Tumor Vascular Microenvironment Determines Responsiveness to Photodynamic Therapy

Abstract

The efficacy of photodynamic therapy (PDT) depends upon the delivery of both photosensitizing drug and oxygen. In this study, we hypothesized that local vascular microenvironment is a determinant of tumor response to PDT. Tumor vascularization and its basement membrane (collagen) were studied as a function of supplementation with basement membrane matrix (Matrigel) at the time of tumor cell inoculation. Effects on vascular composition with consequences to tumor hypoxia, photosensitizer uptake and PDT response were measured. Matrigel-supplemented tumors developed more normalized vasculature, composed of smaller and more uniformly-spaced blood vessels than their unsupplemented counterparts, but these changes did not affect tumor oxygenation or PDT-mediated direct cytotoxicity. However, PDT-induced vascular damage increased in Matrigel-supplemented tumors, following an affinity of the photosensitizer Photofrin for collagen-containing vascular basement membrane coupled with increased collagen content in these tumors. The more highly-collagenated tumors demonstrated more vascular congestion and ischemia after PDT, along with a higher probability of curative outcome that was collagen dependent. In the presence of photosensitizer-collagen localization, PDT effects on collagen were evidenced by a decrease in its association with vessels. Together, our findings demonstrate that photosensitizer localization to collagen increases vascular damage and improves treatment efficacy in tumors with greater collagen content. The vascular basement membrane is thus identified to be a determinant of therapeutic outcome in PDT of tumors.

Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death

“…Major research efforts in PDT over the past decade have focused upon understanding biological responses of target tumors and host tissues (e.g., vascular responses) to PDT, and how to modulate these responses (15, 16). Our laboratory focused on the problem of photosensitizer heterogeneity.…”

Photodynamic Therapy-Induced Microvascular Changes in a Nonmelanoma Skin Cancer Model Assessed by Photoacoustic Microscopy and Diffuse Correlation Spectroscopy

“…Tumor destruction can be obtained by vascular shutdown, direct cell kill, activation of host immune response, or a combination of these mechanisms [9,10]. Most PSs localize in the endothelium and can induce substantial vascular changes during PDT, making microvasculature changes a good target for monitoring the efficacy of PDT [6,[11][12][13][14][15][16]. We have shown recently that blood flow changes assessed with diffuse correlation spectroscopy (DCS), a diffuse optical spectroscopy method to quantify tissue blood flow, can be indicative of PDT efficacy [17].…”

Erlotinib Pretreatment Improves Photodynamic Therapy of Non–Small Cell Lung Carcinoma Xenografts via Multiple Mechanisms

“…Vascular damage contributes to PDT response with many treatment regimens (37, 38). In BPD-PDT, acute vascular shutdown occurs when treatment is performed at short drug-light intervals (e.g., 15 min (38, 39)).…”