title: 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 showed 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 show 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.
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Maas
authors.forename: Shirron L
authors.initials: SL
authors.lastname: Carter
authors.forename: E Paul
authors.initials: EP
authors.lastname: Wileyto
authors.forename: Joann
authors.initials: J
authors.lastname: Miller
authors.forename: Min
authors.initials: M
authors.lastname: Yuan
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Yu
authors.forename: Amy C
authors.initials: AC
authors.lastname: Durham
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Busch
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D004338:Drug Combinations; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018613:Microscopy, Confocal; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010778:Photochemotherapy; D011509:Proteoglycans / Q000378:metabolism / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen