID: 14512194.

61: Merlin JL, Gautier H, Barberi-Heyob M, Teiten MH, Guillemin F. The multidrug resistance modulator SDZ-PSC 833 potentiates the photodynamic activity of chlorin e6 independently of P-glycoprotein in multidrug resistant human breast adenocarcinoma cells. Int J Oncol. 2003 Apr;22(4):733-9. PubMed PMID: 12632062.

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63: Kelbauskas L, Dietel W. Internalization of aggregated photosensitizers by tumor cells: subcellular time-resolved fluorescence spectroscopy on derivatives of pyropheophorbide-a ethers and chlorin e6 under femtosecond one- and two-photon excitations. Photochem Photobiol. 2002 Dec;76(6):686-94. PubMed PMID: 12511052.

64: Embleton ML, Nair SP, Cookson BD, Wilson M. Selective lethal photosensitization of methicillin-resistant Staphylococcus aureus using an IgG-tin (IV) chlorin e6 conjugate. J Antimicrob Chemother. 2002 Dec;50(6):857-64. PubMed PMID: 12461004.

65: Cavanaugh PG. Synthesis of chlorin e6-transferrin and demonstration of its light-dependent in vitro breast cancer cell killing ability. Breast Cancer Res Treat. 2002 Mar;72(2):117-30. PubMed PMID: 12038702.

66: Li L, Kodama K, Saito K, Aizawa K. Phase-resolved fluorescence study of mono-L-aspartyl chlorin E6. J Photochem Photobiol B. 2002 May;67(1):51-6. PubMed PMID: 12007467.

67: Nakamura H, Suzuki Y, Takeichi M, Saito T, Takayama M, Aizawa K. Morphologic evaluation of the antitumor activity of photodynamic therapy (PDT) using mono-L-aspartyl chlorin e6 (NPe6) against uterine cervical carcinoma cell lines. Int J Gynecol Cancer. 2002 Mar-Apr;12(2):177-86. PubMed PMID: 11975677.

68: Haimovici R, Ciulla TA, Miller JW, Hasan T, Flotte TJ, Kenney AG, Schomacker KT, Gragoudas ES. Localization of rose bengal, aluminum phthalocyanine tetrasulfonate, and chlorin e6 in the rabbit eye. Retina. 2002 Feb;22(1):65-74. PubMed PMID: 11884881.

69: Hamblin MR, Miller JL, Rizvi I, Ortel B. Degree of substitution of chlorin e6 on charged poly-L-lysine chains affects their cellular uptake, localization and phototoxicity towards macrophages and cancer cells. J Xray Sci Technol. 2002 Jan 1;10(3):139-52. PubMed PMID: 22388044.

70: Mori K, Yoneya S, Anzail K, Kabasawa S, Sodeyama T, Peyman GA, Moshfeghi DM. Photodynamic therapy of experimental choroidal neovascularization with a hydrophilic photosensitizer: mono-L-aspartyl chlorin e6. Retina. 2001;21(5):499-508. PubMed PMID: 11642380.

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72: Yu JW, Yoon SS, Yang R. Iron chlorin e6 scavenges hydroxyl radical and protects human endothelial cells against hydrogen peroxide toxicity. Biol Pharm Bull. 2001 Sep;24(9):1053-9. PubMed PMID: 11558568.

73: Nagae T, Aizawa K, Uchimura N, Tani D, Abe M, Fujishima K, Wilson SE, Ishimaru S. Endovascular photodynamic therapy using mono-L-aspartyl-chlorin e6 to inhibit Intimal hyperplasia in balloon-injured rabbit arteries. Lasers Surg Med. 2001;28(4):381-8. PubMed PMID: 11344521.

74: Del Governatore M, Hamblin MR, Shea CR, Rizvi I, Molpus KG, Tanabe KK, Hasan T. Experimental photoimmunotherapy of hepatic metastases of colorectal cancer with a 17.1A chlorin(e6) immunoconjugate. Cancer Res. 2000 Aug 1;60(15):4200-5. PubMed PMID: 10945630.

75: Cunderlíková B, Kongshaug M, Gangeskar L, Moan J. Increased binding of chlorin e6 to lipoproteins at low pH values. Int J Biochem Cell Biol. 2000 Jul;32(7):759-68. PubMed PMID: 10856706.

76: Saito K, Mikuniya N, Aizawa K. Effects of photodynamic therapy using mono-L-aspartyl chlorin e6 on vessels and its contribution to the antitumor effect. Jpn J Cancer Res. 2000 May;91(5):560-5. PubMed PMID: 10835502.

77: Gijsens A, Missiaen L, Merlevede W, de Witte P. Epidermal growth factor-mediated targeting of chlorin e6 selectively potentiates its photodynamic activity. Cancer Res. 2000 Apr 15;60(8):2197-202. PubMed PMID: 10786684.

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79: Kessel D, Poretz RD. Sites of photodamage induced by photodynamic therapy with a chlorin e6 triacetoxymethyl ester (CAME). Photochem Photobiol. 2000 Jan;71(1):94-6. PubMed PMID: 10649895.

80: Del Governatore M, Hamblin MR, Piccinini EE, Ugolini G, Hasan T. Targeted photodestruction of human colon cancer cells using charged 17.1A chlorin e6 immunoconjugates. Br J Cancer. 2000 Jan;82(1):56-64. PubMed PMID: 10638967; PubMed Central PMCID: PMC2363172.

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