Kenneth R. Weishaupt

Parabolic Quantitative Structure‐Activity Relationships and Photodynamic Therapy: Application of a Three‐Compartment Model with Clearance to the In Vivo Quantitative Structure‐Activity Relationships of a Congeneric Series of Pyropheophorbide Derivatives Used as Photosensitizers for Photodynamic Therapy

An open three‐compartment pharmacokinetic model was applied to the in vivo quantitative structure‐activity relationship (QSAR) data of a homologous series of pyropheophorbide photosensitizers for photodynamic therapy (PDT). The physical model was a lipid compartment sandwiched between two identical aqueous compartments. The first compartment was assumed to clear irreversibly at a rate K0+. The measured octanol‐water partition coefficients, P1 (where i is the number of carbons in the alkyl chain) and the clearance rate K0 determined the clearance kinetics of the drugs. Solving the coupled differential equations of the three‐compartment model produced clearance kinetics for each of the sensitizers in each of the compartments. The third compartment was found to contain the target of PDT. This series of compounds is quite lipophilic. Therefore these drugs are found mainly in the second compartment. The drug level in the third compartment represents a small fraction of the tissue level and is thus not accessible to direct measurement by extraction. The second compartment of the model accurately predicted the clearance from the serum of mice of the hexyl ether of pyropheophorbide a, one member of this series of compounds. The diffusion and clearance rate constants were those found by fitting the pharmacokinetics of the third compartment to the QSAR data. This result validated the magnitude and mechanistic significance of the rate constants used to model the QSAR data. The PDT response to dose theory was applied to the kinetic behavior of the target compartment drug concentration. This produced a pharmacokinetic‐based function connecting PDT response to dose as a function of time postinjection. This mechanistic dose‐response function was fitted to published, single time point QSAR data for the pheophorbides. As a result, the PDT target threshold dose together with the predicted QSAR as a function of time postinjection was found.

The Role of the Peripheral Benzodiazepine Receptor in Photodynamic Activity of Certain Pyropheophorbide Ether Photosensitizers: Albumin Site II as a Surrogate Marker for Activity¶

A study has been carried out to define the importance of the peripheral benzodiazepine receptor (PBR) as a binding site for a series of chlorin‐type photosensitizers, pyropheophorbide‐a ethers, the subject of a previous quantitative structure–activity relationship study by us. The effects of the PBR ligand PK11195 on the photodynamic activity have been determined in vivo for certain members of this series of alkyl‐substituted ethers: two of the most active derivatives (hexyl and heptyl), the least active derivative (dodecyl [C12]) and one of intermediate activity (octyl [C8]). The photodynamic therapy (PDT) effect was inhibited by PK11195 for both of the most active derivatives, but no effect on PDT activity was found for the less active C12 or C8 ethers. The inhibitory effects of PK11195 were predicted by the binding of only the active derivatives to the benzodiazepine site on albumin, i.e. human serum albumin (HSA)‐Site II. Thus, as with certain other types of photosensitizers, it has been demonstrated with this series of pyropheophorbide ethers that in vitro binding to HSA‐Site II is a predictor of both optimal in vivo activity and binding to the PBR in vivo.

Design and construction of a light-delivery system for photodynamic therapy.

We have developed a device to divide the output from a dye laser into as many as eight beams of equal power with negligible total power loss. In this system, 630-nm s-plane polarized laser light was split by a series of highly polarization-sensitive plate beamsplitters. Each of the beams was coupled to a 200, 400, or 600 microm diameter optical fiber. Brewster-window-type attenuators allowed the power of each beam to be individually set. It was possible to reconfigure the device to produce four, two, or one output(s). We discuss the design requirements of the beamsplitter device and describe its construction from mostly commercially available components. An apparatus for positioning and stabilizing each optical fiber relative to the skin surface of a patient is also described. The illumination from the fiberoptic supported by such an apparatus strikes a defined surface area and is independent of patient movement. Both the beamsplitter device and the optical fiber positioner are used routinely in photodynamic therapy (PDT) of malignant tumors in the clinic and in the laboratory.