Effect of pazopanib on tumor microenvironment and liposome delivery.
Pathologic angiogenesis creates an abnormal microenvironment in solid tumors, characterized by elevated interstitial fluid pressure (IFP) and hypoxia. Emerging theories suggest that judicious downregulation of proangiogenic signaling pathways may transiently "normalize" the vascular bed, making it more suitable for drug delivery and radiotherapy. In this work, we investigate the role of pazopanib, a small-molecule inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, on tumor IFP, angiogenesis, hypoxia, and liposomal drug delivery. Nude mice bearing A549 human non-small cell lung cancer xenografts were treated with 100 mg/kg pazopanib (n = 20) or vehicle (n = 20) through oral gavage for 8 days, followed by a one-time intravenous dose of 10 mg/kg Doxil (liposomal doxorubicin). Pazopanib treatment resulted in significant reduction of tumor IFP and decreased vessel density, assessed by CD31 staining. Despite these trends toward normalization, high-performance liquid chromatography revealed no differences in doxorubicin concentration between pazopanib-treated and control tumors, with Doxil penetration from microvessels being significantly reduced in the pazopanib group. Additionally, tumor hypoxia, evaluated by CA-IX immunostaining and confirmed in a second study by EF5 expression (n = 4, 100 mg/kg pazopanib; n = 4, vehicle), was increased in pazopanib-treated tumors. Our results suggest that the classic definition of tumor "normalization" may undermine the crucial role of vessel permeability and oncotic pressure gradients in liposomal drug delivery, and that functional measures of normalization, such as reduced IFP and hypoxia, may not occur in parallel temporal windows.
Duke University School of Medicine, Durham, North Carolina, USA.
Tina D
TD
Tailor
Gabi
G
Hanna
Pavel S
PS
Yarmolenko
Matthew R
MR
Dreher
Allison S
AS
Betof
Andrew B
AB
Nixon
Ivan
I
Spasojevic
Mark W
MW
Dewhirst
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D016503:Drug Delivery Systems; D045604:Extracellular Fluid / Q000187:drug effects; D006801:Humans; D007191:Indazoles; D008081:Liposomes / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D011312:Pressure; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D014018:Tissue Distribution / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007191:Indazoles; D008081:Liposomes; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D004317:Doxorubicin; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2