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

3-(1'-Hexyloxyethyl)-3-devinyl-pyropheophorbide-a (HPPH or Photochlor), a tumor-avid chlorophyll-a derivative currently undergoing human clinical trials, was conjugated at different peripheral positions (position-17 or 20) of the macrocycle with either Gd(III)-aminobenzyl-DTPA ( Gd(III) DTPA ) or Gd(III)-aminoethylamido-DOTA ( Gd(III)DOTA ) moiety. The corresponding conjugates were evaluated for in vitro uptake and PDT efficacy in Colon26 tumor cell line. The T1, T2 relaxivity, in vivo fluorescence and MR imaging under similar treatment parameters were performed in BALB/c mice bearing Colon26 tumors. Among the analogs investigated, the water soluble Gd(III)-aminoethylamido-DOTA linked at position-17 of HPPH, i.e., HPPH-17-DOTA-Gd(III) demonstrated strong potential for tumor imaging by both MR and fluorescence, while maintaining the PDT activity at the MR imaging dose (7/10 BALB/c mice implanted with Colon26 tumors were tumor free on day 60). In contrast to Gd(III) DTPA (Magnavist) and Gd(III)DOTA), the HPPH-Gd(III) DOTA retains in tumor for a long period of time (24 to 48 h) and provide an option of fluorescence-guided phototherapy of cancer. Thus, a single agent can be used for dual-imaging and therapy. However, further detailed pharmacokinetic, pharmacodynamic and toxicological studies of the conjugate are required in higher animals (rats and dogs under the guidelines of FDA) before initiating Phase I human clinical trials.

Keywords: FI, Fluorescence imaging; MRI, Magnetic resonance imaging; PDT, Photodynamic therapy.