Molecular Imaging Of Cancer Research Articles

Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer.

To improve prostate-specific membrane antigen (PSMA)-targeted theranostic approaches, robust murine models of prostate cancer are needed. However, important characteristics of preclinical PSMA imaging-that is, the reproducibility of the imaging signal and the relationship between quantitative cell surface PSMA expression and lesion detectability with small-animal PET/CT-have not been defined yet. Methods: Murine prostate cancer RM1 sublines (ras myc transformed cells of C57BL/6 prostate origin) expressing varying levels of human PSMA were injected into the shoulder of C57BL/6 mice on day 0. 68Ga-PSMA11 PET/CT was performed on days 7 and 8 and interpreted by 2 masked readers to determine interday and interreader reproducibility. PSMA expression was quantified on days 7 and 8 by flow cytometry of fine-needle aspiration tumor biopsy samples. Cell surface PSMA expression was correlated with PET signal. The threshold for PET positivity was based on the clinical Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. Results: The maximum and average percentages of injected 68Ga-PSMA11 activity per gram of tissue (%IA/g) correlated nearly perfectly as determined by 2 independent readers and on 2 separate days (intraclass correlation coefficient, 1.00/0.89 and 0.95/0.88, respectively). The number of PSMA molecules per cell increased from the RM1-yellow fluorescent protein subline (PSMA-; 2,000/cell) to the RM1-low subline (PSMA+; 17,000/cell), the RM1-medium subline (PSMA++; 22,000/cell), and the RM1-PGLS subline (PSMA-positive, green fluorescent protein-positive, and luciferase-positive; PSMA+++; 45,000/cell). Expression levels correlated with the visual positivity rate on 68Ga-PSMA11 PET and with the PSMA PET %IA/g. The PSMA threshold for PET positivity was approximately 20,000 per cell. Signal correlation was close at lower PSMA levels (RM1-low to RM1-medium; 10-23 %IA/g) but was lost at higher PSMA levels (RM1-medium to RM1-PGLS; 23-27 %IA/g). Conclusion: The in vivo relationship between 68Ga-PSMA11 PET/CT and PSMA expression level in a murine model of prostate cancer was robust for lower cell surface PSMA expression levels (≤22,000/cell). Thus, preclinical 68Ga-PSMA11 PET/CT can be used as an imaging biomarker to test PSMA-targeted interventions in murine models.

Novel 64Cu Labeled RGD2-BBN Heterotrimers for PET Imaging of Prostate Cancer.

Bombesin receptor 2 (BB2) and integrin αvβ3 receptor are privileged targets for molecular imaging of cancer because of their overexpression in a number of tumor tissues. The most recent developments in heterodimer-based radiopharmaceuticals concern BB2- and integrin αvβ3-targeting compounds, consisting of bombesin (BBN) and cyclic arginine-glycine-aspartic acid peptides (RGD), connected through short length linkers. Molecular imaging probes based on RGD-BBN heterodimer design exhibit improved tumor targeting efficacy compared to the single-receptor targeting peptide monomers. However, their application in clinical study is restricted because of inefficient synthesis or unfavorable in vivo properties, which could depend on the short linker nature. Thus, the aim of the present study was to develop a RGD2-BBN heterotrimer, composed of (7-14)BBN-NH2 peptide (BBN) linked to the E[ c(RGDyK)]2 dimer peptide (RGD2), bearing the new linker type [Pro-Gly]12. The heterodimer E[c(RGDyK)]2-PEG3-Glu-(Pro-Gly)12-BBN(7-14)-NH2 (RGD2-PG12-BBN) was prepared through conventional solid phase synthesis, then conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODA-GA). In 64Cu labeling, the NODA-GA chelator showed superior radiochemical characteristics compared to DOTA (70% vs 40% yield, respectively). Both conjugates displayed dual targeting ability, showing good αvβ3 affinities and high BB2 receptor affinities which, in the case of the NODA-GA conjugate, were in the same range as the best RGD-BBN heterodimer ligands reported to date ( Ki = 24 nM). 64Cu-DOTA and 64Cu-NODA-GA probes were also found to be stable after 1 h incubation in mouse serum (>90%). In a microPET study in prostate cancer PC-3 xenograft mice, both probes showed low tumor uptake, probably due to poor pharmacokinetic properties in vivo. Overall, our study demonstrates that novel RGD-BBN heterodimer with long linker can be prepared and they preserve high binding affinities to BB2 and integrin αvβ3 receptor binding ability. The present study represents a step forward in the design of effective heterodimer or heterotrimer probes for dual targeting.

Molecular Imaging of Cancer Using X-ray Computed Tomography with Protease Targeted Iodinated Activity-Based Probes.

X-ray computed tomography (CT) is a robust, precise, fast, and reliable imaging method that enables excellent spatial resolution and quantification of contrast agents throughout the body. However, CT is largely inadequate for molecular imaging applications due mainly to its low contrast sensitivity that forces the use of large concentrations of contrast agents for detection. To overcome this limitation, we generated a new class of iodinated nanoscale activity-based probes (IN-ABPs) that sufficiently accumulates at the target site by covalently binding cysteine cathepsins that are exceptionally highly expressed in cancer. The IN-ABPs are comprised of a short targeting peptide selective to specific cathepsins, an electrophilic moiety that allows activity-dependent covalent binding, and tags containing dendrimers with up to 48 iodine atoms. IN-ABPs selectively bind and inhibit activity of recombinant and intracellular cathepsin B, L, and S. We compared the in vivo kinetics, biodistribution, and tumor accumulation of IN-ABPs bearing 18 and 48 iodine atoms each, and their control counterparts lacking the targeting moiety. Here we show that although both IN-ABPs bind specifically to cathepsins within the tumor and produce detectable CT contrast, the 48-iodine bearing IN-ABP was found to be optimal with signals over 2.1-fold higher than its nontargeted counterpart. In conclusion, this study shows the synthetic feasibility and potential utility of IN-ABPs as potent contrast agents that enable molecular imaging of tumors using CT.

Tumor Targeting via Sialic Acid: [68Ga]DOTA-en-pba as a New Tool for Molecular Imaging of Cancer with PET.

The aim of this study was to demonstrate the potential of Ga-68-labeled macrocycle (DOTA-en-pba) conjugated with phenylboronic vector for tumor recognition by positron emission tomography (PET), based on targeting of the overexpressed sialic acid (Sia). The imaging reporter DOTA-en-pba was synthesized and labeled with Ga-68 at high efficiency. Cell binding assay on Mel-C and B16-F10 melanoma cells was used to evaluate melanin production and Sia overexpression to determine the best model for demonstrating the capability of [68Ga]DOTA-en-pba to recognize tumors. The in vivo PET imaging was done with B16-F10 tumor-bearing SCID mice injected with [68Ga]DOTA-en-pba intravenously. Tumor, blood, and urine metabolites were assessed to evaluate the presence of a targeting agent. The affinity of [68Ga]DOTA-en-pba to Sia was demonstrated on B16-F10 melanoma cells, after the production of melanin as well as Sia overexpression was proved to be up to four times higher in this cell line compared to that in Mel-C cells. Biodistribution studies in B16-F10 tumor-bearing SCID mice showed blood clearance at the time points studied, while uptake in the tumor peaked at 60min post-injection (6.36 ± 2.41% ID/g). The acquired PET images were in accordance with the ex vivo biodistribution results. Metabolite assessment on tumor, blood, and urine samples showed that [68Ga]DOTA-en-pba remains unmetabolized up to at least 60min post-injection. Our work is the first attempt for in vivo imaging of cancer by targeting overexpression of sialic acid on cancer cells with a radiotracer in PET.

Dual-Targeted Molecular Imaging of Cancer.

Molecular imaging is critical to personalized and precision medicine. Although singly targeted imaging probes are making an impact both clinically and preclinically, molecular imaging strategies using bispecific probes have enabled improved visualization of cancer in recent years through synergistic targeting of two ligands. In this Focus on Molecular Imaging review, we outline how peptide-, antibody-, and nanoparticle-based platforms have affected this emerging strategy, providing examples and pointing out areas in which the greatest clinical impact may be realized.

Low-intensity focused ultrasound (LIFU)-activated nanodroplets as a theranostic agent for noninvasive cancer molecular imaging and drug delivery.

Theranostics is a new trend in the tumor research field, which involves the integration of diagnostic and therapeutic functions using imageable nanoparticles coupled with therapeutic drugs. Imaging-guided targeted delivery of therapeutics and diagnostics using nanocarriers hold great promise to minimize the side effects of conventional chemotherapy. Ultrasound microbubbles have been employed as theranostic agents over the last decade, which provide both real-time dynamic imaging for diagnosis and precise control for targeted tumor therapy. However, the intrinsic defects of microbubbles such as poor tissue penetration, short circulation time and instability hinder microbubble-based theranostic applications. In recent years, liquid-to-gas transitional perfluorocarbon nanoparticles have been developed as promising diagnostic and therapeutic nanoagents to solve the abovementioned problems. In this study, phase-changeable, folate-targeted perfluoropentane nanodroplets loaded with 10-hydroxycamptothecin (HCPT) and superparamagnetic Fe3O4 (denoted as FA-HCPT-Fe3O4-PFP NDs) are prepared and investigated for multimodal tumor imaging and targeted therapy. After intravenous administration into nude mice bearing SKOV3 ovarian cancer, FA-HCPT-Fe3O4-PFP NDs exhibit the ability to enhance MR and PA imaging. Furthermore, after the phase transition activated by low-intensity focused ultrasound (LIFU) sonication, FA-HCPT-Fe3O4-PFP NDs remarkably enhance US imaging at the tumor location. Meanwhile, the HCPT released from FA-HCPT-Fe3O4-PFP NDs during the liquid-to-gas transition provides a therapeutic effect on tumor cells with relatively low side effects to normal tissue. Therefore, the combination of LIFU and FA-HCPT-Fe3O4-PFPNDs presents an ideal modality for tumor-targeted theranostics.

Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE): Proposed miTNM Classification for the Interpretation of PSMA-Ligand PET/CT.

Prostate-specific membrane antigen (PSMA)-ligand PET imaging provides unprecedented accuracy for whole-body staging of prostate cancer. As PSMA-ligand PET/CT is increasingly adopted in clinical trials and routine practice worldwide, a unified language for image reporting is urgently needed. We propose a molecular imaging TNM system (miTNM, version 1.0) as a standardized reporting framework for PSMA-ligand PET/CT or PET/MRI. miTNM is designed to organize findings in comprehensible categories to promote the exchange of information among physicians and institutions. Additionally, flowcharts integrating findings of PSMA-ligand PET and morphologic imaging have been designed to guide image interpretation. Specific applications, such as assessment of prognosis or impact on management, should be evaluated in future trials. miTNM is a living framework that evolves with clinical experience and scientific data.

Peripheral Nerve Nanoimaging: Monitoring Treatment and Regeneration.

Accidental and iatrogenic trauma are major causes of peripheral nerve injury. Healing after nerve injury is complex and often incomplete, which can lead to acute or chronic pain and functional impairment. Current assessment methods for nerve regeneration lack sensitivity and objectivity. There is a need for reliable and reproducible, noninvasive strategies with adequate spatial and temporal resolution for longitudinal evaluation of degeneration or regeneration after injury/treatment. Methods for noninvasive monitoring of the efficacy and effectiveness of neurotherapeutics in nerve regeneration or of neuropathic pain are needed to ensure adequacy and responsiveness to management, especially given the large variability in the patient populations, etiologies, and complexity of nerve injuries. Surrogate biomarkers are needed with positive predictive correlation for the dynamics and kinetics of neuroregeneration. They can provide direct real-time insight into the efficacy and mechanisms of individualized therapeutic intervention. Here, we review the state-of-the-art tools, technologies, and therapies in peripheral nerve injury and regeneration as well as provide perspectives for the future. We present compelling evidence that advancements in nanomedicine and innovation in nanotechnology such as nanotheranostics hold groundbreaking potential as paradigm shifts in noninvasive peripheral nerve imaging and drug delivery. Nanotechnology, which revolutionized molecular imaging in cancer and inflammatory disease, can be used to delineate dynamic molecular imaging signatures of neuroinflammation and neuroregeneration while simultaneously monitoring cellular or tissue response to drug therapy. We believe that current clinical successes of nanotechnology can and should be adopted and adapted to the science of peripheral nerve injury and regeneration.

Modulation of ultrasound-switchable fluorescence for improving signal-to-noise ratio.

Simultaneously achieving high signal-to-noise ratio (SNR) (or sensitivity) and high resolution is desired in biomedical imaging. However, conventional imaging modality has a tradeoff between SNR (or sensitivity) and resolution. We developed a method to simultaneously achieve high SNR (or sensitivity) and high resolution for fluorescence imaging in deep tissue. We first introduce a recently developed deep-tissue high-resolution imaging technique termed as ultrasound-switchable fluorescence (USF). An approach of modulating ultrasound exposure time is adopted to increase the detectability of the USF signal. The control parameters of modulation of ultrasound—such as (1) frequency, (2) duty cycle, and (3) exposure duration—are varied to study their influence on the USF signal and SNR. We conclude that high SNR can be achieved by modulating ultrasound exposure without sacrificing the spatial resolution. This is important for future fluorescence molecular imaging of cancer in deep tissue.

Abstract 1868: Molecular imaging of human esophageal cancer for early detection

Abstract Esophageal cancer was the sixth common cancer for incidence and ranks fourth for death rate in China, and squamous cell carcinoma is the main histological type. It is usually in an advanced stage at the time of diagnosis, resulting in an overall 5-year survival rate of <15%. Early detection can lead to an improvement in patient outcomes but is limited by nonspecific contrast mechanisms. As all we know, antibody and peptides establish a biological basis for image contrast, which could achieve sufficient target-to-background ratio for in vivo detection. In this paper, an EGFR antibody (Cetuximab) conjugated with an NIR dye (NIRDye800) was used for early detection of esophageal cancer. We demonstrated our technology could identify esophageal cancer in small size (<1 mm) and high-grade dysplasia from low-grade dysplasia. And 4.2-fold greater fluorescence intensity for esophageal cancer compared with surrounding normal esophageal tissues. No toxicity was observed in our experiments. The result indicated that this targeted, antibody-based imaging agents have great potential in early detection of esophageal cancer and other epidermal cancer. Citation Format: Xibo Ma, Hui Meng, Jie Tian. Molecular imaging of human esophageal cancer for early detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1868. doi:10.1158/1538-7445.AM2017-1868

A novel CXCR4-targeted near-infrared (NIR) fluorescent probe (Peptide R-NIR750) specifically detects CXCR4 expressing tumors

C-X-C chemokine receptor 4 (CXCR4) is over-expressed in multiple human cancers and correlates with tumor aggressiveness, poor prognosis and increased risk for distant metastases. Imaging agents for CXCR4 are thus highly desirable. We developed a novel CXCR4-targeted near-infrared (NIR) fluorescent probe (Peptide R-NIR750) conjugating the new developed CXCR4 peptidic antagonist Peptide R with the NIR fluorescent dye VivoTag-S750. Specific CXCR4 binding was obtained in cells overexpressing human CXCR4 (B16-hCXCR4 and human melanoma cells PES43), but not in CXCR4 low expressing cells (FB-1). Ex vivo evaluation demonstrated that PepR-NIR750 specifically detects B16-hCXCR4-derived subcutaneous tumors and lung metastases. Fluorescence Molecular Tomography (FMT) in vivo imaging was performed on mice carrying subcutaneous CHO and CHO-CXCR4 tumors. PepR-NIR750 accumulates only in CXCR4-positive expressing subcutaneous tumors. Additionally, an intense NIR fluorescence signal was detected in PES43-derived lung metastases of nude mice injected with PepR-NIR750 versus mice injected with VivoTag-S750. With a therapeutic intent, mice bearing PES43-derived lung metastases were treated with Peptide R. A the dramatic reduction in PES43-derived lung metastases was detected through a decrease of the PepR-NIR750 signal. PepR-NIR750 is a specific probe for non-invasive detection of human high CXCR4-expressing tumors and metastatic lesion and thus a valuable tool for cancer molecular imaging.

Generation and evaluation of antibody agents for molecular imaging of CD44v6-expressing cancers.

AimThe aim of this study was to generate and characterize scFv antibodies directed to human CD44v6, as well as to radiolabel and evaluate top candidates in vitro and in vivo for their potential use in CD44v6-targeted molecular imaging in cancer patients.Materials and methodsPhage display selections were used to isolate CD44v6-specific scFvs. A chain shuffling strategy was employed for affinity maturation based on a set of CD44v6-specific first-generation clones. Two second-generation scFv clones were then chosen for labeling with 111In or 125I and assessed for CD44v6-specific binding on cultured tumor cells. In vivo uptake and distribution was evaluated in tumor-bearing mice using a dual tumor model. Finally, a proof-of-concept small animal PET-CT study was performed on one of the candidates labeled with 124I.ResultsTwo affinity-matured clones, CD44v6-scFv-A11 and CD44v6-scFv-H12, displayed promising binding kinetics. Seven out of eight radiolabeled conjugates demonstrated CD44v6-specific binding. In vivo studies on selected candidates demonstrated very advantageous tumor-to-organ ratios, in particular for iodinated conjugates, where 125I-labeled scFvs exhibited favorable kinetics and tumor-to-blood ratios above five already at 24 hours p.i.. The small animal PET-CT study using 124I-labeled CD44v6-scFv-H12 was in line with the biodistribution data, clearly visualizing the high CD44v6-expressing tumor.ConclusionThe single chain fragments, CD44v6-scFv-A11 and CD44v6-scFv-H12 specifically bind to CD44v6, and the radiolabeled counterparts provide high tumor-to-blood ratios and fast clearance from organs and blood. We conclude that radioiodinated CD44v6-scFv-A11 and CD44v6-scFv-H12 possess features highly suitable for stringent molecular imaging.

Metallic nanoparticles: green synthesis and spectroscopic characterization

Metallic nanoparticles are finding new applications in medical, pharmaceutical, food and agriculture sectors. Applications include drug delivery, targeted cancer remedies, biomarker mapping, gene delivery and molecular imaging. This article reviews green strategies for the preparation of metallic nanoparticles, using enzymes, vitamins, monosaccharides, polysaccharides and biodegradable polymers. Microwave-assisted synthesis is detailed. Then, we review nanoparticle characterization using UV–visible spectroscopy and Fourier transform infrared spectroscopy. We also present applications for water purification.

Radiolabelled Polymeric Materials for Imaging and Treatment of Cancer: Quo Vadis?

Owing to their tunable blood circulation time and suitable plasma stability, polymer-based nanomaterials hold a great potential for designing and utilising multifunctional nanocarriers for efficient imaging and effective treatment of cancer. When tagged with appropriate radionuclides, they may allow for specific detection (diagnosis) as well as the destruction of tumours (therapy) or even customization of materials, aiming to both diagnosis and therapy (theranostic approach). This review provides an overview of recent developments of radiolabelled polymeric nanomaterials (natural and synthetic polymers) for molecular imaging of cancer, specifically, applying nuclear techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Different approaches to radiolabel polymers are evaluated from the methodical radiochemical point of view. This includes new bifunctional chelating agents (BFCAs) for radiometals as well as novel labelling methods. Special emphasis is given to eligible strategies employed to evade the mononuclear phagocytic system (MPS) in view of efficient targeting. The discussion encompasses promising strategies currently employed as well as emerging possibilities in radionuclide-based cancer therapy. Key issues involved in the clinical translation of radiolabelled polymers and future scopes of this intriguing research field are also discussed.

Application of Deep Learning in Automated Analysis of Molecular Images in Cancer: A Survey.

Molecular imaging enables the visualization and quantitative analysis of the alterations of biological procedures at molecular and/or cellular level, which is of great significance for early detection of cancer. In recent years, deep leaning has been widely used in medical imaging analysis, as it overcomes the limitations of visual assessment and traditional machine learning techniques by extracting hierarchical features with powerful representation capability. Research on cancer molecular images using deep learning techniques is also increasing dynamically. Hence, in this paper, we review the applications of deep learning in molecular imaging in terms of tumor lesion segmentation, tumor classification, and survival prediction. We also outline some future directions in which researchers may develop more powerful deep learning models for better performance in the applications in cancer molecular imaging.

Molecular Imaging of IGF-1R in Cancer.

The important role of insulin-like growth factor 1 receptor (IGF-1R) in malignant tumors has been well established. Increased IGF-1R activity promotes cancer cell proliferation, migration, and invasion and is associated with tumor metastasis, treatment resistance, poor prognosis, and shortened survival in patients with cancer. However, while IGF-1R has become a promising target for cancer therapy, IGF-1R-targeted therapy is ineffective in unselected patients. It is therefore essential to evaluate IGF-1R expression before treatment in order to identify responsive patients, monitor therapy efficacy, and estimate prognosis. Insulin-like growth factor 1 receptor molecular imaging is an optimal method for assessing the expression of IGF-1R in vivo accurately and noninvasively. In this review, we will summarize the current status of IGF-1R molecular imaging in cancer, in which 5 major classes of ligands that have been developed for noninvasive IGF-1R molecular imaging will be discussed: natural ligands, monoclonal antibodies, antibody fragments, affibodies, and small molecules. For decades, IGF-1R molecular imaging is studied in full swing and more effort is needed in the future.

Molecular Imaging of Cancer with Nanoparticle-Based Theranostic Probes.

Although advancements in medical technology supporting cancer diagnosis and treatment have improved survival, these technologies still have limitations. Recently, the application of noninvasive imaging for cancer diagnosis and therapy has become an indispensable component in clinical practice. However, current imaging contrasts and tracers, which are in widespread clinical use, have their intrinsic limitations and disadvantages. Nanotechnologies, which have improved in vivo detection and enhanced targeting efficiency for cancer, may overcome some of the limitations of cancer diagnosis and therapy. Theranostic nanoparticles have great potential as a therapeutic model, which possesses the ability of their nanoplatforms to load targeted molecule for both imaging and therapeutic functions. The resulting nanosystem will likely be critical with the growth of personalized medicine because of their diagnostic potential, effectiveness as a drug delivery vehicle, and ability to oversee patient response to therapy. In this review, we discuss the achievements of modern nanoparticles with the goal of accurate tumor imaging and effective treatment and discuss the future prospects.

Molecular imaging using by diffusion-weighted imaging of brain tumor through signal intensity: Progress in molecular cancer imaging

Introduction: Characterizing variations of brain tumors has significant effect in the treatment process of the affected patients. Brain metastatic tumors are usually diagnosed following by the neurological symptoms in patients. Purpose of this article is to find role of diffusion-weighted magnetic resonance imaging (DW-MRI) and apparent diffusion coefficient (ADC) values in the evaluation of different benign and malignant brain mass lesions before surgery with histopathological correlation. Materials and Methods: MR examination of 54 patients with brain metastatic tumor referring to 7th-Tir Hospital (Tehran, Iran) were randomly selected and imaged with T2W Multi-echo sequences and GRE-EPI (DWI) in addition to taking the routine sequence of the brain. Diffusion parameters during treatment were evaluated for early non-invasive biomarkers. In analyzing the data, the min ADC values were measured within the tumors and the mean values were evaluated. The data was analyzed by ANOVA, Pairwise post-hoc, and Tukey's HSD test applying GraphPadPrism. Results: The ADC min values of low-grade gliomas (1.09±0.20×10-3 mm2/s) were significantly higher than those of other tumors (p<0.001). The obtained ADC value of 0.5613±0.0258 indicated BMT with lung origin, the value of 1.009±0.03820 revealed BMT with liver and breast origin, and the value of 1.556±0.035 showed BMT with colon and prostate origin. Conclusion: According to our results DW-MRI parameters during treatment were evaluated for early non-invasive biomarkers. The ADC changes from mid- to post-treatment suggest such a possible early non-invasive biomarker.

Targeting Activated Platelets: A Unique and Potentially Universal Approach for Cancer Imaging.

Rationale The early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques. We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer. Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer.Methods The scFvGPIIb/IIIa, which binds specifically to the activated form of the platelet integrin receptor GPIIb/IIIa present on activated platelets, was conjugated to either Cy7, 64Cu or ultrasound-enhancing microbubbles. Using the Cy7 labelled scFvGPIIb/IIIa, fluorescence imaging was performed in mice bearing four different human tumour xenograft models; SKBr3, MDA-MB-231, Ramos and HT-1080 cells. Molecular imaging via PET and ultrasound was performed using the scFvGPIIb/IIIa-64Cu and scFvGPIIb/IIIa-microbubbles, respectively, to further confirm specific targeting of scFvGPIIb/IIIa to activated platelets in the tumour stroma.Results Using scFvGPIIb/IIIa we successfully showed specific targeting of activated platelets within the microenvironment of human tumour xenografts models via three different molecular imaging modalities. The presence of platelets within the tumour microenvironment, and as such their relevance as a molecular target epitope in cancer was further confirmed via immunofluorescence of human tumour sections of various cancer types, thus validating the translational importance of our novel approach to human disease.Conclusion Our study provides proof of concept for imaging and localization of tumours by molecular targeting activated platelets. We illustrate the utility of a unique scFv as a versatile biotechnological tool which can be conjugated to various contrast agents for molecular imaging of cancer using three different imaging modalities. These findings warrant further development of this activated platelet specific scFvGPIIb/IIIa, potentially as a universal marker for cancer diagnosis and ultimately for drug delivery in an innovative theranostic approach.

Targeted CT contrast agents for molecular imaging of cancer based on cathepsins elevated activity

Targeted CT contrast agents for molecular imaging of cancer based on cathepsins elevated activity