International Journal of Radiation Oncology*Biology*Physics
Biology contributionCombining vascular and cellular targeting regimens enhances the efficacy of photodynamic therapy
Introduction
Photodynamic therapy (PDT) is an established cancer treatment modality in which a photosensitizer absorbs light and generates cytotoxic reactive oxygen species leading to cellular damage (1). It has been applied to both treatment of superficial tumors (such as cutaneous basal cell carcinoma and head and neck tumors) and to deeper tumors accessible by endoscopies (including esophageal and lung cancers) (2). In the United States, PDT with Photofrin has been approved for the treatment of Barrett's esophagus and endobronchial and esophageal carcinomas (3), and perhaps the most successful approval of PDT is with verteporfin for injection (Visudyne) to treat age-related macular degeneration (AMD) (4).
The mechanisms of how PDT causes tissue damage involve a complex interplay among the tissue, the photosensitizer, and light. To be photoactive, adequate amounts of photosensitizer and light must be deposited simultaneously in the target tissue with sufficient oxygen supply. The effectiveness of treatment can therefore be affected by any factors influencing the photosensitizer distribution, photobleaching, light delivery, blood flow, and oxygen distribution in the target tissue. For a particular tissue and a photosensitizer, the spatial distribution and compartmentalization of the photosensitizer change temporally after drug administration. The time between photosensitizer injection and light treatment (drug-light interval) is therefore a critical parameter in determining the site target and efficacy, mainly through drug distribution in different tissue compartments (5).
In general, a photosensitizer is confined within the tumor vasculature initially after injection and PDT that employs a short drug-light interval largely damages tumor vasculature (6, 7, 8, 9, 10, 11). This mechanism is mainly responsible for some of the more successful clinical implementations of PDT today, including AMD treatment with verterpofin (4) and prostate cancer treatment with TOOKAD (12, 13). In this vascular-targeting regime, it is hypothesized that photosensitizing effects occur when the drug is still largely localized within the blood vessels, thereby maximizing the singlet oxygen dose to the blood cells and endothelial cells (14). Flow stasis can then occur from a combination of vasoconstriction, endothelial cell damage and thrombosis. After vascular shutdown, tumor cells are largely killed by tissue ischemia (15, 16). Whereas a long drug-light interval allows free diffusion of the photosensitizer out into the tissue, to be accumulated into the tumor cellular compartment and consequent light irradiation generates more direct tumor cytotoxicity (5, 17, 18). In fact, our earlier studies have shown that direct cellular targeting can be achieved while preserving blood flow (19, 20).
While many studies have explored ways to maximize the therapeutic effect of PDT (21), recent efforts are more focused on utilizing targeting strategies that are directed at the tumor vasculature. However, it should be realized that neither vascular targeting nor cellular targeting PDT regime alone is perfect for tumor cell killing. Solely vascular targeting may be a good approach for purely vascular diseases such as AMD (22), yet it may not be enough for tumors because peripheral tumor vessels are shown to be somewhat resistant to both vascular-targeting agents (23) and PDT-induced vascular effects (12, 24, 25). Despite the extensive central tumor necrosis induced by vascular targeting PDT, tumor vessels/cells can regrow from the peripheral rim after treatment. The major problem for cellular-targeting PDT is that it suffers from complex issues such as heterogeneity of tumor microenvironment and inhomogeneous photosensitizer distribution. Additionally, tissue hypoxia has been identified as a major obstacle to direct targeting tumor cells by PDT (1, 5). It is generally believed that, compared with the well-perfused outer tumor region, the less-perfused tumor inner region is more hypoxic and therefore more resistant to radiotherapy, chemotherapy, and cellular targeting PDT as well (26). Inadequate photosensitizer delivery due to heterogeneous tumor perfusion, vascular permeability, and tumor interstitial pressure can also affect the effectiveness of cellular targeting PDT (26). Combination of tumor vascular and cellular targeting approaches can be a way to overcome the problem associated with each individual targeting strategy and to achieve maximal opportunity of tumor eradication (27).
Since the potential target of PDT can be effectively modified by using different drug-light intervals, it is hypothesized that the combination of a short interval PDT (vascular targeting) and a long interval PDT (cellular targeting) will damage both tumor vascular and cellular compartments. Such a combination may compensate each other and lead to an enhanced therapeutic effect. Specifically, we demonstrate in this study that a long drug-light interval PDT followed immediately by a short interval PDT is the best way to achieve both vascular and cellular targeting on tumor tissue.
Section snippets
Photosensitizer
Verteporfin (BPD, lipid-formulated benzoporphyrin derivative monoacid ring A) was obtained from QLT Inc. (Vancouver, British Columbia, Canada). A stock saline solution of verteporfin was reconstituted according to the manufacturer's instructions and stored at 4°C in the dark. It was injected i.v. 0.25 mg/kg at 15 min before light irradiation or 1.0 mg/kg at 3 h before light irradiation.
Animals and tumor model
Male Copenhagen rats (6–8 weeks old) obtained from Charles River Laboratories, Wilmington, MA) were used
Results
The fluorescence of verteporfin in the s.c. MatLyLu tumor at 15 min and 3 h after injection (i.v., 1 mg/kg) is shown in Fig. 2A. The perfused blood vessels in the same microscopic field were visualized by a fluorescent dye DiOC7(3). Tumor distribution of verteporfin at 15 min after injection was almost identical to the perfusion marker DiOC7(3), indicating the dominant intravascular localization with slight diffusion beyond the vascular boundaries. A distinct difference in verteporfin
Discussion
Photosensitizer pharmacokinetic distribution after administration provides an opportunity to alternate the primary target from tumor vasculature initially to parenchyma at longer times after injection. To enhance the therapeutic effect of PDT, a combined approach of PDT that targets both tumor vascular and cellular compartments was hypothesized and tested here. Verteporfin, an approved photosensitizer for the treatment of AMD (33), was selected in this study because it has a fast plasma
Acknowledgments
The authors thank QLT Inc. (Vancouver, Canada) for providing the verteporfin.
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This work was supported by National Cancer Institute Grant PO1CA84203 and Department of Defense Grant W81XWH-04–1–0077.