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© 2015 The Authors. Published by the British Institute of Radiology

Applications of nanoparticles for diagnosis and therapy of cancer

Department of Experimental Molecular Imaging, Helmholtz Institute for Biomedical

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Sarah C. Baetke1, M.Sc., Twan Lammers1, PhD, DSc, Fabian Kiessling1,*, MD

Corresponding author: Fabian Kiessling, Department of Experimental Molecular Imaging,

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Engineering, RWTH Aachen University, Aachen, Germany

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Medical Faculty, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany,

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Tel: +49 (0)241 80-80116, Fax: +49 (0)241 80-82006, E-mail: [email protected]

Short title:

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Demands on diagnostic and therapeutic nanoparticles

Funding: This work was supported by the European Research Council (ERC Starting Grant

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309495: NeoNaNo).

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Review article

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Word count: 4715 words

Manuscript - clean

Applications of nanoparticles for diagnosis and therapy of cancer

Short title:

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Demands on diagnostic and therapeutic nanoparticles

Abstract

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During the last decades, a plethora of nanoparticles have been developed and evaluated and a

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real hype has been created around their potential application as diagnostic and therapeutic agents. Despite their suggestion as potential diagnostic agents, only a single diagnostic

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nanoparticle formulation, namely iron oxide nanoparticles, found its way into clinical routine

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so far. This fact is primarily due to difficulties in achieving appropriate pharmacokinetic properties and a reproducible synthesis of monodispersed nanoparticles. Furthermore,

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concerns exist about their biodegradation, elimination and toxicity.

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The majority of nanoparticle formulations that are currently routinely used in the clinic are

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employed for therapeutic purposes. These therapeutic nanoparticles aim to more efficiently deliver a (chemo-) therapeutic drug to the pathological site, while avoiding its accumulation in healthy organs and tissues, and are predominately based on the “enhanced permeability and

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retention” (EPR) effect.

Furthermore, based on their ability to integrate diagnostic as well as therapeutic entities within a single nanoparticle formulation, nanoparticles hold great promise for theranostic purposes, and are considered to be highly useful for personalizing nanomedicine-based

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treatments.

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In this review article, we present applications of diagnostic and therapeutic nanoparticles,

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summarize frequently used non-invasive imaging techniques, and describe the role of EPR in the accumulation of nanotheranostic formulations. In this context, the clinical potential of

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nanotheranostics and image-guided drug delivery for individualized and improved (chemo-) therapeutic interventions is addressed.

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Introduction Currently, in vivo molecular imaging comprises an important focus area of medical research. The rapidly evolving field of molecular imaging improves early disease detection, disease staging, and enables image-guided therapy and treatment personalization. Furthermore, it

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provides essential information on the therapy efficacy. However, molecular imaging requires the use of molecular imaging probes to visualize and characterize biological processes at the

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cellular and molecular level (1-5).

Recent advances in nanotechnology have led to the development of various nanoparticle

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formulations for diagnostic and therapeutic applications. Diagnostic nanoparticles aim to

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visualize pathologies and to improve the understanding of important (patho-) physiological principles of various diseases and disease treatments. Clinically, however, nanodiagnostics are

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only useful in a limited number of situations, due to the complex demands on their

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pharmacokinetic properties and elimination. Therefore, the majority of nanoparticle formulations currently used in the clinics is applied for therapeutic purposes. Therapeutic

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nanoparticles aim to improve the accumulation and release of pharmacologically active agents

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at the pathological site, increase therapeutic efficacy, and reduce the incidence and intensity of side effects by reducing their localization in healthy tissues (6-9). The intrinsic

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characteristics of nanoparticles hold great promise for integrating diagnostic and therapeutic agents into a single nanoparticle formulation, enabling their application for theranostic purposes, such as monitoring the biodistribution and target site accumulation, visualizing and quantifying drug release, and longitudinally assessing the therapeutic efficacy. Such

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theranostic nanoparticles may be used for personalizing nanomedicine-based therapies by enabling patient preselection and by controlling therapeutic efficacy (7-15).

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In this review article, indications of current nanoparticle formulations for diagnostic and

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therapeutic applications and a brief overview of non-invasive imaging modalities will be

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given. In addition, the suitability of nanoparticles as molecular imaging probes and contrast agents to enhance disease diagnosis and treatment, as well as their potential clinical application to facilitate personalized therapy interventions will be addressed and discussed.

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General considerations on medical imaging modalities and probes In this section, a brief overview of frequently used non-invasive imaging modalities with respect to the application of nanoparticles will be provided. Medical imaging comprises the non-invasive assessment of anatomical (or morphological), functional and molecular

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information, which enables the diagnosis of pathophysiological abnormalities. Current imaging modalities that are routinely used in preclinical research and clinical practice include

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magnetic resonance imaging (MRI), computed tomography (CT), ultrasound (US), optical

imaging (OI) and photoacoustic imaging (PAI), as well as positron emission tomography

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(PET) and single photon emission computed tomography (SPECT). These modalities are

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based on different underlying physical principles and, therefore, possess specific advantages and disadvantages with respect to sensitivity and specificity to contrast agents, tissue contrast,

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spatial resolution, quantitativeness, and tissue penetration (3,16-18). An overview of the

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clinically most relevant imaging modalities and their characteristics is provided in table 1.

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Table 1: Overview of routinely used imaging modalities in the clinic, their specific advantages and disadvantages, and examples of nanoparticulate contrast agents for the respective imaging method. Please note

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that the sensitivity and penetration depth values are based both on the literature and on our own experience, and strongly depend on the method and tissue properties. Table adapted from [16,17].

Nanoparticulate

Advantages

Disadvantages

contrast agents

contrast agents

- low sensitivity to

milli- to

- gadolinium-containing

contrast agents

micromolar

Magnetic

- high spatial

resonance

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method

Sensitivity to

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Imaging

- high costs

- unlimited

- time-intensive

resolution

(~10-500µm)

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imaging (MRI)

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probes [19] - (ultrasmall) superparamagnetic

penetration

iron oxide

depth

nanoparticles

- excellent soft tissue contrast - versatile options for structural,

((U)SPIO) [20] - paramagnetic liposomes and polymers [21,22]

functional and

- paraCEST agents [23]

metabolic tissue

- hyperpolarized

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characterization

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- insufficient soft

(~ 20-200µm)

tissue contrast

depth - good soft tissue contrast after injection of

and liposomes [25,26]

without injection

- barium-based

of contrast agents

nanoparticles [27]

- radiation

- gold-based

exposure

nanoparticles [28,29]

- low sensitivity to

- bismuth nanoparticles

contrast agents

[30]

contrast agent

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- low costs

- user dependence

and spatial

- not appropriate

detectable

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resolution

for whole body

(~50-100µm)

imaging

- targeted and nontargeted gas-filled microbubbles [31-33] - nanobubbles [34] - air-releasing polymers

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- rapidly operable

single MB

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- high temporal

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- fast Ultrasound (US)

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penetration

- iodine-based micelles

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- unlimited

millimolar

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tomography (CT)

- high resolution

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Computed

- real-time

[35]

imaging

- low penetration

for contrast

depth (

Applications of nanoparticles for diagnosis and therapy of cancer.

During the last decades, a plethora of nanoparticles have been developed and evaluated and a real hype has been created around their potential applica...
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