Original articlePreparation of a chlorophyll derivative and investigation of its photodynamic activities against cholangiocarcinoma
Introduction
Cholangiocarcinoma (CCA) is a malignant tumor originating from biliary tract epithelial cells [1]. Due to its difficulty of diagnosis and high fatality rate, it is becoming the most common hepatic tumor-induced death [1], [2]. As CCA is resistant to traditional chemotherapy and radiotherapy, surgery is the only therapeutic mode offering a cure. However, recurrence frequently occurs and the 5-year survival rate is only 5%–10% [3].
Photodynamic therapy (PDT) is a non-invasive treatment that involves the accumulation of a photosensitizer in malignant tissue followed by irradiation with laser light of an appropriate wavelength [4], [5]. In the presence of oxygen, the activated photosensitizer can generate singlet oxygen (1O2) and reactive oxygen species (ROS) that ultimately leads to cell death through apoptosis or necrosis [6], [7]. Up to date, many studies have been conducted on the use of PDT on CCA, which indicated that PDT has a promising trend toward improved survival as well as improvement in quality of life [8], [9]. However, because clinically approved PDT drugs generally give many problems due to the prolonged cutaneous photo-sensitivity, poor water-solubility and inadequate selectivity, the clinical application of PDT is limited [10], [11].
In general, an ideal photosensitizer for tumor PDT requires good tissue penetration, low dark toxicity but strong photocytotoxicity, high extinction coefficient, rapid removal from the body and multiple administration routes [12], [13]. Recently, the chlorophyll a and its derivatives have been considered as having great promises and efficacy for treatment of some cancers due to their long-wavelength absorbance, and most efforts in our laboratory have been directed toward the synthesis of new potential photosensitizers related to chlorophyll [14].
As a degraded product of chlorophyll, pyropheophorbide-a is well known as an ideal synthetic precursor for the synthesis of photodynamic therapy drugs. In the present study, a novel chlorophyll derivative, N,N-bis(2-carboxyethyl)pyropheophorbide a (BPPA), had been synthesized and characterized. The cellular uptake, intracellular localization, in vitro and in vivo PDT efficacy were further investigated to evaluate the efficacy of PDT in treatment of CCA.
Section snippets
Synthesis and photophysical properties of BPPA
The synthesis of N,N-bis(2-carboxyethyl)pyropheophorbide a amide (BPPA) as showed in Scheme 1. Pyropheophorbide-a is a derivative from plant chlorophyll. It was reacted with dimethyl 3,3′-azanediyldipropionate in the presence of HBTU and triethylamine to give N,N-dimethoxycarbonylethyl-pyropheophorbide-a amide (compound 2). After hydrolysis of compoud 2 with NaOH solution in THF, a novel chlorin (or dihydroporphin) derivative 1 was obtained with 95.3% yield. Compound 1 was purified by column
Conclusions
A novel chlorophyll derivative, N,N-bis(2-carboxyethyl)pyropheophorbide a amide, was synthesized and characterized. BPPA showed strong absorption at 669 nm and singlet oxygen quantum yield of 0.54. The cellular uptake, subcellular localization, bio-distribution, in vitro and in vitro PDT efficacy of BPPA were studied. The results suggested that BPPA could be a promising drug candidate for PDT in the treatment of CCA.
Materials and methods
Pyropheophorbide-a was supplied by Shanghai Xianhui Pharmaceutical Co., Ltd. Other chemicals and reagents were obtained from Sinopharm Chemical Reagent Co., Ltd and used as supplied without further purification. All reactions were taken under an atmosphere of N2 with magnetic stirring. Solvents were purified and dried by distillation over adequate drying agent according to standard procedures. 1H NMR and 13C NMR spectra were recorded on a Bruker AMX-400 and are reported in ppm relative to TMS
Conflict of interests
None.
Acknowledgements
This work was supported by National Natural Science Foundation of China (No. 21372042, 81301878, 21402236), Foundation of Shanghai government (Nos. 15XD1523400, 14140903500, 15431904100, 13431900700, 14431906200, 201370, 14ZR1439900, 14ZR1439800, 15ZR1439900, 16ZR1400600, and 15411960400) and Foundation of Songjiang government (No. 15SJGG45)
References (25)
- et al.
Spectroscopic and biological studies of a novel synthetic chlorin derivative with prospects for use in PDT
Bioorg. Med. Chem.
(2009) - et al.
Novel 3,6-bis(imidazolidine)acridines as effective photosensitizers for photodynamic therapy
Bioorg. Med. Chem.
(2014) - et al.
Mechanisms in photodynamic therapy. Part one: photosensitizers, photochemistry and cellular localization
Photodiagn. Photodyn. Ther.
(2004) - et al.
The synthesis and photophysicochemical behaviour of novel water-soluble cationic indium(III) phthalocyanine
Dyes Pigm.
(2009) - et al.
Chemical determination of singlet oxygen from photosensitizers illuminated with LED: New calculation methodology considering the influence of photobleaching
J. Photochem. Photobiol. A: Chem.
(2012) - et al.
Current research in perineural invasion of cholangiocarcinoma
J. Exp. Clin. Cancer Res.
(2010) - et al.
Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998
Gut
(2001) - et al.
Chemotherapy for cholangiocarcinoma: an update
World J. Gastrointest. Oncol.
(2013) - et al.
Antitumor effect of photodynamic therapy with chlorin-based photosensitizer DH-II-24 in colorectal carcinoma
Cancer Sci.
(2009) - et al.
Non-destructive evaluation of the effects of combined bisphosphonate and photodynamic therapy on bone strain in metastatic vertebrae using image registration
Ann. Biomed. Eng.
(2011)
Is there any evidence for a role of local treatment in cholangiocarcinoma?
Viszeralmedizin
Technology insight: photodynamic therapy for cholangiocarcinoma
Nature Rev. Gastroenterol. Hepatol.
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