title: Fibrinolytic Enzyme Cotherapy Improves Tumor Perfusion and Therapeutic Efficacy of Anticancer Nanomedicine.
abstract: Elevated interstitial fluid pressure and solid stress within tumors contribute to poor intratumoral distribution of nanomedicine. In this study, we hypothesized that the presence of fibrin in tumor extracellular matrix contributes to hindered intratumoral distribution of nanocarriers and that this can be overcome through the use of a fibrinolytic enzyme such as tissue plasminogen activator (tPA). Analysis of fibrin expression in human tumor biopsies showed significant fibrin staining in nearly all tumor types evaluated. However, staining was heterogeneous across and within tumor types. We determined the effect of fibrin on the diffusion, intratumoral distribution, and therapeutic efficacy of nanocarriers. Diffusivity of nanocarriers in fibrin matrices was limited and could be improved significantly by coincubation with tPA.In vivo, coadministration of tPA improved the anticancer efficacy of nanoparticle-encapsulated paclitaxel in subcutaneous syngeneic mouse melanoma and orthotopic xenograft lung cancer models. Furthermore, treatment with tPA led to decompression of blood vessels and improved tumor perfusion. Cotreatment with tPA resulted in greater intratumoral penetration of a model nanocarrier (Doxil), leading to enhanced availability of the drug in the tumor core. Fibrinolytics such as tPA are already approved for other indications. Fibrinolytic cotherapy is therefore a rapidly translatable strategy for improving therapeutic effectiveness of anticancer nanomedicine.Cancer Res; 77(6); 1465-75. ©2017 AACR.
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Ameya R
authors.initials: AR
authors.lastname: Kirtane
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Sadhukha
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Hyunjoon
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Vidhi
authors.initials: V
authors.lastname: Khanna
authors.affiliation: Research Animal Resources, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Brenda
authors.initials: B
authors.lastname: Koniar
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota. jpanyam@umn.edu.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jayanth
authors.initials: J
authors.lastname: Panyam
mesh_terms: D000418:Albumins / Q000008:administration & dosage*; D000818:Animals; D005260:Female; D005337:Fibrin / Q000378:metabolism*; D005342:Fibrinolysis; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D050997:Nanomedicine; D017239:Paclitaxel / Q000008:administration & dosage*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D005343:Fibrinolytic Agents; D005337:Fibrin; D010959:Tissue Plasminogen Activator; D017239:Paclitaxel