Inorganic nanoparticle-based contrast agents for molecular imaging

doi:10.1016/j.molmed.2010.09.004

Trends in Molecular Medicine

Volume 16, Issue 12, December 2010, Pages 561-573

https://doi.org/10.1016/j.molmed.2010.09.004 Get rights and content

Inorganic nanoparticles (NPs) including semiconductor quantum dots (QDs), iron oxide NPs and gold NPs have been developed as contrast agents for diagnostics by molecular imaging. Compared with traditional contrast agents, NPs offer several advantages: their optical and magnetic properties can be tailored by engineering the composition, structure, size and shape; their surfaces can be modified with ligands to target specific biomarkers of disease; the contrast enhancement provided can be equivalent to millions of molecular counterparts; and they can be integrated with a combination of different functions for multimodal imaging. Here, we review recent advances in the development of contrast agents based on inorganic NPs for molecular imaging, and also touch on contrast enhancement, surface modification, tissue targeting, clearance and toxicity. As research efforts intensify, contrast agents based on inorganic NPs that are highly sensitive, target-specific and safe to use are expected to enter clinical applications in the near future.

Section snippets

NPs as molecular imaging agents

Molecular imaging is a new frontier of biomedical research for visualizing, characterizing and monitoring biological processes in cells, tissues and organisms using sensitive instrumentation and contrast mechanisms [1]. Molecular imaging interrogates biological processes to report on and reveal the molecular abnormalities that form the basis of diseases. As a result, molecular imaging provides a powerful tool for the diagnosis of diseases including cancer, cardiovascular syndrome and

Molecular imaging modalities

Inorganic NPs are an actively explored technology for the development of contrast agents for molecular imaging. Figure 1 and Table 1 list the types of inorganic NPs being developed as imaging agents, and Figure 1 also shows some typical examples of inorganic NP-based molecular imaging 6, 9, 13, 14, 15, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33. Before discussing the performance of these contrast agents, it will be helpful to provide a brief introduction to the imaging modalities whose

Major inorganic NPs for molecular imaging

Among the inorganic NPs displayed in Figure 1a, iron oxide NPs have been used clinically as contrast agents for MR imaging, whereas the other two have been mainly evaluated in the preclinical setting. In addition, recent advances in synthesis have produced many novel NPs with potential applications in molecular imaging, and Table 1 shows a partial list of these inorganic NPs. These and additional examples can also be found in the Molecular Imaging and Contrast Agent Database (//www.ncbi.nlm.nih.gov/

Surface modification of inorganic NPs

The surfaces of inorganic NPs often need to be modified to: i) allow transfer from a nonhydrolytic solvent into an aqueous medium; ii) increase the circulation time in the blood stream by adding a poly(ethylene glycol) (PEG) coating, or PEGylation; iii) enhance the targeting efficiency via the conjugation of binding ligands; and iv) increase functionality via the addition of other components including drugs. Three important issues must be taken into consideration when modifying the surfaces of

Delivery and targeting of inorganic NPs

NPs provide a range of advantages over molecular contrast agents traditionally used for molecular imaging. For example, the differences in vasculatures between normal and cancerous tissues enhance the accumulation of NPs in solid tumors (Figure 3a). Endothelial cells in normal tissues are well aligned and closely packed, whereas those in solid tumors are relatively leaky 81, 82, 83. Because of their large sizes, inorganic NPs circulating in the bloodstream cannot easily enter normal tissues yet

Biodistribution, clearance and the toxicity of inorganic NPs

In reality, it is impossible to have all injected NPs accumulated at the site of disease. As such, the biodistribution of inorganic NPs has to be considered and optimized from the beginning. Typically, inorganic NPs administered intravenously are mostly taken up by the liver and spleen, with the amount of accumulated particles depending on the particle size, shape and surface chemistry. There are several reports on the biodistribution of QDs, iron oxide NPs and gold colloids 57, 104, 105, 106,

Multimodal imaging with inorganic NPs

To diagnose malignancy accurately and at an early stage, it is often necessary to use a combination of different imaging modalities simultaneously. As such, there has been a strong interest in developing new imaging techniques based on optical and spectroscopic mechanisms. Notable examples include OCT, PAT, SERS and multiphoton microscopy. To keep pace with these emerging techniques, inorganic NPs need to be engineered with a variety of properties, and in some cases, they also need to enhance

Concluding remarks

Many types of inorganic NPs have been proposed and evaluated as potential contrast agents for molecular imaging, but most are still being tested in vitro or in vivo with small animals. Although a few (e.g. iron oxide NPs for MR imaging) have been approved for clinical use, most are still in development and will need to solve the potential toxicity issue. It is expected that some of the inorganic NPs (e.g. gold colloids) will overcome these hurdles and eventually move into the clinical phase. In

Acknowledgements

Our research in this field has been supported in part by an National Institutes of Health (NIH) Director's Pioneer Award (DP1 OD000798), an NIH research grant (1R01 CA138527) from the NCI and startup funds from Washington University in St. Louis.

References (126)

X. Gao
In vivo molecular and cellular imaging with quantum dots
Curr. Opin. Biotechnol.
(2005)
G.M. Lanza
Magnetic resonance molecular imaging with nanoparticles
Journal of Nuclear Cardiology
(2004)
A.K. Iyer
Exploiting the enhanced permeability and retention effect for tumor targeting
Drug Discov. Today
(2006)
P. Ghosh
Gold nanoparticles in delivery applications
Adv. Drug Deliv. Rev.
(2008)
R.A. Heesakkers
MRI with a lymph-node-specific contrast agent as an alternative to CT scan and lymph-node dissection in patients with prostate cancer: a prospective multicohort study
Lancet Oncol.
(2008)
J. Zhou
Dual-modality in vivo imaging using rare-earth nanocrystals with near-infrared to near-infrared (NIR-to-NIR) upconversion luminescence and magnetic resonance properties
Biomaterials
(2010)
W.C.W. Chan
Luminescent quantum dots for multiplexed biological detection and imaging
Curr. Opin. Biotechnol.
(2002)
C. Sun
Magnetic nanoparticles in MR imaging and drug delivery
Adv. Drug Deliv. Rev.
(2008)
R. Weissleder
Long-circulating iron oxides for MR imaging
Adv. Drug Deliv. Rev.
(1995)
X. Montet
Nanoparticle Imaging of Integrins on Tumor Cells
Neoplasia
(2006)

C.W. Jung et al.

Physical and chemical properties of superparamagnetic iron oxide MR contrast agents: ferumoxides, ferumoxtran, ferumoxsil

Magn. Reson. Imaging

(1995)

C.A. Haynes et al.

Globular proteins at solid/liquid interfaces

Colloid Sur. B

(1994)

J.J. Gray

The interaction of proteins with solid surfaces

Curr. Opin. Struct. Biol.

(2004)

C. Corot

Recent advances in iron oxide nanocrystal technology for medical imaging

Adv. Drug Deliv. Rev.

(2006)

Y. Zhang

Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake

Biomaterials

(2002)

H. Hashizume

Openings between defective endothelial cells explain tumor vessel leakiness

Am. J. Pathol.

(2000)

R. Weissleder et al.

Molecular imaging

Radiology

(2001)

S. Achilefu

Introduction to concept and strategies for molecular imaging

Chem. Rev.

(2010)

K. Licha

Contrast agents for optical imaging

Topics Curr. Chem.

(2002)

Y.M. Erdi

The use of PET for radiotherapy

Curr. Medical Imaging Rev.

(2007)

S.E. Skrabalak

Gold nanocages: Synthesis, properties, and applications

Acc. Chem. Res.

(2008)

C.J. Murphy

Gold nanoparticles in biology: Beyond toxicity to cellular imaging

Acc. Chem. Res.

(2008)

D.L. Thorek

Superparamagnetic iron oxide nanoparticle probes for molecular imaging

Ann. Biomed. Eng.

(2006)

E.V. Shashkov

Quantum dots as multimodal photoacoustic and photothermal contrast agents

Nano Lett.

(2008)

R.A. Farrer

Highly efficient multiphoton-absorption-induced luminescence from gold nanoparticles

Nano Lett.

(2005)

E. Dulkeith

Plasmon emission in photoexcited gold nanoparticles

Phys. Rev. B

(2004)

R. Popovtzer

Targeted gold nanoparticles enable molecular CT imaging of cancer

Nano Lett.

(2008)

J.F. Hainfeld

Gold nanoparticles: a new X-ray contrast agent

British J. Radiol.

(2006)

X. Qian

In vivo tumor targeting and spectroscopic detection with surface-enhanced raman nanoparticle tags

Nat. Biotechnol.

(2008)

P.C. Li

In vivo photoacoustic molecular imaging with simultaneous multiple selective targeting using antibody-conjugated gold nanorods

Opt. Express

(2008)

G.A.F. van Tilborg

Annexin A5-functionalized bimodal lipid-based contrast agents for the detection of apoptosis

Bioconjug. Chem.

(2006)

E. Karathanasis

Imaging nanoprobe for prediction of outcome of nanoparticle chemotherapy by using mammography

Radiology

(2009)

X. Gao

In vivo cancer targeting and imaging with semiconductor quantum dots

Nat. Biotechnol.

(2004)

P.M. Allen

InAs(ZnCdS) quantum dots optimized for biological imaging in the near-Infrared

J. Am. Chem. Soc.

(2009)

J. Gao

Ultrasmall near-infrared non-cadmium quantum dots for in vivo tumor imaging

Small

(2010)

Y.-M. Huh

In vivo magnetic resonance detection of cancer by using multifunctional magnetic nanocrystals

J. Am. Chem. Soc.

(2005)

X. Yang

Nanoparticles for photoacoustic imaging

Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology

(2009)

C. Kim

In vivo molecular photoacoustic tomography of melanomas targeted by bio-conjugated gold nanocages

ACS Nano

(2010)

C.L. Zavaleta

Multiplexed imaging of surface enhanced raman scattering nanotags in living mice using noninvasive raman spectroscopy

Proc. Natl. Acad. Sci.

(2009)

L. Tong

Bright three-photon luminescence from gold/silver alloyed nanostructures for bioimaging with negligible photothermal toxicity

Angew. Chem. Int. Ed.

(2010)

J. Park

Two-photon-induced photoluminescence imaging of tumors using near-infrared excited gold nanoshells

Opt. Exp.

(2008)

G.V. Maltzahn

Computationally guided photothermal tumor therapy using long-circulating gold nanorod antennas

Cancer Res.

(2009)

M. Nyk

High contrast in vitro and in vivo photoluminescence bioimaging using near infrared to near infrared up-conversion in Tm³⁺ and Yb³⁺ doped fluoride nanophosphors

Nano Lett.

(2008)

R.H. Hashemi

MRI: The basics

(2010)

R.A. Robb

X-ray computed tomography: from basic principles to applications

Ann. Rev. Biophys. Bioeng.

(1982)

M.E. Phelps

PET: Physics, instrumentation, and scanners

(2006)

M. Rodriguez-Porcel

Imaging of VEGF receptor in a rat myocardial infarction model using PET

J. Nucl. Med.

(2008)

T. Olafsen

Optimizing radiolabeled engineered anti-p185HER2 antibody fragments for in vivo imaging

Cancer Res.

(2005)

W.P. Li

Receptor-binding, biodistribution, and metabolism studies of ⁶⁴Cu-DOTA-cetuximab, a PET-imaging agent for epidermal growth-factor receptor-positive tumors

Cancer Biotherapy Radiopharmaceuticals

(2008)

G. Niu

Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with ⁶⁴Cu-DOTA-trastuzumab

Eur. J. Nucl. Med. Mol. Imaging

(2009)

Cited by (214)

Tunable X-ray-induced luminescence in lanthanide-doped LaPO<inf>4</inf> nanoparticles
2024, Ceramics International
X-ray luminescent nanoparticles have gained significant attention as promising tools for implementing multimodal imaging and radiation-based treatments in theragnostics. The intricate comprehension of their properties and the underlying mechanisms driving the conversion of X-rays into light is critical for their success in various applications. LaPO₄ nanoparticles doped with various individual luminescence centers, gadolinium (Gd³⁺), europium (Eu³⁺), dysprosium (Dy³⁺), and terbium (Tb³⁺), were produced via co-precipitation and investigated for their behavior upon X-ray excitation using energies of up to 225 kV. These materials evidenced a radioluminescent response dependent on the dopant concentrations, with emission lines from 300 to 700 nm, providing insights into the luminescence quenching effect in these structures. The luminescent characteristics of the nanoparticles were studied under continuous irradiation, evidencing the materials’ ability to withstand high absorbed doses and preserve their properties. Furthermore, the influence of dopant concentrations on crystallite size and the dependence of luminescence on thermal treatments was investigated. The assessment of nanoparticle stability in aqueous suspension was evaluated over a broad pH range, revealing a tendency of the LaPO₄ surface to selectively interact with electropositive species. This insight enhances our comprehension of the colloidal stability of the material, positioning it for extended applications and in vitro evaluations, along with further surface functionalization.
Semiconducting polymer dots for fluorescence biosensing and imaging
2024, Semiconducting Polymer Materials for Biosensing Applications
Semiconducting polymer dots (Pdots), which are primarily derived from π-conjugated polymers (CPs), have emerged as a class of soft fluorescent nanomaterials. Owing to the distinguished properties resulting from CPs and nanosized materials, such as extraordinary brightness, a fast emission rate, strong photostability, and outstanding biocompatibility, Pdots have shown increasing applications in biosensing, bioimaging, and biomedical areas. In this chapter, we focus on the basic concepts, preparation, and biofunctionalization of Pdots, the fluorescence biosensing and imaging applications of functionalized Pdots, and the outlook for future directions of Pdots.
Trends and prospects of 2-D tungsten disulphide (WS<inf>2</inf>) hybrid nanosystems for environmental and biomedical applications
2023, Advances in Colloid and Interface Science
Recently, 2D layered transition metal dichalcogenides (TMDCs) with their ultrathin sheet nanostructure and diversified electronic structure have drawn attention for various advanced applications to achieve high-performance parameters. Unique 2D TMDCs mainly comprise transition metal and chalcogen element where chalcogen element layers sandwich the transition metal element layer. In such a case, various properties can be enhanced and controlled depending on the targeted application. Among manipulative 2D TMDCs, tungsten disulphide (WS₂) is one of the emerging nano-system due to its fascinating properties in terms of direct band gap, higher mobility, strong photoluminescence, good thermal stability, and strong magnetic field interaction. The advancement in characterization techniques, especially scattering techniques, can help in study of opto-electronic properties of 2D TMDCs along with determination of layer variations and investigation of defect. In this review, the fabrication and applications are well summarized to optimize an appropriate WS₂-TMDCs assembly according to focused field of research. Here, the scientific investigations on 2D WS₂ are studied in terms of its structure, role of scattering techniques to study its properties, and synthesis routes followed by its potential applications for environmental remediation (e.g., photocatalytic degradation of pollutants, gas sensing, and wastewater treatment) and biomedical domain (e.g., drug delivery, photothermal therapy, biomedical imaging, and biosensing). Further, a special emphasis is given to the significance of 2D WS₂ as a substrate for surface-enhanced Raman scattering (SERS). The discussion is further extended to commercial and industrial aspects, keeping in view major research gaps in existing research studies.
Inorganic imaging nanoprobes for breast cancer diagnosis
2023, Radiation Medicine and Protection
Breast cancer is one of the most prevalent cancers worldwide, and early diagnosis and screening are vital to its successful treatment. Although medical imaging methods can assist in the early detection of breast cancer, imaging methods that are currently used for clinical diagnosis have drawbacks, such as low sensitivity and accuracy. Contrast agents are often used in diagnostic imaging to address these drawbacks. Nanocontrast agents have attracted considerable attention in recent years due to their unique physicochemical characteristics. Among these agents, inorganic nanoprobes have been substantially developed through improvements in synthesis techniques and pairings with other organic molecules. This paper mainly summarizes the specific applications of inorganic nanoprobes in the magnetic resonance imaging, fluorescence imaging, radionuclide imaging, and bimodal/multimodal imaging of breast cancer.
Tumor microenvironment-triggered intratumoral in-situ biosynthesis of inorganic nanomaterials for precise tumor diagnostics
2023, Coordination Chemistry Reviews
The severe side effects and low bioavailability of conventional chemotherapeutic drugs are the major problems that current clinical cancer treatments suffer from. In recent years, tumor microenvironment (TME)-responsive nanomedicine that design has been shown to be safe and effective for tumor diagnosis and therapy. In particular, as a branch of intratumoral nanosynthetic medicine (INSM), the in situ biosynthesis of inorganic nanomaterials within tumor in response to specific TME triggers show incomparable advantages since they can avoid clearance by innate immune system and preferably enhance the intratumoral retention, which favors the early diagnosis and treatment of tumors. In this review, we systematically summarize the recent cutting-edge advances in the intratumoral biosynthesis of inorganic nanomaterials for cancer diagnosis and treatment with an emphasis on the specific TME triggers available for triggering the process of intratumoral in-situ biosynthesis. More significantly, the rational and extraordinary design concepts and rationales are unveiled by some typical cases. Additionally, the unresolved issues, potential solutions, our perspectives and future direction are comprehensively discussed, which are expected to provide different insights into this INSM of inorganic materials and enlighten related researchers and practitioners.
Silica-based nanocarriers
2023, Bionanocatalysis: From Design to Applications
Silica-based nanomaterials have long been used in medical research due to their high biocompatibility and malleable physiochemical properties. In nanomedicine, silica nanomaterials are easily modified, have a significant amount of individual surface area, and are highly biocompatible. As nanocarriers for drug delivery, single-nucleotide polymorphisms (SNPs) may mitigate the low bioavailability, short circulation life span, and undesirable biodistribution associated with many treatments. For improved cell selectivity as well as instant emission design capabilities, ligands that act as substrate sites or “gatekeepers” have been conjugated to SNPs, while physical and chemical characteristics of SNPs, such as the size of particle, their shape, and structure of mesoporous nanoparticles, have been engineered to enhance delivery efficiency and spatiotemporal precision. In spite of many improvements, traditional SNPs are mainly used as nanocarriers for selective onsite distribution and proscribed release because the naked silica framework is harmless.

View all citing articles on Scopus

View full text

Trends in Molecular Medicine

ReviewFeature ReviewInorganic nanoparticle-based contrast agents for molecular imaging

Section snippets

NPs as molecular imaging agents

Molecular imaging modalities

Major inorganic NPs for molecular imaging

Surface modification of inorganic NPs

Delivery and targeting of inorganic NPs

Biodistribution, clearance and the toxicity of inorganic NPs

Multimodal imaging with inorganic NPs

Concluding remarks

Acknowledgements

Curr. Opin. Biotechnol.

Journal of Nuclear Cardiology

Drug Discov. Today

Adv. Drug Deliv. Rev.

Lancet Oncol.

Biomaterials

Curr. Opin. Biotechnol.

Adv. Drug Deliv. Rev.

Adv. Drug Deliv. Rev.

Neoplasia

Magn. Reson. Imaging

Colloid Sur. B

Curr. Opin. Struct. Biol.

Adv. Drug Deliv. Rev.

Biomaterials

Am. J. Pathol.

Molecular imaging

Radiology

Introduction to concept and strategies for molecular imaging

Chem. Rev.

Contrast agents for optical imaging

Topics Curr. Chem.

The use of PET for radiotherapy

Curr. Medical Imaging Rev.

Gold nanocages: Synthesis, properties, and applications

Acc. Chem. Res.

Gold nanoparticles in biology: Beyond toxicity to cellular imaging

Acc. Chem. Res.

Superparamagnetic iron oxide nanoparticle probes for molecular imaging

Ann. Biomed. Eng.

Quantum dots as multimodal photoacoustic and photothermal contrast agents

Nano Lett.

Highly efficient multiphoton-absorption-induced luminescence from gold nanoparticles

Nano Lett.

Plasmon emission in photoexcited gold nanoparticles

Phys. Rev. B

Targeted gold nanoparticles enable molecular CT imaging of cancer

Nano Lett.

Gold nanoparticles: a new X-ray contrast agent

British J. Radiol.

In vivo tumor targeting and spectroscopic detection with surface-enhanced raman nanoparticle tags

Nat. Biotechnol.

In vivo photoacoustic molecular imaging with simultaneous multiple selective targeting using antibody-conjugated gold nanorods

Opt. Express

Annexin A5-functionalized bimodal lipid-based contrast agents for the detection of apoptosis

Bioconjug. Chem.

Imaging nanoprobe for prediction of outcome of nanoparticle chemotherapy by using mammography

Radiology

In vivo cancer targeting and imaging with semiconductor quantum dots

Nat. Biotechnol.

InAs(ZnCdS) quantum dots optimized for biological imaging in the near-Infrared

J. Am. Chem. Soc.

Ultrasmall near-infrared non-cadmium quantum dots for in vivo tumor imaging

Small

In vivo magnetic resonance detection of cancer by using multifunctional magnetic nanocrystals

J. Am. Chem. Soc.

Nanoparticles for photoacoustic imaging

Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology

In vivo molecular photoacoustic tomography of melanomas targeted by bio-conjugated gold nanocages

ACS Nano

Multiplexed imaging of surface enhanced raman scattering nanotags in living mice using noninvasive raman spectroscopy

Proc. Natl. Acad. Sci.

Bright three-photon luminescence from gold/silver alloyed nanostructures for bioimaging with negligible photothermal toxicity

Angew. Chem. Int. Ed.

Two-photon-induced photoluminescence imaging of tumors using near-infrared excited gold nanoshells

Opt. Exp.

Computationally guided photothermal tumor therapy using long-circulating gold nanorod antennas

Cancer Res.

Review
Feature Review
Inorganic nanoparticle-based contrast agents for molecular imaging

High contrast in vitro and in vivo photoluminescence bioimaging using near infrared to near infrared up-conversion in Tm³⁺ and Yb³⁺ doped fluoride nanophosphors

Receptor-binding, biodistribution, and metabolism studies of ⁶⁴Cu-DOTA-cetuximab, a PET-imaging agent for epidermal growth-factor receptor-positive tumors

Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with ⁶⁴Cu-DOTA-trastuzumab