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A Phthalocyanine
Photosensitizer for Photodynamic Therapy
Oleinick, Nancy1,
Hoppel, Charles1, Kenney, Malcolm1,
Kinsella, Timothy1, Mukhtar, Hasan1,
Nieminen, Anna-Liisa1, Sibata, Claudio1,
Remick, Scot1, Stevens, Seth1
and Whitacre, Cecilia1
Case Western Reserve University and the CWRU/UHC/Ireland Comprehensive
Cancer Center, Cleveland, OH 441061
8
Abstract-
Pc 4 is a silicon phthalocyanine which our group has been developing
as a photosensitizer for photodynamic therapy. It is non-sulfonated
and contains two axial ligands on the central silicon, a hydroxyl and
a dimethylamino propylsiloxy ligand. Pc 4 has several features that
make it an attractive photosensitizer, including favorable absorption
spectrum, photochemistry, and pharmacokinetics, and good activity against
a variety of murine tumors and human tumor xenografts in athymic nude
mice at doses that produce little or no cutaneous photosensitization.
Of interest is the tendency of Pc 4 to preferentially target the malignant
cells of murine tumors, as opposed to cells of the tumor vasculature.
As a result, vascular shutdown is a late event in Pc 4-PDT. Mechanistic
studies in vitro and in vivo reveal the efficient induction of apoptosis
in most cells and in all tumor systems that have been investigated.
The Drug Decision Network of the National Cancer Institute supported
the studies to bring Pc 4 into clinical trial, including formulation,
toxicity, pharmacokinetics, and efficacy studies, as well as synthesis
of sufficient Pc 4 for the first Phase I trial. The US FDA has now issued
an Investigational New Drug Number for Pc 4, and dose escalation is
beginning in patients with dermal cancers. The trial is designed to
determine Pc 4 pharmacokinetics in patients as well as the maximum tolerated
dose for Pc 4 and for light. Linked translational studies will document
the severity and timing of any cutaneous photosensitivity and the extent
to which apoptosis and associated molecular markers occur in response
to Pc 4-PDT. If the trial identifies a useful dose combination for future
study, Pc 4 will be the only phthalocyanine photosensitizer in clinical
PDT in the US and one of the very few photosensitizers developed by
an academic research group independent of commercial support to this
point. The investigators are indebted to the Roswell Connection for
inspiration, consultation, and critical review of our PDT grant applications.
(Supported by NCI grants P01 CA48735 and P30 CA47303)
Keywords: photodynamic
therapy, phthalocyanine
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