Fibrinolytic Enzyme Cotherapy Improves Tumor Perfusion and Therapeutic Efficacy of Anticancer Nanomedicine
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Abstract
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.
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Pretreatment with tPA did not affect biodistribution but improved penetration of Doxil into B16F10 tumors.
“In another study, researchers reported that pretreatment with tPA has not affected biodistribution. However, improved the penetration of Doxil® into B16F10 tumors [38].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [38]
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References 58 · Cited by 38
- Authors
- Kirtane, A. R., Sadhukha, T., Kim, H., Khanna, V., Koniar, B., & Panyam, J.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Panyam, Jayanth
- Venue
- Cancer Research
- Published
- 2017-03-14
- Volume
- 77
- Issue
- 6
- Pages
- 1465-1475
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5523511
- OpenAlex
- W2578223899
- Cited by
- 38
- References
- 58
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 2
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000114)
- National Center for Advancing Translational Sciences
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Keywords
- tissue plasminogen activator, fibrin, tumor extracellular matrix, intratumoral drug distribution, nanocarriers, tumor perfusion, interstitial fluid pressure, solid stress, pegylated liposomal doxorubicin, melanoma, lung cancer, nanoparticle diffusion
- MeSH terms
- Albumins, Animals, Female, Fibrin, Fibrinolysis, Fibrinolytic Agents, Humans, Lung Neoplasms, Melanoma, Experimental, Mice, Inbred C57BL, Tissue Plasminogen Activator, Tumor Cells, Cultured, Paclitaxel, Xenograft Model Antitumor Assays, Nanomedicine, Mice
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