Targeting the invincible barrier for drug delivery in solid cancers: interstitial fluid pressure

Steven K Libutti,Lawrence Tamarkin,Naris Nilubol

doi:10.18632/oncotarget.26267

Steven K Libutti, Lawrence Tamarkin + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.26267

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Journal: Oncotarget	Publication Date: Nov 6, 2018
Citations: 31	License type: CC BY 3.0

Affiliation: National Institutes of Health

Abstract

Although a number of new systemic therapeutic options in patients with advanced solid cancers have emerged due to the improved knowledge of molecular dysregulation in cancers, the durable, long-term, objective responses infrequently occur. This editorial article highlights the major limitation of current systemic therapy due to an inefficient drug delivery. While several mechanisms contributing to cancer drug resistance have been described, the common key barrier among solid cancers is the unique tumor microenvironment that causes the high interstitial fluid pressure (IFP). We discussed the mechanism causing an elevated IFP and how it interferes with drug delivery. To target the high IFP, we demonstrated the novel approach using gold nanoparticle carrying recombinant human tumor necrosis factor (TNF), a vascular disrupting agent, that preferentially and specifically targets tumors while the systemic toxicity is markedly reduced. The addition of cytotoxic agent by either directly conjugating to the gold nanoparticle or by systemic administration following gold nanoparticle carrying TNF resulted in significantly reduced tumor burden and increased survival in multiple mouse models with primary and metastatic endocrine cancer and pancreatic ductal carcinoma. A clinical trial in patients with advanced solid cancers is warranted based on the promising results in preclinical studies.

Highlights

In the era of “precision medicine” for cancer, efforts have been made to identify agents that preferentially target expressed molecular pathways specific to the cancer cells
To target the high interstitial fluid pressure (IFP), we demonstrated the novel approach using gold nanoparticle carrying recombinant human tumor necrosis factor (TNF), a vascular disrupting agent, that preferentially and targets tumors while the systemic toxicity is markedly reduced
The high interstitial fluid pressure (IFP) in the tumor microenvironment is the key barrier commonly seen in solid cancers that has not been widely considered and that can impede therapeutic drug delivery to tumors

Summary

Introduction

In the era of “precision medicine” for cancer, efforts have been made to identify agents that preferentially target expressed molecular pathways specific to the cancer cells. To target the high IFP, we demonstrated the novel approach using gold nanoparticle carrying recombinant human tumor necrosis factor (TNF), a vascular disrupting agent, that preferentially and targets tumors while the systemic toxicity is markedly reduced.

Results

Conclusion