Imaging methods to evaluate tumor microenvironment factors affecting nanoparticle drug delivery and antitumor response.

Amber S Moody,William C Zamboni,Paul A Dayton

doi:10.20517/cdr.2020.94

Abstract

Standard small molecule and nanoparticulate chemotherapies are used for cancer treatment; however, their effectiveness remains highly variable. One reason for this variable response is hypothesized to be due to nonspecific drug distribution and heterogeneity of the tumor microenvironment, which affect tumor delivery of the agents. Nanoparticle drugs have many theoretical advantages, but due to variability in tumor microenvironment (TME) factors, the overall drug delivery to tumors and associated antitumor response are low. The nanotechnology field would greatly benefit from a thorough analysis of the TME factors that create these physiological barriers to tumor delivery and treatment in preclinical models and in patients. Thus, there is a need to develop methods that can be used to reveal the content of the TME, determine how these TME factors affect drug delivery, and modulate TME factors to increase the tumor delivery and efficacy of nanoparticles. In this review, we will discuss TME factors involved in drug delivery, and how biomedical imaging tools can be used to evaluate tumor barriers and predict drug delivery to tumors and antitumor response.

Highlights

The tumor microenvironment (TME) is characterized by many factors including increased concentrations of extracellular matrix proteins such as collagen, hyaluronan, and fibronectins, as well as low extracellular pH, tortuous neovasculature, and hypoxia[1]
Other nanoparticles used in imaging can be targeted with tumor specific antigens to allow for monitoring of cancer nanotherapy including tumor associated macrophage targeted fluorescent nanoparticles[34], antigen specific targeted nanoparticles radiolabeled with indium-111 and imaged with single photon emission computed tomography (SPECT)[35], positron emission tomography (PET) imaged 64Cu-labeled HER-2 targeted PEGylated liposomal doxorubicin for HER-2 positive metastatic breast cancer[36], and targeted ultrasound contrast agents for vascular endothelial growth factor receptor-2 or avb3 used to image tumor neovasculature and aid in assessment of tumor malignancy and treatment response[37]
Standard imaging modalities currently used in the clinic are CT, magnetic resonance imaging (MRI), PET, SPECT, and ultrasound where there are both advantages and disadvantages to these techniques when evaluating the tumor microenvironment

Summary

INTRODUCTION

The tumor microenvironment (TME) is characterized by many factors including increased concentrations of extracellular matrix proteins such as collagen, hyaluronan, and fibronectins, as well as low extracellular pH, tortuous neovasculature, and hypoxia[1]. Other nanoparticles used in imaging can be targeted with tumor specific antigens to allow for monitoring of cancer nanotherapy including tumor associated macrophage targeted fluorescent nanoparticles (ferumoxytol-VT680XL)[34], antigen specific targeted nanoparticles radiolabeled with indium-111 and imaged with single photon emission computed tomography (SPECT)[35], positron emission tomography (PET) imaged 64Cu-labeled HER-2 targeted PEGylated liposomal doxorubicin for HER-2 positive metastatic breast cancer[36], and targeted ultrasound contrast agents (or targeted microbubbles) for vascular endothelial growth factor receptor-2 or avb used to image tumor neovasculature and aid in assessment of tumor malignancy and treatment response[37] This allows the nanoparticle agents to be used for targeted delivery and interaction with the TME, resulting in increased accumulation, facilitated drug release, and an increase in uniform distribution[38]. The goal is to present a high-level overview of current imaging methods used to characterize the TME relative to nanoparticle drug delivery

Introduction

Findings

CONCLUSION AND FUTURE WORK