Advances in Molecular Imaging

Targeted Optical Contrast Agents for Cancer Diagnostics

Anne Hellebust; Rebecca Richards-Kortum

Nanomedicine. 2012;7(3):429-445.

Abstract and Introduction

Abstract

Over the last three decades, our understanding of the molecular changes associated with cancer development and progression has advanced greatly. This has led to new cancer therapeutics targeted against specific molecular pathways; such therapies show great promise to reduce mortality, in part by enabling physicians to tailor therapy for patients based on a molecular profile of their tumor. Unfortunately, the tools for definitive cancer diagnosis – light microscopic examination of biopsied tissue stained with nonspecific dyes – remain focused on the analysis of tissue ex vivo. There is an important need for new clinical tools to support the molecular diagnosis of cancer. Optical molecular imaging is emerging as a technique to help meet this need. Targeted, optically active contrast agents can specifically label extra- and intracellular biomarkers of cancer. Optical images can be acquired in real time with high spatial resolution to image-specific molecular targets, while still providing morphologic context. This article reviews recent advances in optical molecular imaging, highlighting the advances in technology required to improve early cancer detection, guide selection of targeted therapy and rapidly evaluate therapeutic efficacy.

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Abstract and Introduction
Background
Endogenous Optical Contrast
Fluorescent Contrast Agents for Molecular Imaging
Nanoparticle-based Contrast Agents for Molecular Imaging
Multimodal Contrast Agents
Delivery of Molecular Imaging Agents
Conclusion
Future Perspective
References
Sidebar

Sidebar

Executive Summary

Molecular Optical Imaging

Molecular optical imaging combines advances in optical imaging with targeted, optically active contrast agents to enable noninvasive, real-time monitoring of the molecular changes associated with cancer development and progression.
Low-cost optical imaging systems are available to acquire optical molecular imaging with a wide range of fields of view and spatial resolution, spanning the whole organ to the subcellular levels.
Targeted, optically active contrast agents enable optical imaging of many biomarkers of cancer, associated with the initiation, development and progression of neoplastic lesions.

Molecular Markers & Targeting

Advances in biomarker discovery and validation have been used to identify targeting moieties to label cancer-specific targets.
Antibodies, antibody fragments, peptides, aptamers and small molecules are being explored as potential targeting moieties for optically active contrast agents.

Fluorescent Dyes

Fluorescent dyes possess many attractive properties as optical labels for use in optical molecular imaging systems: they have a low molecular weight, high quantum yield, are relatively low cost and there are many conjugation protocols available to attach targeting moieties. However, the depth of tissue imaging that can be achieved using fluorescence-based contrast agents is one limitation.
Fluorescently labeled glucose derivatives allow for high-resolution, real-time visualization of changes in cell metabolism.
Smart fluorescent probes only produce signal in the presence of a target, thereby lowering nonspecific background and improving specificity.

Nanoparticles

Metal nanoparticles can provide optical contrast via either absorption, scattering or luminescence.
The surface plasmon resonance peak of gold nanoparticles is strongly influenced by particle size, shape, material composition and interparticle spacing. It can be tuned to the near-infrared spectral region.
Nanoshells, comprised of a metal shell and dielectric core, can be tuned over a broad range by varying the core-to-shell ratio and overall particle size for imaging and photothermal ablation purposes.
Rare earth nanocrystals provide a biocompatible alternative to traditional cadmium-based quantum dots.

Multimodal Agents

Multimodal agents have been developed to enable simultaneous imaging with traditional medical imaging modalities and optical modalities. Integration of multiple modalities can result in the ability to image deep tissue with a traditional imaging modality to identify suspicious areas; these areas can then be examined with higher spatial resolution to more precisely determine tumor location with a companion optical modality.

Delivery

Two primary routes of administration exist for delivery of optical molecular imaging agents: topical application and intravenous injection.
Both routes of administration are affected by major delivery barriers, which are obstacles to the translation of these technologies.
Delivery of imaging agents to cytoplasmic and nuclear targets adds an additional level of complexity, but various peptides have improved intracellular delivery.

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