Photodynamic therapy with the phthalocyanine photosensitizer Pc 4: the case experience with preclinical mechanistic and early clinical-translational studies.

Photodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancers. PDT involves either local or systemic administration of a photosensitizing drug, which preferentially localizes within the tumor, followed by illumination of the involved organ with light, usually from a laser source. Here, we provide a selective overview of our experience with PDT at Case Western Reserve University, specifically with the silicon phthalocyanine photosensitizer Pc 4. We first review our in vitro studies evaluating the mechanism of cell killing by Pc 4-PDT. Then we briefly describe our clinical experience in a Phase I trial of Pc 4-PDT and our preliminary translational studies evaluating the mechanisms behind tumor responses. Preclinical work identified (a) cardiolipin and the anti-apoptotic proteins Bcl-2 and Bcl-xL as targets of Pc 4-PDT, (b) the intrinsic pathway of apoptosis, with the key participation of caspase-3, as a central response of many human cancer cells to Pc 4-PDT, (c) signaling pathways that could modify apoptosis, and (d) a formulation by which Pc 4 could be applied topically to human skin and penetrate at least through the basal layer of the epidermis. Clinical-translational studies enabled us to develop an immunohistochemical assay for caspase-3 activation, using biopsies from patients treated with topical Pc 4 in a Phase I PDT trial for cutaneous T-cell lymphoma. Results suggest that this assay may be used as an early biomarker of clinical response.

Observation of non-Förster-type energy-transfer behavior in quantum dot-phthalocyanine conjugates.

The effect of linker chain length on the energy transfer from CdSe quantum dots (QDs) to silicon phthalocyanine (Pc) photodynamic therapy agents was investigated by steady-state and femtosecond time-resolved spectroscopy with 500 nm light for the specific excitation of the QD energy donor. The conjugation between the QD and the Pc was achieved with linker chains varying from 4 to 9 bond lengths by incorporating 1-6 methylene groups into the axial ligand of the Pc. With increasing chain length, the energy-transfer efficiency increased, which appears to be opposed to a purely Förster-type resonance energy-transfer behavior that is commonly discussed for the energy transfer in QD conjugates. The obtained results provide strong evidence for a capping-layer-mediated energy transfer in the QD-based donor-acceptor conjugates.

Synthesis and photophysical properties of silicon phthalocyanines with axial siloxy ligands bearing alkylamine termini.

Eleven silicon phthalocyanines which can be grouped into two homologous series [SiPc[OSi(CH3)2(CH2)(n)N(CH3)2]2, n = 1-6 (series 1), and SiPc[OSi(CH3)2(CH2)3N((CH2)(n)H)2]2, n = 1-6 (series 2)] as well as an analogous phthalocyanine, SiPc[OSi(CH3)2(CH2)3NH2]2, were synthesized. The ground state absorption spectra, the triplet state dynamics, and singlet oxygen quantum yields of 10 of these phthalocyanines were measured. All compounds displayed similar ground state absorption spectral properties in dimethylformamide solution with single Q band maxima at 668 +/- 2 nm and B band maxima at 352 +/- 1 nm. Photoexcitation of all compounds in the B bands generated the optical absorptions of the triplet states which decayed with lifetimes in the hundreds of microseconds region. Oxygen quenching bimolecular rate constants near 2 x 10(9) M(-1) s(-1) were measured, indicating that energy transfer to oxygen was exergonic. Singlet oxygen quantum yields, phi(delta), were measured, and those phthalocyanines in which the axial ligands are terminated by dimethylamine residues at the end of alkyl chains having four or more methylene links exhibited yields near > or = 0.35. Others gave singlet oxygen quantum yields near 0.2, and still others showed singlet oxygen yields of <0.1. The reduced singlet oxygen yields are probably caused by a charge transfer quenching of the 1pi,pi* state of the phthalocyanine by interaction with the lone pair electrons on the nitrogen atoms of the amine termini. In some cases, these can approach and interact with the electronically excited pi-framework, owing to diffusive motions of the flexible oligo-methylene tether.