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The Structures of Gd(III) Chelates Conjugated at the Periphery of 3‐(1’‐Hexyloxy)ethyl‐3‐devinylpyropheophorbide‐a (HPPH) Have a Significant Impact on the Imaging and Therapy of Cancer
Author(s) -
Zhang Shunqing,
Cheruku Ravindra R.,
Dukh Mykhaylo,
Tabaczynski Walter,
Patel Nayan J.,
White William H.,
Missert Joseph R.,
Spernyak Joseph A.,
Pandey Ravindra K.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000449
Subject(s) - dota , conjugate , in vivo , chemistry , conjugated system , pharmacokinetics , in vitro , chelation , gadolinium , fluorescence lifetime imaging microscopy , cancer , cancer research , fluorescence , pharmacology , medicine , biochemistry , biology , organic chemistry , mathematical analysis , mathematics , microbiology and biotechnology , polymer , physics , quantum mechanics
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, T 1 , T 2 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.