Activatable fluorescence: From small molecule to nanoparticle

doi:10.1016/j.addr.2016.08.010

Advanced Drug Delivery Reviews

Volume 113, April 2017, Pages 97-121

https://doi.org/10.1016/j.addr.2016.08.010 Get rights and content

Abstract

Molecular imaging has emerged as an indispensable technology in the development and application of drug delivery systems. Targeted imaging agents report the presence of biomolecules, including therapeutic targets and disease biomarkers, while the biological behaviour of labelled delivery systems can be non-invasively assessed in real time. As an imaging modality, fluorescence offers additional signal specificity and dynamic information due to the inherent responsivity of fluorescence agents to interactions with other optical species and with their environment. Harnessing this responsivity is the basis of activatable fluorescence imaging, where interactions between an engineered fluorescence agent and its biological target induce a fluorogenic response. Small molecule activatable agents are frequently derivatives of common fluorophores designed to chemically react with their target. Macromolecular scale agents are useful for imaging proteins and nucleic acids, although their biological delivery can be difficult. Nanoscale activatable agents combine the responsivity of fluorophores with the unique optical and physical properties of nanomaterials. The molecular imaging application and overall complexity of biological target dictate the most advantageous fluorescence agent size scale and activation strategy.

Graphical abstract

Section snippets

Introduction to fluorescence molecular imaging

Molecular biology has revolutionized our understanding of living systems and the players and mechanisms involved in health and disease. Analytical techniques for gene and protein profiling provide comprehensive snapshots of biological processes that can reveal molecular abnormalities and identify therapeutic targets and biomarkers. Complementing these static approaches is molecular imaging where biological processes are non-invasively visualized and quantitated at the cellular and subcellular

Activatable fluorescence molecular imaging

Always-on fluorescence agents rely on selective localisation of the agent at the biological target and rapid clearance from systemic circulation and off-target tissues in order to provide a high target-to-background signal (TBR) [50], [52], [53], [54]. From a drug delivery perspective, this pharmacokinetic requirement directly conflicts the therapeutic need for long plasma circulation times to enhance drug accumulation in target tissues. Additionally, always-on theranostic systems can report on

Activatable fluorescence agents based on small molecule fluorophores

Numerous activatable fluorescence agents for molecular imaging have been developed by controlling the fluorescence emission of conventional small molecule fluorophores [76], [77], [78]. The simplest approach is to design an initially non-fluorescent dye that chemically or physically interacts with its target to generate a fluorescent structure and therefore an intensometric fluorogenic response. This interaction may involve one of the photophysical mechanisms described in the previous section

Activatable fluorescence agents based on macromolecular structures

Activatable fluorescence imaging of large biological targets such as proteins and nucleic acids necessitates many unique interactions between the fluorescence agent and the biomolecule over a large area. In this situation, target interactions are unlikely to modify the chemical structure of small molecule fluorophores to generate a fluorogenic response. To image these large biomolecules, multiple optically-active species are integrated in a macromolecular construct such that interaction with

Activatable fluorescence agents based on nanomaterials

Nanoscale materials can also be chosen as building blocks in the design of activatable fluorescence agents, both as optically-inactive carriers of molecular fluorophores and as the fluorescence agent itself, adding myriad valuable options to the molecular imaging toolkit. While nanoparticle-based fluorescence agents are designed to detect many of the same biological targets as their small molecule and macromolecule-scale counterparts, their nanoscale size and resultant material properties are

Perspective

Small molecule activatable fluorescence agents are excellent for imaging biological targets that consist of a small number of atoms. Simple targets can be detected by their chemical properties, either through binding or reactivity. This review highlights recent strategies that have come to light for imaging these small targets, with an emphasis on modular components for target interaction or fluorescence generation. Modular designs are emphasized for their potential to be translated between

Acknowledgments

This work is supported by the Terry Fox Research Institute (TFRI-#1022), the Princess Margaret Cancer Foundation, the Canadian Institutes of Health Research (RMF111823; MOP119597; MOP133678), the Ontario Institute for Cancer Research (ZHENG G—OICR—SIP), the Natural Sciences and Engineering Research Council of Canada (NSERC-386613-10/UT#489078), the Canada Foundation for Innovation (21765), the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research, and the Knudson Postdoctoral

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^☆: This review is part of the Advanced Drug Delivery Reviews theme issue on “Molecular Imaging”.

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Activatable fluorescence: From small molecule to nanoparticle☆

Abstract

Graphical abstract

Section snippets

Introduction to fluorescence molecular imaging

Activatable fluorescence molecular imaging

Activatable fluorescence agents based on small molecule fluorophores

Activatable fluorescence agents based on macromolecular structures

Activatable fluorescence agents based on nanomaterials

Perspective

Acknowledgments

Drug Discov. Today

J. Control. Release

Drug Discov. Today

Mol. Oncol.

Semin. Nucl. Med.

Nano Today

Adv. Cancer Res.

Biomaterials

Adv. Drug Deliv. Rev.

FEBS Lett.

Biochimie

Adv. Drug Deliv. Rev.

J. Photochem. Photobiol. B Biol.

J. Control. Release

Cell

Gastrointest. Endosc. Clin. N. Am.

Eur. Urol.

Adv. Drug Deliv. Rev.

Curr. Opin. Chem. Biol.

World Neurosurg.

J. Mol. Struct.

Curr. Opin. Biotechnol.

Bioconjug. Chem.

Curr. Opin. Chem. Biol.

Bioconjug. Chem.

Talanta

Coord. Chem. Rev.

A molecular imaging primer: modalities, imaging agents, and applications

Physiol. Rev.

Molecular imaging agents: impact on diagnosis and therapeutics in oncology

Expert Rev. Mol. Med.

The challenges of integrating molecular imaging into the optimization of cancer therapy

Integr. Biol.

Companion diagnostics and molecular imaging-enhanced approaches for oncology clinical trials

J. Drug Des. Dev. Ther.

Molecular imaging of HER2-positive breast cancer: a step toward an individualized ‘image and treat’ strategy

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The use of molecular imaging combined with genomic techniques to understand the heterogeneity in cancer metastasis

Br. J. Radiol.

Nanotheranostics and image-guided drug delivery: current concepts and future directions

Mol. Pharm.

Multifunctional nanoparticles for multimodal imaging and theragnosis

Chem. Soc. Rev.

Nanomaterials for theranostics: recent advances and future challenges

Chem. Rev.

Theranostic lipid nanoparticles for cancer medicine

Image guided biodistribution and pharmacokinetic studies of theranostics

Theranostics

Theranostics: from molecular imaging using Ga-68 labeled tracers and PET/CT to personalized radionuclide therapy — the Bad Berka experience

Theranostics

Activatable photosensitizers for imaging and therapy

Chem. Rev.

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Advances in cellular, subcellular, and nanoscale imaging in vitro and in vivo

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