Fibrinolytic enzyme cotherapy improves tumor perfusion and therapeutic efficacy of anticancer nanomedicine

Ameya R. Kirtane, Tanmoy Sadhukha, Hyunjoon Kim, Vidhi Khanna, Brenda Koniar, Jayanth Panyam

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1465-1475
Number of pages11
JournalCancer Research
Volume77
Issue number6
DOIs
StatePublished - Mar 15 2017

Bibliographical note

Funding Information:
This work was funded by the Center for Pharmaceutical Development, University of Minnesota (J. Panyam), and the DoctoralDissertation Fellowship, University of Minnesota (A.R. Kirtane). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Publisher Copyright:
© 2017 American Association for Cancer Research.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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