Chlorophyll-a analogues conjugated with aminobenzyl-DTPA as potential bifunctional agents for magnetic resonance imaging and photodynamic therapy.
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.
Li
Guolin
G
Photodynamic Therapy Center, Department of Nuclear Medicine and Radiology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Slansky
Adam
A
Dobhal
Mahabeer P
MP
Goswami
Lalit N
LN
Graham
Andrew
A
Chen
Yihui
Y
Kanter
Peter
P
Alberico
Ronald A
RA
Spernyak
Joseph
J
Morgan
Janet
J
Mazurchuk
Richard
R
Oseroff
Allan
A
Grossman
Zachary
Z
Pandey
Ravindra K
RK
D062365:Aminobenzoates / Q000737:chemistry*; D000818:Animals; D002734:Chlorophyll / Q000031:analogs & derivatives*; D003432:Cross-Linking Reagents; D019786:Gadolinium DTPA / Q000031:analogs & derivatives; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis; D004369:Pentetic Acid / Q000737:chemistry*; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D051381:Rats; D013997:Time Factors; D014407:Tumor Cells, Cultured
D062365:Aminobenzoates; D003432:Cross-Linking Reagents; D017319:Photosensitizing Agents; D002734:Chlorophyll; D004369:Pentetic Acid; D019786:Gadolinium DTPA