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Journal ArticleDOI

Molecular imaging as a tool for translating breast cancer science

09 Dec 2008-Breast Cancer Research (BioMed Central)-Vol. 10, Iss: 1, pp 1-12
TL;DR: This review briefly describes different imaging modalities used in molecular imaging and then reviews applications of molecular imaging to breast cancer, with a focus on translational work.
Abstract: The ability to measure biochemical and molecular processes underlies progress in breast cancer biology and treatment. These assays have traditionally been performed by analysis of cell culture or tissue samples. More recently, functional and molecular imaging has allowed the in vivo assay of biochemistry and molecular biology, which is highly complementary to tissue-based assays. This review briefly describes different imaging modalities used in molecular imaging and then reviews applications of molecular imaging to breast cancer, with a focus on translational work. It includes sections describing work in functional and physiological tumor imaging, imaging gene product expression, imaging the tumor microenvironment, reporter gene imaging, and cell labeling. Work in both animal models and human is discussed with an eye towards studies that have relevance to breast cancer treatment in patients.

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Citations
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TL;DR: In this paper, ultrasmall silica nanoparticles are functionalized with anti-human epidermal growth factor receptor 2 (HER2) single-chain variable fragments to exhibit high tumor-targeting efficiency and efficient renal clearance.
Abstract: Controlling the biodistribution of nanoparticles upon intravenous injection is the key to achieving target specificity. One of the impediments in nanoparticle-based tumor targeting is the inability to limit the trafficking of nanoparticles to liver and other organs leading to smaller accumulated amounts in tumor tissues, particularly via passive targeting. Here we overcome both these challenges by designing nanoparticles that combine the specificity of antibodies with favorable particle biodistribution profiles, while not exceeding the threshold for renal filtration as a combined vehicle. To that end, ultrasmall silica nanoparticles are functionalized with anti-human epidermal growth factor receptor 2 (HER2) single-chain variable fragments to exhibit high tumor-targeting efficiency and efficient renal clearance. This ultrasmall targeted nanotheranostics/nanotherapeutic platform has broad utility, both for imaging a variety of tumor tissues by suitably adopting the targeting fragment and as a potentially useful drug delivery vehicle.

118 citations

Journal Article
TL;DR: The conjugation of anti-HER2 scFv fragments to the silica nanoparticles is proposed, increasing specificity and limiting the final size of the immunoconjugates below the renal clearance threshold.
Abstract: 606 Objectives: To design and characterize ultrasmall (HD: ~7 nm) core-shell hybrid silica nanoparticles that are functionalized with anti-human epidermal growth factor receptor 2 (HER2) single-chain variable fragments with high tumor targeting efficiency, low liver accumulation, and efficient renal clearance. Methods: Azide-functionalized scFv fragment (25-kDa) was generated based on Trastuzumab, using a variable light/heavy chain (VL-linker-VH) construct. Aminated PEG-NH2-Cy5-C’ dots (C’ dots: Cornell Prime dots, 6.6 nm) were first prepared and reacted with dibenzocyclooctyne-PEG4-N-hydroxysuccinimidyl ester (DBCO-PEG4-NHS ester) to form DBCO-PEG-NH2-Cy5-C’ dots. Afterwards, p-SCN-Bn-deferoxamine (DFO-NCS) was added and reacted with remaining amine groups to form DFO-DBCO-PEG-Cy5-C’ dots. Subsequently, DFO-DBCO-PEG-Cy5-C’ dots were mixed with anti-HER2 scFv-azide, yielding DFO-scFv-PEG-Cy5-C’ dots. In vitro and in vivo studies were performed to assess targeted delivery, penetration, and distribution of as-synthesized nanoimmunoconjugates in HER2-expressing BT-474 and HER2 non-expressing MDA-MB-231 cells, as well as xenografted / orthotopic tumor models. Pharmacokinetic analyses, radio-dosimetry, stability, and acute toxicity studies were also conducted. Results: Anti-HER2 scFv containing an azide functionalized non-natural amino acid at position HC44 was selected for subsequent C’ dot bioconjugation studies. 89Zr-DFO-scFv-PEG-Cy5-C’ dots were synthesized by integrating five functional moieties (i.e., encapsulated Cy5 near-infrared fluorescent dye, PEG stealth layer, Click Chemistry DBCO, 89Zr-chelated DFO and scFv fragment) into a single particle platform, while maintaining overall particle sizes to ~7.3 nm. The numbers of Cy5, DBCO, DFO and scFv per C’ dot were estimated to be approximately 1.9, 22, 6.6 and 1.4, respectively. Flow cytometry with BT-474 cells showed a significant concentration-dependent increase in median fluorescence intensity, 6-7 times higher than that of MDA-MB-231. For in vivo work, DFO-scFv-PEG-Cy5-C9 dots were radiolabeled with 89Zr and systemically injected to non-tumor-bearing or BT-474 tumor-bearing mice for assessment of biodistribution, radio stability, whole-body clearance, and in vivo HER2-targeted uptake. Cardiac and bladder activities were clearly observed in all groups at 2 h p.i. by PET imaging. The accumulation of 89Zr-DFO-scFv-PEG-Cy5-C’ dots in BT-474 tumors was estimated to be 8.2±1.1 %ID/g and progressively rose over the next 24-48 hours, with an average maximal value of 13.2±2.9 %ID/g (n=5). In the two control groups, similar particle activity trends were found for major organs/tissues, noting significantly lower tumor uptake values (~5 %ID/g) (n=5). Statistically significant specific enhancements in target-to-background ratios were achieved for the targeted group in BT-474 models, noting maximum tumor-to-liver and tumor-to-muscle ratios of 2.5±0.5 and 12.0±3.4, respectively. Both Cy5 widefield microscopy and autoradiography confirmed significant penetration of targeted particles throughout BT-474 tissue specimens. Similar target enhancement was demonstrated in orthotopic BT-474 models. Finally, no acute toxicity or histopathology was observed. Conclusions: Taken together, the foregoing data demonstrate that we have successfully overcome key in vivo barriers to improving target-specific delivery, penetration, accumulation, and retention of nanoimmunoconjugates in HER2+ breast cancer models using a renally-clearable particle imaging platform. The successful design and demonstration of such a clinically-promising, ultrasmall nanoimmunoconjugate for detection of HER2-expressing breast cancers serves as the foundation for staging, risk stratification, treatment planning, and next-stage targeted therapeutic developments.

94 citations

Journal ArticleDOI
TL;DR: This review focuses on PET and SPECT imaging which can provide sensitive serial non invasive information of tumor characteristics.

89 citations

Journal ArticleDOI
TL;DR: There has been a surge in reports of contrast agents bearing multiple functionality, potentially providing not only a powerful and highly sensitised means of co-localising physiological/disease status and anatomy, but also the tracking and delineation of multiple markers and indeed subsequent or simultaneous highly localized therapy ("theragnostics").
Abstract: A number of medical imaging techniques are used heavily in the provision of spatially resolved information on disease and physiological status and accordingly play a critical role in clinical diagnostics and subsequent treatment. Though, for most imaging modes, contrast is potentially enhanced through the use of contrast agents or improved hardware or imaging protocols, no single methodology provides, in isolation, a detailed mapping of anatomy, disease markers or physiological status. In recent years, the concept of complementing the strengths of one imaging modality with those of another has come to the fore and been further bolstered by the development of fused instruments such as PET/CT and PET/MRI stations. Coupled with the continual development in imaging hardware has been a surge in reports of contrast agents bearing multiple functionality, potentially providing not only a powerful and highly sensitised means of co-localising physiological/disease status and anatomy, but also the tracking and delineation of multiple markers and indeed subsequent or simultaneous highly localized therapy (“theragnostics”).

86 citations

Journal ArticleDOI
TL;DR: The cyanine dye IR820 has optical and thermal generation properties similar to those of indocyanine green (ICG) but with improved in vitro and in vivo stability and could be an alternative to ICG when greater stability, longer image collection times, or more predictable peak locations are desirable.
Abstract: Near-infrared (NIR) fluorophores are the focus of extensive research for combined molecular imaging and hyperthermia. In this study, we showed that the cyanine dye IR820 has optical and thermal gen...

80 citations

References
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Journal ArticleDOI
TL;DR: The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression, a higher rate of objective response, a longer duration of response, and a lower rate of death at 1 year.
Abstract: Background The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. Methods We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide with (143 women) or without trastuzumab (138 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). Results The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 ...

10,532 citations

Journal ArticleDOI
TL;DR: There are several risk subgroups for which the available data are insufficient to recommend for or against screening, including women with a personal history of breast cancer, carcinoma in situ, atypical hyperplasia, and extremely dense breasts on mammography.
Abstract: New evidence on breast Magnetic Resonance Imaging (MRI) screening has become available since the American Cancer Society (ACS) last issued guidelines for the early detection of breast cancer in 2003. A guideline panel has reviewed this evidence and developed new recommendations for women at different defined levels of risk. Screening MRI is recommended for women with an approximately 20-25% or greater lifetime risk of breast cancer, including women with a strong family history of breast or ovarian cancer and women who were treated for Hodgkin disease. There are several risk subgroups for which the available data are insufficient to recommend for or against screening, including women with a personal history of breast cancer, carcinoma in situ, atypical hyperplasia, and extremely dense breasts on mammography. Diagnostic uses of MRI were not considered to be within the scope of this review.

2,332 citations

Journal ArticleDOI
TL;DR: Thirteen categories of breast tumor markers were considered, six of which were new for the guideline, and certain multiparameter gene expression assays not all applications for these markers were supported, however.
Abstract: Purpose To update the recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast cancer. Methods For the 2007 update, an Update Committee composed of members from the full Panel was formed to complete the review and analysis of data published since 1999. Computerized literature searches of MEDLINE and the Cochrane Collaboration Library were performed. The Update Committee’s literature review focused attention on available systematic reviews and metaanalyses of published tumor marker studies. In general, significant health outcomes (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used for making recommendations. Recommendations and Conclusions

2,079 citations

Journal ArticleDOI
TL;DR: These magnetism-engineered iron oxide (MEIO) nanoprobes, when conjugated with antibodies, showed enhanced magnetic resonance imaging (MRI) sensitivity for the detection of cancer markers compared with probes currently available and could enhance the ability to visualize other biological events critical to diagnostics and therapeutics.
Abstract: Successful development of ultra-sensitive molecular imaging nanoprobes for the detection of targeted biological objects is a challenging task Although magnetic nanoprobes have the potential to perform such a role, the results from probes that are currently available have been far from optimal Here we used artificial engineering approaches to develop innovative magnetic nanoprobes, through a process that involved the systematic evaluation of the magnetic spin, size and type of spinel metal ferrites These magnetism-engineered iron oxide (MEIO) nanoprobes, when conjugated with antibodies, showed enhanced magnetic resonance imaging (MRI) sensitivity for the detection of cancer markers compared with probes currently available Also, we successfully visualized small tumors implanted in a mouse Such high-performance, nanotechnology-based molecular probes could enhance the ability to visualize other biological events critical to diagnostics and therapeutics

1,774 citations

Journal ArticleDOI
TL;DR: Immunotargeted nanoshells are engineered to both scatter light in the NIR enabling optical molecular cancer imaging and to absorb light, allowing selective destruction of targeted carcinoma cells through photothermal therapy.
Abstract: Nanoshells are a novel class of optically tunable nanoparticles that consist of a dielectric core surrounded by a thin gold shell. Based on the relative dimensions of the shell thickness and core radius, nanoshells may be designed to scatter and/or absorb light over a broad spectral range including the near-infrared (NIR), a wavelength region that provides maximal penetration of light through tissue. The ability to control both wavelength-dependent scattering and absorption of nanoshells offers the opportunity to design nanoshells which provide, in a single nanoparticle, both diagnostic and therapeutic capabilities. Here, we demonstrate a novel nanoshell-based all-optical platform technology for integrating cancer imaging and therapy applications. Immunotargeted nanoshells are engineered to both scatter light in the NIR enabling optical molecular cancer imaging and to absorb light, allowing selective destruction of targeted carcinoma cells through photothermal therapy. In a proof of principle experiment, ...

1,756 citations