Permanent occlusion of feeding arteries and draining veins in solid mouse tumors by vascular targeted photodynamic therapy (VTP) with Tookad.
BACKGROUND
Antiangiogenic and anti-vascular therapies present intriguing alternatives to cancer therapy. However, despite promising preclinical results and significant delays in tumor progression, none have demonstrated long-term curative features to date. Here, we show that a single treatment session of Tookad-based vascular targeted photodynamic therapy (VTP) promotes permanent arrest of tumor blood supply by rapid occlusion of the tumor feeding arteries (FA) and draining veins (DV), leading to tumor necrosis and eradication within 24-48 h.


RESULTS
A mouse earlobe MADB106 tumor model was subjected to Tookad-VTP and monitored by three complementary, non-invasive online imaging techniques: Fluorescent intravital microscopy, Dynamic Light Scattering Imaging and photosensitized MRI. Tookad-VTP led to prompt tumor FA vasodilatation (a mean volume increase of 70%) with a transient increase (60%) in blood-flow rate. Rapid vasoconstriction, simultaneous blood clotting, vessel permeabilization and a sharp decline in the flow rates then followed, culminating in FA occlusion at 63.2 sec+/-1.5SEM. This blockage was deemed irreversible after 10 minutes of VTP treatment. A decrease in DV blood flow was demonstrated, with a slight lag from FA response, accompanied by frequent changes in flow direction before reaching a complete standstill. In contrast, neighboring, healthy tissue vessels of similar sizes remained intact and functional after Tookad-VTP.


CONCLUSIONS
Tookad-VTP selectively targets the tumor feeding and draining vessels. To the best of our knowledge, this is the first mono-therapeutic modality that primarily aims at the larger tumor vessels and leads to high cure rates, both in the preclinical and clinical arenas.
Madar-Balakirski
Noa
N
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Tempel-Brami
Catherine
C
Kalchenko
Vyacheslav
V
Brenner
Ori
O
Varon
David
D
Scherz
Avigdor
A
Salomon
Yoram
Y
D000818:Animals; D001158:Arteries / Q000473:pathology; D001429:Bacteriochlorophylls / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects / Q000528:radiation effects; D001783:Blood Flow Velocity / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D004423:Ear; D051379:Mice; D009336:Necrosis; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy; D010539:Permeability / Q000187:drug effects / Q000528:radiation effects; D010778:Photochemotherapy / Q000379:methods*; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects / Q000528:radiation effects; D014680:Veins / Q000473:pathology
D001429:Bacteriochlorophylls; C456120:palladium-bacteriopheophorbide