与氨基苄基二乙三胺五乙酸共轭的叶绿素-a类似物作为磁共振成像和光动力疗法的潜在双功能剂。
Chlorophyll-a analogues conjugated with aminobenzyl-DTPA as potential bifunctional agents for magnetic resonance imaging and photodynamic therapy.
作者信息
Li Guolin, Slansky Adam, Dobhal Mahabeer P, Goswami Lalit N, Graham Andrew, Chen Yihui, Kanter Peter, Alberico Ronald A, Spernyak Joseph, Morgan Janet, Mazurchuk Richard, Oseroff Allan, Grossman Zachary, Pandey Ravindra K
机构信息
Photodynamic Therapy Center, Department of Nuclear Medicine and Radiology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
出版信息
Bioconjug Chem. 2005 Jan-Feb;16(1):32-42. doi: 10.1021/bc049807x.
A clinically relevant photosensitizer, 3-devinyl-3-(1-hexyloxyethyl)pyropheophorbide-a (HPPH, a chlorophyll-a derivative), was conjugated with Gd(III)-aminobenzyl-diethylenetriaminepentaacetic acid (DTPA), an experimental magnetic resonance (MR) imaging agent. In vivo reflectance spectroscopy confirmed tumor uptake of HPPH-aminobenzyl-Gd(III)-DTPA conjugate was higher than free HPPH administered intraveneously (iv) to C3H mice with subcutaneously (sc) implanted radiation-induced fibrosarcoma (RIF) tumor cells. In other experiments, Sprague-Dawley (SD) rats with sc implanted Ward Colon Carcinoma cells yielded markedly increased MR signal intensities from tumor regions-of-interest (ROIs) 24 h post-iv injection of HPPH-aminobenzyl-Gd(III)-DTPA conjugate as compared to unconjugated HPPH. In both in vitro (RIF tumor cells) and in vivo (mice bearing RIF tumors and rats bearing Ward Colon tumors) the conjugate produced significant increases in tumor conspicuity at 1.5 T and retained therapeutic efficacy following PDT. Also synthesized were a series of novel bifunctional agents containing two Gd(III) atoms per HPPH molecule that remained tumor-avid and PDT-active and yielded improved MR tumor conspicuity compared to their corresponding mono-Gd(III) analogues. Administered iv at a MR imaging dose of 10 micromol/kg, these conjugates produced severe skin phototoxicity. However, by replacing the hexyl group of the pyropheophorbide-a with a tri(ethylene glycol) monomethyl ether (PEG-methyl ether), these conjugates produced remarkable MR tumor enhancement at 8 h post-iv injection, significant tumoricidal activity (80% of mice were tumor-free on day 90), and reduced skin phototoxicity compared to their corresponding hexyl ether analogues. The poor water-solubility characteristic of these conjugates was resolved by incorporation into a liposomal formulation. This paper presents the synthesis of tumor-avid contrast enhancing agents for MR imaging and thus represents an important milestone toward improving cancer diagnosis and tumor characterization. More importantly, this paper describes a new family of bifunctional agents that combine two modalities into a single cost-effective "see and treat" approach, namely, a single agent that can be used for contrast agent-enhanced MR imaging followed by targeted photodynamic therapy.
一种具有临床相关性的光敏剂,即3-去乙烯基-3-(1-己氧基乙基)焦脱镁叶绿酸-a(HPPH,一种叶绿素-a衍生物),与钆(III)-氨基苄基-二乙烯三胺五乙酸(DTPA,一种实验性磁共振(MR)成像剂)进行了偶联。体内反射光谱证实,对于皮下(sc)植入辐射诱导纤维肉瘤(RIF)肿瘤细胞的C3H小鼠,静脉内(iv)注射HPPH-氨基苄基-钆(III)-DTPA偶联物后,肿瘤对其摄取高于游离HPPH。在其他实验中,皮下植入沃德结肠癌细胞的斯普拉格-道利(SD)大鼠在静脉注射HPPH-氨基苄基-钆(III)-DTPA偶联物24小时后,与未偶联的HPPH相比,肿瘤感兴趣区域(ROIs)的MR信号强度显著增加。在体外(RIF肿瘤细胞)和体内(携带RIF肿瘤的小鼠和携带沃德结肠癌的大鼠)实验中,该偶联物在1.5 T时均显著提高了肿瘤的清晰度,并且在光动力疗法(PDT)后仍保留治疗效果。还合成了一系列新型双功能剂,每个HPPH分子含有两个钆(III)原子,这些双功能剂保持肿瘤亲和性和PDT活性,与相应的单钆(III)类似物相比,其MR肿瘤清晰度更高。以10 μmol/kg的MR成像剂量静脉注射这些偶联物会产生严重的皮肤光毒性。然而,通过用三(乙二醇)单甲醚(PEG-甲醚)取代焦脱镁叶绿酸-a的己基,这些偶联物在静脉注射8小时后产生了显著的MR肿瘤增强效果、显著的杀肿瘤活性(90天时80%的小鼠无肿瘤),并且与相应的己基醚类似物相比,皮肤光毒性降低。通过将这些偶联物掺入脂质体制剂中,解决了它们水溶性差的问题。本文介绍了用于MR成像的肿瘤亲和性造影剂增强剂的合成,因此代表了改善癌症诊断和肿瘤特征的一个重要里程碑。更重要的是,本文描述了一个新的双功能剂家族,它们将两种模式结合成一种具有成本效益的“可视且可治疗”方法,即一种可用于造影剂增强MR成像然后进行靶向光动力疗法的单一药剂。