Analysis of Effective Molecular Diffusion Rates for Verteporfin in Subcutaneous Versus Orthotopic Dunning Prostate Tumors¶

Abstract

Photosensitizer biodistribution change inside tissue is one of the dominant factors in photodynamic therapy efficacy. In this study, the pharmacokinetics of a benzoporphyrin derivative (BPD), delivered in verteporfin for injection formulation, have been quantified in the rat Dunning prostate tumor MAT-LyLu model, using both subcutaneous and orthotopic sites. Blood plasma sampling indicated that BPD had a bi-exponential metabolic lifetime in vivo, with the two lifetimes being 9.6 min and 8.3 h. The spatial distributions in the tumor were quantified as a function of distance from the perfused blood vessels, using fluorescence histologic images of the tumor. A fluorescent vascular marker was used to obtain locations and shapes of perfused capillaries at a wavelength of emission different from that of BPD and to allow colocalized images to be acquired of vessel and BPD locations. Using the BPD fluorescence images obtained 15 min after intravenous administration, a forward finite-element solution to the diffusion equation was used to predict the drug distribution by matching the fluorescence intensity images observed microscopically. An inverse solver was used to minimize the root mean square error between the image of simulated diffusion and the experimental image, resulting in estimation of the diffusion coefficient of BPD in the tumor models. Effective diffusion coefficients were 0.88 and 1.59 microm2/s for the subcutaneous and orthotopically grown tumors, respectively, indicating that orthotopic tumors have significantly higher vascular extravasation rates as compared with subcutaneous tumors. This analysis supports the hypothesis that leakage rates of the photosensitizer vary considerably. Thus, although varying the time between injection and optical irradiation may be used to vary the targeting between vascular and less vascular areas, the precise time of treatment will depend on the nature of the permeability of the vasculature in the tissue being treated.

Protoporphyrin IX fluorescence photobleaching increases with the use of fractionated irradiation in the esophagus

“…The clinical dosimetry system in vivo was developed and demonstrated in previous studies. 11,15,[17][18][19] Briefly, the system uses blue light (405 nm wavelength) excitation and very small optical fibers (100 m core diameter) to limit the penetration and distance traveled by light that is detected. The light that is captured from the tissue must have originated within a few scattering distances (typically 100 to 300 m) of the fibers surface for significant probability of detection.…”

Microvascular blood flow dynamics associated with photodynamic therapy, pulsed dye laser irradiation and combined regimens

“…PDL irradiation is then used to heat selectively the pre-treated vessels compromised by PDT. We believe BPD is an excellent choice as a photosensitizer for PDT of cutaneous vascular lesions based on three key attributes: (1) Vascular predominance at early time points after administration [20][21][22]; (2) proven safety and efficacy in humans [8,23], and (3) photosensitivity of relatively short duration (1-5 days for BPD depending on the dose administered) [23].…”

Contrast enhanced-magnetic resonance imaging as a surrogate to map verteporfin delivery in photodynamic therapy

“…3,4 An orthotopic xenograft (AsPC-1) murine model (n ¼ 7) for PaC PDT was used in accordance with the policies and approved protocol of the Institutional Animal Care and Use Committee (IACUC) at Dartmouth College. 5 The animals were fed a chlorophyll-free diet (MP Biomedicals, Solon, OH) to minimize autofluorescence.…”