The structure of Gd(III) chelates conjugated at the periphery of 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH) make significant impact in imaging and therapy of cancer.,ChemMedChem

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The structure of Gd(III) chelates conjugated at the periphery of 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH) make significant impact in imaging and therapy of cancer.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-09-11 , DOI: 10.1002/cmdc.202000449
Shunqing Zhang ₁ , Ravindra R Cheruku ₁ , Mykhaylo Dukh ₁ , Walter Tabaczynski ₁ , Nayan J Patel ₁ , William H White ₁ , Joseph R Missert ₁ , Joseph A Spernyak ₂ , Ravindra K Pandey ₁

Affiliation

3‐(1’‐Hexyloxyethyl)‐3‐devinyl‐pyropheophorbide‐a (HPPH or Photochlor), a tumor‐avid chlorophyll‐a derivative currently undergoing human clinical trials, was conjugated at various peripheral positions (position‐17 or 20) of HPPH with either Gd(III)‐aminobenzyl‐DTPA (Gd(III) DTPA) or Gd(III)‐aminoethylamido‐DOTA (Gd(III) DOTA). The corresponding conjugates were evaluated for in vitro PDT efficacy, T₁, T₂ relaxivities, in vivo fluorescence, and MR imaging under similar treatment parameters. Among these analogs, the water‐soluble Gd(III)‐aminoethylamido‐DOTA linked at position‐17 of HPPH, i. e., HPPH‐17‐Gd(III) DOTA, demonstrated strong potential for tumor imaging by both MR and fluorescence, while maintaining the PDT efficacy in BALB/c mice bearing Colon‐26 tumors (7/10 mice were tumor free on day 60). In contrast to Gd(III) DTPA (Magnevist) and Gd(III) DOTA (Dotarem), the HPPH‐Gd(III) DOTA retains in the tumor for a long period of time (24 to 48 h) and provides an option of fluorescence‐guided cancer therapy. Thus, a single agent can be used for cancer‐imaging and therapy. However, further detailed pharmacokinetic, pharmacodynamic, and toxicological studies of the conjugate are required before initiating Phase I human clinical trials.

中文翻译：

结合在 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH) 外围的 Gd(III) 螯合物的结构对癌症的成像和治疗产生重大影响。

3-(1'-Hexyloxyethyl)-3-devinyl-pyropheophorbide-a (HPPH or Photochlor) 是一种亲肿瘤的叶绿素-a 衍生物，目前正在进行人体临床试验，在不同的外围位置（位置 17 或 20）缀合HPPH 与 Gd(III)-氨基苄基-DTPA (Gd(III) DTPA) 或 Gd(III)-氨基乙基酰胺-DOTA (Gd(III) DOTA)。评估相应缀合物的体外 PDT 功效、T ₁、T ₂弛豫度、体内荧光和类似治疗参数下的 MR 成像。在这些类似物中，水溶性 Gd(III)-氨基乙基酰胺-DOTA 连接在 HPPH 的 17 位，即。例如，HPPH-17-Gd(III) DOTA 显示出通过 MR 和荧光进行肿瘤成像的强大潜力，同时在携带 Colon-26 肿瘤的 BALB/c 小鼠中保持 PDT 功效（7/10 小鼠在当天没有肿瘤60）。与 Gd(III) DTPA (Magnevist) 和 Gd(III) DOTA (Dotarem) 相比，HPPH-Gd(III) DOTA 在肿瘤中保留了很长一段时间（24 到 48 小时），并提供了一种选择荧光引导的癌症治疗。因此，单一药剂可用于癌症成像和治疗。然而，在开始 I 期人体临床试验之前，需要对偶联物进行更详细的药代动力学、药效学和毒理学研究。

更新日期：2020-11-06

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