Chlorophyll-a Analogues Conjugated with Aminobenzyl-DTPA as Potential Bifunctional Agents for Magnetic Resonance Imaging and Photodynamic Therapy

Abstract

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.

Contrast-Enhanced MRI-Guided Photodynamic Cancer Therapy with a Pegylated Bifunctional Polymer Conjugate

“…MRI is a non-invasive imaging modality and has several advantages over other imaging modalities since it provides three-dimensional anatomic images with high spatial resolution. The combination of MRI with photodynamic therapy provides image-guidance for laser irradiation (14,15), and non-invasive assessment of the therapeutic efficacy of PDT (16). Previously, we have shown that contrast-enhanced MRI-guided photodynamic therapy using a bifunctional polymer conjugate containing an MRI contrast agent and a photosensitizer is effective for tumor imaging and cancer treatment (17).…”

Erythrocytes Membrane Photodestruction Sensitized Chlorophyll a Derivatives: Some Structure-Activity Regularities

“…Here the methylpheophorbide a (2) and its analogs (8,12) were used us a starting material for the chlorins synthesis. The main reaction centers of these phorbine derivatives (exo-cycle vinyl group, keto group and ester group) were used for peripheral substituent's modification.…”

Development of novel bifunctional agents with and without tumor imaging ability

“…37 In an independent study, we have shown that bifunctional conjugates containing PS and the cyanine dyes can be used as tumor imaging and PDT agents. 11,37 In these conjugates, the function of the fluorophore is to visualize the tumor location and treatment site. The presence of the photosensitizer allows subsequent tumor ablation.…”