Theranostic Probes for Targeting Tumor Microenvironment: An Overview

Abstract

Long gone is the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues, and immune cells in their environment, which is now known as the tumor microenvironment (TME). It has been found that the interactions between tumors and their surrounds promote tumor growth, invasion, and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design, and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME such as tumor vasculature, ECM, stromal cells, and the lymphatic system. This review explores how these significant factors in the TME, supply tumors with the required growth factors and signaling molecules to proliferate, invade, and metastasize. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis, and anticancer drug delivery systems. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (Positron Emission Tomography (PET) and Single Photon Emission Computer Tomography (SPECT)).

Keywords: imaging; nanoparticle; nanotheronostics; probe; tumor microenvironment.

Figure 1

Illustration of theranostic probes incorporated for targeting the tumor microenvironment.

Figure 2

Results of a dynamic Positron Emission Tomography (PET) scan as a function of time after injection with ¹⁸F-fluoromisonidazole. A single reconstructed PET slice is displayed through the center of the head and neck tumor. First 5 frames were of 1-min duration, followed by 5 frames of 5-min duration. At 30 min after injection, the patient was removed from the scanner and then reimaged at 90 and 180 min after injection. Images were co-registered using a low-dose CT scan (depicted in the final image in the series). This series shows evolution of ¹⁸F-fluoromisonidazole distribution within the patient from initial blood pool to selective sequestration within the hypoxic tumor subvolume. This research was originally published in JNM. Carlin, Sean, and John L. Humm. PET of hypoxia: current and future perspectives. J. Nucl. Med. 2012, 53, (8), 1171–1174. © by the Society of Nuclear Medicine and Molecular Imaging, Inc. [26].

Figure 3

PET images of FaDu xenograft-bearing nude mouse injected with ¹²⁴I-L19-SIP (3.7 MBq, 25 μg). Coronal images were acquired at 24 (a) and 48 h (b) after injection. Image planes were chosen where both tumors were visible. Uptake of ¹²⁴I in the stomach (arrow) and to some extent in bladder (urine) is visible at 24 h p.i., but has disappeared at 48 h p.i. This research was originally published in European Journal of Nuclear Medicine and Molecular Imaging. Bernard M. Tijink. ¹²⁴I-L19-SIP for immune PET imaging of tumour vasculature and guidance of ¹³¹I-L19-SIP radioimmunotherapy © 2016 Springer International Publishing AG [62].

Figure 4

The targeted delivery of LyP-1-PM to highly metastatic breast tumor in vivo. (A) In vivo near-infrared fluorescent images of mice after intravenous administration of DiD-loaded LyP-1-PM or PM at different time points and (B) ex vivo image of tumors and organsafter the tumor-bearing mice above were sacrificed at 96 h. Reprinted with permission from [80]. Copyright 2009 American Chemical Society.