Receptor-Targeted Fluorescence-Guided Surgery With Low Molecular Weight Agents (original) (raw)
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Development of Tumor-Targeted Near Infrared Probes for Fluorescence Guided Surgery
Bioconjugate Chemistry, 2013
Complete surgical resection of malignant disease is the only reliable method to cure cancer. Unfortunately, quantitative tumor resection is often limited by a surgeon's ability to locate all malignant disease and distinguish it from healthy tissue. Fluorescence-guided surgery has emerged as a tool to aid surgeons in the identification and removal of malignant lesions. While nontargeted fluorescent dyes have been shown to passively accumulate in some tumors, the resulting tumor-to-background ratios are often poor, and the boundaries between malignant and healthy tissues can be difficult to define. To circumvent these problems, our laboratory has developed high affinity tumor targeting ligands that bind to receptors that are overexpressed on cancer cells and deliver attached molecules selectively into these cells. In this study, we explore the use of two tumor-specific targeting ligands (i.e., folic acid that targets the folate receptor (FR) and DUPA that targets prostate specific membrane antigen (PSMA)) to deliver near-infrared (NIR) fluorescent dyes specifically to FR and PSMA expressing cancers, thereby rendering only the malignant cells highly fluorescent. We report here that all FR-and PSMA-targeted NIR probes examined bind cultured cancer cells in the low nanomolar range. Moreover, upon intravenous injection into tumor-bearing mice with metastatic disease, these same ligand−NIR dye conjugates render receptor-expressing tumor tissues fluorescent, enabling their facile resection with minimal contamination from healthy tissues.
Real-Time Fluorescence Image-Guided Oncologic Surgery
Advances in Cancer Research, 2014
Medical imaging plays a critical role in cancer diagnosis and planning. Many of these patients rely on surgical intervention for curative outcomes. This requires a careful identification of the primary and microscopic tumors, and the complete removal of cancer. Although there have been efforts to adapt traditional-imaging modalities for intraoperative image guidance, they suffer from several constraints such as large hardware footprint, high-operation cost, and disruption of the surgical workflow. Because of the ease of image acquisition, relatively low-cost devices and intuitive operation, optical imaging methods have received tremendous interests for use in real-time image-guided surgery. To improve imaging depth under low interference by tissue autofluorescence, many of these applications utilize light in the near-infrared (NIR) wavelengths, which is invisible to human eyes. With the availability of a wide selection of tumor-avid contrast agents, advancements in imaging sensors, electronic and optical designs, surgeons are able to combine different attributes of NIR optical imaging techniques to improve treatment outcomes. The emergence of diverse commercial and experimental image guidance systems, which are in various stages of clinical translation, attests to the potential high impact of intraoperative optical imaging methods to improve speed of oncologic surgery with high accuracy and minimal margin positivity.
New technologies for fluorescence image-guided surgery
2014
To date, surgery is the most common and successful way to treat cancer. Tumour identification during surgery, however, can be challenging as it relies on the surgeon’s ability to differentiate healthy from diseased tissue, based on visual appearance and palpation. Additional contrast mechanisms are needed to further improve cancer detection during surgery. In this work, I explore the possibility of improving surgical outcomes by using intra-operative fluorescence imaging technologies to identify otherwise invisible lesions. A theoretical model is developed to quantify and characterise the imaging performance of fluorescence image-guided surgery (FIGS) and to guide the development of imaging systems. This model shows excellent potential for performance characterisation of FIGS devices, particularly when small lesions are involved. The design, development and testing of FIGS devices for open and keyhole surgery are described. These devices exploit near infrared (NIR) wavelengths to ac...
Theranostics, 2014
Cancer is a major threat to human health. Diagnosis and treatment using precision medicine is expected to be an effective method for preventing the initiation and progression of cancer. Although anatomical and functional imaging techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have played an important role for accurate preoperative diagnostics, for the most part these techniques cannot be applied intraoperatively. Optical molecular imaging is a promising technique that provides a high degree of sensitivity and specificity in tumor margin detection. Furthermore, existing clinical applications have proven that optical molecular imaging is a powerful intraoperative tool for guiding surgeons performing precision procedures, thus enabling radical resection and improved survival rates. However, detection depth limitation exists in optical molecular imaging methods and further breakthroughs from optical to mul...
Cancer control : journal of the Moffitt Cancer Center
The excision of tumors by wide local excision is challenging because the mass must be removed entirely without ever viewing it directly. Positive margin rates in sarcoma resection remain in the range of 20% to 35% and are associated with increased recurrence and decreased survival. Fluorescence-guided surgery (FGS) may improve surgical accuracy and has been utilized in other surgical specialties. ABY-029, an anti-epidermal growth factor receptor Affibody molecule covalently bound to the near-infrared fluorophore IRDye 800CW, is an excellent candidate for future FGS applications in sarcoma resection; however, conventional methods with direct surface tumor visualization are not immediately applicable. A novel technique involving imaging through a margin of normal tissue is needed. We review the past and present applications of FGS and present a novel concept of indirect FGS for visualizing tumor through a margin of normal tissue and aiding in excising the entire lesion as a single, co...
EpCAM as multi-tumour target for near-infrared fluorescence guided surgery
BMC cancer, 2016
Evaluation of resection margins during cancer surgery can be challenging, often resulting in incomplete tumour removal. Fluorescence-guided surgery (FGS) aims to aid the surgeon to visualize tumours and resection margins during surgery. FGS relies on a clinically applicable imaging system in combination with a specific tumour-targeting contrast agent. In this study EpCAM (epithelial cell adhesion molecule) is evaluated as target for FGS in combination with the novel Artemis imaging system. The NIR fluorophore IRDye800CW was conjugated to the well-established EpCAM specific monoclonal antibody 323/A3 and an isotype IgG1 as control. The anti-EpCAM/800CW conjugate was stable in serum and showed preserved binding capacity as evaluated on EpCAM positive and negative cell lines, using flow cytometry and cell-based plate assays. Four clinically relevant orthotopic tumour models, i.e. colorectal cancer, breast cancer, head and neck cancer, and peritonitis carcinomatosa, were used to evaluat...
Detection limits of intraoperative near infrared imaging for tumor resection
Journal of Surgical Oncology, 2010
Background and Objectives-The application of fluorescent molecular imaging to surgical oncology is a developing field with the potential to reduce morbidity and mortality. However, the detection thresholds and other requirements for successful intervention remain poorly understood. Here we modeled and experimentally validated depth and size of detection of tumor deposits, trade-offs in coverage and resolution of areas of interest, and required pharmacokinetics of probes based on differing levels of tumor target presentation. Methods-Three orthotopic tumor models were imaged by widefield epifluorescence and confocal microscopes, and the experimental results were compared with pharmacokinetic models and light scattering simulations to determine detection thresholds. Results-Widefield epifluorescence imaging can provide sufficient contrast to visualize tumor margins and detect tumor deposits 3-5 mm deep based on labeled monoclonal antibodies at low objective magnification. At higher magnification, surface tumor deposits at cellular resolution are detectable at TBR ratios achieved with highly expressed antigens. Conclusions-A widefield illumination system with the capability for macroscopic surveying and microscopic imaging provides the greatest utility for varying surgical goals. These results have implications for system and agent designs, which ultimately should aid complete resection in most surgical beds and provide real-time feedback to obtain clean margins.
NIR fluorescence-guided tumor surgery: new strategies for the use of indocyanine green
International Journal of Nanomedicine
Surgery is the frontline treatment for a large number of cancers. The objective of these excisional surgeries is the complete removal of the primary tumor with sufficient safety margins. Removal of the entire tumor is essential to improve the chances of a full recovery. To help surgeons achieve this objective, near-infrared fluorescence-guided surgical techniques are of great interest. The concomitant use of fluorescence and indocyanine green (ICG) has proved effective in the identification and characterization of tumors. Moreover, ICG is authorized by the Food and Drug Administration and the European Medicines Agency and is therefore the subject of a large number of studies. ICG is one of the most commonly used fluorophores in near-infrared fluorescence-guided techniques. However, it also has some disadvantages, such as limited photostability, a moderate fluorescence quantum yield, a high plasma protein binding rate, and undesired aggregation in aqueous solution. In addition, ICG does not specifically target tumor cells. One way to exploit the capabilities of ICG while offsetting these drawbacks is to develop high-performance near-infrared nanocomplexes formulated with ICG (with high selectivity for tumors, high tumor-to-background ratios, and minimal toxicity). In this review article, we focus on recent developments in ICG complexation strategies to improve near-infrared fluorescence-guided tumor surgery. We describe targeted and nontargeted ICG nanoparticle models and ICG complexation with targeting agents.
Development of a drug–device combination for fluorescence-guided surgery in neuroendocrine tumors
Journal of Biomedical Optics, 2020
Significance: The use of cancer-targeted contrast agents in fluorescence-guided surgery (FGS) has the potential to improve intraoperative visualization of tumors and surgical margins. However, evaluation of their translational potential is challenging. Aim: We examined the utility of a somatostatin receptor subtype-2 (SSTR2)-targeted fluorescent agent in combination with a benchtop near-infrared fluorescence (NIRF) imaging system to visualize mouse xenografts under conditions that simulate the clinical FGS workflow for open surgical procedures. Approach: The dual-labeled somatostatin analog, 67 Ga-MMC(IR800)-TOC, was injected into mice (n ¼ 24) implanted with SSTR2-expressing tumors and imaged with the customized OnLume NIRF imaging system (Madison, Wisconsin). In vivo and ex vivo imaging were performed under ambient light. The optimal dose (0.2, 0.5, and 2 nmol) and imaging time point (3, 24, 48, and 72 h) were determined using contrast-to-noise ratio (CNR) as the image quality parameter. Video captures of tumor resections were obtained to provide an FGS readout that is representative of clinical utility. Finally, a log-transformed linear regression model was fitted to assess congruence between fluorescence readouts and the underlying drug distribution. Results: The drug-device combination provided high in vivo and ex vivo contrast (CNRs > 3, except lung at 3 h) at all time points with the optimal dose of 2 nmol. The optimal imaging time point was 24-h post-injection, where CNRs > 6.5 were achieved in tissues of interest (i.e., pancreas, small intestine, stomach, and lung). Intraoperative FGS showed excellent utility for examination of the tumor cavity pre-and post-resection. The relationship between fluorescence readouts and gamma counts was linear and strongly correlated (n ¼ 334, R 2 ¼ 0.71; r ¼ 0.84; P < 0.0001). Conclusion: The innovative OnLume NIRF imaging system enhanced the evaluation of 67 Ga-MMC(IR800)-TOC in tumor models. These components comprise a promising drugdevice combination for FGS in patients with SSTR2-expressing tumors.