scholarly journals Comparison of Folate Receptor Targeted Optical Contrast Agents for Intraoperative Molecular Imaging

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Elizabeth De Jesus ◽  
Jane J. Keating ◽  
Sumith A. Kularatne ◽  
Jack Jiang ◽  
Ryan Judy ◽  
...  
Keyword(s):  
Contrast Agents ◽  
Animal Studies ◽  
Near Infrared ◽  
Fluorescent Dyes ◽  
Folate Receptor ◽  
Intraoperative Imaging ◽  
Nir Dyes ◽  
Optical Contrast Agents

Background. Intraoperative imaging can identify cancer cells in order to improve resection; thus fluorescent contrast agents have emerged. Our objective was to do a preclinical comparison of two fluorescent dyes, EC17 and OTL38, which both target folate receptor but have different fluorochromes. Materials. HeLa and KB cells lines were used for in vitro and in vivo comparisons of EC17 and OTL38 brightness, sensitivity, pharmacokinetics, and biodistribution. In vivo experiments were then performed in mice. Results. The peak excitation and emission wavelengths of EC17 and OTL38 were 470/520 nm and 774/794 nm, respectively. In vitro, OTL38 required increased incubation time compared to EC17 for maximum fluorescence; however, peak signal-to-background ratio (SBR) was 1.4-fold higher compared to EC17 within 60 minutes (p<0.001). Additionally, the SBR for detecting smaller quantity of cells was improved with OTL38. In vivo, the mean improvement in SBR of tumors visualized using OTL38 compared to EC17 was 3.3 fold (range 1.48–5.43). Neither dye caused noticeable toxicity in animal studies. Conclusions. In preclinical testing, OTL38 appears to have superior sensitivity and brightness compared to EC17. This coincides with the accepted belief that near infrared (NIR) dyes tend to have less autofluorescence and scattering issues than visible wavelength fluorochromes.

scholarly journals Synthesis and Photothermal Effects of Intracellular Aggregating Nanodrugs Targeting Nasopharyngeal Carcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Ying Zhong ◽  
Naveen Kumar Bejjanki ◽  
Xiangwan Miao ◽  
Huanhuan Weng ◽  
Quanming Li ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Cancer Cells ◽  
Laser Irradiation ◽  
Animal Studies ◽  
Near Infrared ◽  
Folate Receptor ◽  
Treatment Options ◽  
Iron Oxide Nanoparticle ◽  
Local Concentration

Chemotherapy for the treatment of nasopharyngeal carcinoma (NPC) is usually associated with many side effects; therefore, its treatment options have not yet been completely resolved. Improving distribution to the targeted tumor region and enhancing the cellular uptake of drugs can efficiently alleviate the above adverse medical effects. Near-infrared (NIR) laser light-mediated photothermal therapy (PTT) and photodynamic therapy (PDT) are promising strategies for cancer treatment. In the present study, we developed an efficient multifunctional nanocluster with enhanced targeting and aggregation efficiency for PTT and PDT that is composed of a biocompatible folic acid (FA), indocyanine green (ICG) and 2-cyanobenzothiazole (CBT)-functionalized peptide labeled with an aldehyde sodium alginate-modified magnetic iron oxide nanoparticle (ASA-MNP)-based nanocarrier. FA can bind to folate receptors on cancer cell membranes to enhance nanocluster uptake. CBT-modified peptide can react with glutathione (GSH), which is typically present at higher levels in cancer cells, to form intracellular aggregates and increase the local concentration of the nanodrug. In in vitro studies, these nanodrugs displayed the desired uptake capacity by NPC cells and the ability to suppress the growth of cancer cells under laser irradiation. Animal studies validated that these nanodrugs are safe and nontoxic, efficiently accumulate in NPC tumor sites following injection via the caudal vein, and shows superior inhibition of tumor growth in a tumor-bearing mouse model upon near-infrared laser irradiation. The results indicate the potential application of the multifunctional nanoparticles (NPs), which can be used as a new method for the treatment of folate receptor-positive NPC.

scholarly journals A Targeted Folate Receptor-α Near-infrared Fluorescent Agent Used for in Vitro Diagnosis of Endometrial Cytology

2020 ◽  
Author(s):  
Dongxin Liang ◽  
Xiaoqian Tuo ◽  
Lanbo Zhao ◽  
Kailu Zhang ◽  
Yiran Wang ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Efficient Method ◽  
Predictive Value ◽  
Near Infrared ◽  
Folate Receptor ◽  
Intraoperative Imaging ◽  
False Negative ◽  
Endometrial Cytology ◽  
In Vitro Diagnosis

Abstract Background Endometrial cancer is the second-most prevalent cancer after breast cancer. Endometrial cytology test is a new diagnosis method for endometrial lesions. However, some unresolved issues limited the application of endometrial cytology test (ECT) in early diagnosis and screening of endometrial cancer. Evidence suggests that FRα is overexpressed in various solid tumors such as endometrial cancer, breast carcinoma, ovarian cancer and so on. Based on the expression of FR-α, the agent used in intraoperative imaging, FRα-targeting antibody drugs and diagnosis were developed previously. Nevertheless, research regarding agents used in the diagnosis of endometrial cancer is rarely carried out yet. Methods To obtain a promising and efficient method for in vitro and screening diagnosis of endometrial cytology, we performed the synthesis and evaluation of the new near-infrared targeting fluorescent dye folic acid-ZW800-1 (ZW-FA) and to explore its potential feasibility for in vitro diagnosis of endometrial cancer. Characterisation and Folate receptor-α (FR-α) targeting verification of ZW-FA were performed first and 92 patients were recruited, after liquid-based cytology preparations, during a 15-month period. ZW-FA and Hematoxylin-Eosin (H&E) staining were performed on all cytological slides successively; the histological diagnoses were regarded as the gold standard for ROC curve analysis. Results The cut-off value of ZW-FA fluorescence intensity is 62.9745; the sensitivity (Se), specificity (Sp), false-negative rate (FNR), false-positive rate (FPR), positive predictive value (PV+) percentage and negative predictive value (PV–) of the ZW-FA method are 84.6%, 85.2%, 15.4%,14.8%, 93.2% and 69.7%, respectively. Conclusions ZW-FA is potentially efficient for in vitro diagnosis of endometrial lesions based on the FR-α expression level of different endometrial lesions. This research offers a promising and efficient method for in vitro and screening diagnosis of endometrial cytology. Trial registration: ChiCTR1800020123. Registered December 15, 2018.

Fluorescein-Inspired Near-Infrared Chemodosimeter for Luminescence Bioimaging

2019 ◽  
Vol 26 (21) ◽  
pp. 4029-4041 ◽  
Author(s):  
Hai-Yan Wang ◽  
Huisheng Zhang ◽  
Siping Chen ◽  
Yi Liu
Keyword(s):  
Near Infrared ◽  
Living System ◽  
Tissue Penetration ◽  
Deep Tissue ◽  
Biological Targets ◽  
Nir Dyes ◽  
Photo Damage ◽  
Temporal And Spatial

Luminescence bioimaging is widely used for noninvasive monitoring of biological targets in real-time with high temporal and spatial resolution. For efficient bioimaging in vivo, it is essential to develop smart organic dye platforms. Fluorescein (FL), a traditional dye, has been widely used in the biological and clinical studies. However, visible excitation and emission limited their further application for in vivo bioimaging. Nearinfrared (NIR) dyes display advantages of bioimaging because of their minimum absorption and photo-damage to biological samples, as well as deep tissue penetration and low auto-luminescence from background in the living system. Thus, some great developments of near-infrared fluorescein-inspired dyes have emerged for bioapplication in vitro and in vivo. In this review, we highlight the advances in the development of the near-infrared chemodosimeters for detection and bioimaging based on the modification of fluoresceininspired dyes naphtho-fluorescein (NPF) and cyanine-fluorescein (Cy-FL).

Push–pull type meso-ester substituted BODIPY near-infrared dyes as contrast agents for photoacoustic imaging

2017 ◽  
Vol 15 (21) ◽  
pp. 4531-4535 ◽  
Author(s):  
Yong Ni ◽  
Ravi Kumar Kannadorai ◽  
Sidney W.-K. Yu ◽  
Young-Tae Chang ◽  
Jishan Wu
Keyword(s):  
Contrast Agents ◽  
Near Infrared ◽  
Photoacoustic Imaging ◽  
Nir Absorption ◽  
Photo Stability

Push–pull meso-ester BODIPYs with intense NIR absorption and good photo-stability were used for in vitro and in vivo photoacoustic imaging.

scholarly journals Comparison of Five Near-Infrared Fluorescent Folate Conjugates in an Ovarian Cancer Model

2021 ◽  
Author(s):  
Elvira García de Jalón ◽  
Katrin Kleinmanns ◽  
Vibeke Fosse ◽  
Ben Davidson ◽  
Line Bjørge ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Near Infrared ◽  
Ex Vivo ◽  
Folate Receptor ◽  
Fluorescence Signal ◽  
Cancer Model ◽  
Target Binding ◽  
The Impact

Abstract Purpose Fluorescence imaging (FLI) using targeted near-infrared (NIR) conjugates aids the detection of tumour lesions pre- and intraoperatively. The optimisation of tumour visualisation and contrast is essential and can be achieved through high tumour-specificity and low background signal. However, the choice of fluorophore is recognised to alter biodistribution and clearance of conjugates and is therefore a determining factor in the specificity of target binding. Although ZW800-1, IRDye® 800CW and ICG are the most commonly employed NIR fluorophores in clinical settings, the fluorophore with optimal in vivo characteristics has yet to be determined. Therefore, we aimed to characterise the impact the choice of fluorophore has on the biodistribution, specificity and contrast, by comparing five different NIR fluorophores conjugated to folate, in an ovarian cancer model. Procedures ZW800-1, ZW800-1 Forte, IRDye® 800CW, ICG-OSu and an in-house synthesised Cy7 derivative were conjugated to folate through an ethylenediamine linker resulting in conjugates 1–5, respectively. The optical properties of all conjugates were determined by spectroscopy, the specificity was assessed in vitro by flow cytometry and FLI, and the biodistribution was studied in vivo and ex vivo in a subcutaneous Skov-3 ovarian cancer model. Results We demonstrated time- and receptor-dependent binding of folate conjugates in vitro and in vivo. Healthy tissue clearance characteristics and tumour-specific signal varied between conjugates 1–5. ZW800-1 Forte (2) revealed the highest contrast in folate receptor alpha (FRα)-positive xenografts and showed statistically significant target specificity. While conjugates 1, 2 and 3 are renally cleared, hepatobiliary excretion and no or very low accumulation in tumours was observed for 4 and 5. Conclusions The choice of fluorophore has a significant impact on the biodistribution and tumour contrast. ZW800-1 Forte (2) exhibited the best properties of those tested, with significant specific fluorescence signal.

Synthesis, In Vitro Receptor Binding, and In Vivo Evaluation of Fluorescein and Carbocyanine Peptide-Based Optical Contrast Agents

2002 ◽  
Vol 45 (10) ◽  
pp. 2003-2015 ◽  
Author(s):  
Samuel Achilefu ◽  
Hermo N. Jimenez ◽  
Richard B. Dorshow ◽  
Joseph E. Bugaj ◽  
Elizabeth G. Webb ◽  
...  
Keyword(s):  
Contrast Agents ◽  
Receptor Binding ◽  
Optical Contrast ◽  
In Vivo Evaluation ◽  
Optical Contrast Agents

scholarly journals Intraoperative near-infrared imaging with receptor-specific versus passive delivery of fluorescent agents in pituitary adenomas

2019 ◽  
Vol 131 (6) ◽  
pp. 1974-1984 ◽  
Author(s):  
Steve S. Cho ◽  
Jun Jeon ◽  
Love Buch ◽  
Shayoni Nag ◽  
MacLean Nasrallah ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Near Infrared ◽  
Fluorescent Dyes ◽  
Folate Receptor ◽  
Intraoperative Imaging ◽  
Fluorescence Signal ◽  
Nonfunctioning Pituitary Adenomas ◽  
Nir Imaging ◽  
Nir Fluorescence ◽  
Significant Difference

OBJECTIVEIntraoperative molecular imaging with tumor-targeted fluorescent dyes can enhance resection rates. In contrast to visible-light fluorophores (e.g., 5-aminolevulinic-acid), near-infrared (NIR) fluorophores have increased photon tissue penetration and less contamination from tissue autofluorescence. The second-window ICG (SWIG) technique relies on passive accumulation of indocyanine green (ICG) in neoplastic tissues. OTL38, conversely, targets folate receptor overexpression in nonfunctioning pituitary adenomas. In this study, we compare the properties of these 2 modalities for NIR imaging of pituitary adenomas to better understand the potential for NIR imaging in neurosurgery.METHODSA total of 39 patients with pituitary adenomas were enrolled between June 2015 and January 2018 in 2, sequential, IRB-approved studies. Sixteen patients received systemic ICG infusions 24 hours prior to surgery, and another 23 patients received OTL38 infusions 2–3 hours prior to surgery. NIR fluorescence signal-to-background ratio (SBR) was recorded during and after resection. Immunohistochemistry was performed on the 23 adenomas resected from patients who received OTL38 to assess expression of folate receptor–alpha (FRα).RESULTSAll 16 adenomas operated on after ICG administration demonstrated strong NIR fluorescence (mean SBR 4.1 ± 0.69 [SD]). There was no statistically significant difference between the 9 functioning and 7 nonfunctioning adenomas (p = 0.9). After administration of OTL38, the mean SBR was 1.7 ± 0.47 for functioning adenomas, 2.6 ± 0.91 for all nonfunctioning adenomas, and 3.2 ± 0.53 for the subset of FRα-overexpressing adenomas. Tissue identification with white light alone for all adenomas demonstrated 88% sensitivity and 90% specificity. SWIG demonstrated 100% sensitivity but only 29% specificity for both functioning and nonfunctioning adenomas. OTL38 was 75% sensitive and 100% specific for all nonfunctioning adenomas, but when assessment was limited to the 9 FRα-overexpressing adenomas, the sensitivity and specificity of OTL38 were both 100%.CONCLUSIONSIntraoperative imaging with NIR fluorophores demonstrates highly sensitive detection of pituitary adenomas. OTL38, a folate-receptor–targeted fluorophore, is highly specific for nonfunctioning adenomas but has no utility in functioning adenomas. SWIG, which relies on passive diffusion into neoplastic tissue, is applicable to both functioning and nonfunctioning pituitary adenomas, but it is less specific than targeted fluorophores. Thus, targeted and nontargeted NIR fluorophores play important, yet distinct, roles in intraoperative imaging. Selectively and intelligently using either agent has the potential to greatly improve resection rates and outcomes for patients with intracranial tumors.

scholarly journals Tracking macrophages in diabetic neuropathy with two-color nanoemulsions for near-infrared fluorescent imaging and microscopy

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
James M. Nichols ◽  
Caitlin V. Crelli ◽  
Lu Liu ◽  
Hoang Vu Pham ◽  
Jelena M. Janjic ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Fluorescence Microscopy ◽  
Diabetic Neuropathy ◽  
Colloidal Stability ◽  
Near Infrared ◽  
Fluorescent Dyes ◽  
Wild Type ◽  
Nirf Imaging

Abstract Background The incidence of diabetes and diabetic peripheral neuropathy continues to rise, and studies have shown that macrophages play an important role in their pathogenesis. To date, macrophage tracking has largely been achieved using genetically-encoded fluorescent proteins. Here we present a novel two-color fluorescently labeled perfluorocarbon nanoemulsion (PFC-NE) designed to monitor phagocytic macrophages in diabetic neuropathy in vitro and in vivo using non-invasive near-infrared fluorescent (NIRF) imaging and fluorescence microscopy. Methods Presented PFC-NEs were formulated with perfluorocarbon oil surrounded by hydrocarbon shell carrying two fluorescent dyes and stabilized with non-ionic surfactants. In vitro assessment of nanoemulsions was performed by measuring fluorescent signal stability, colloidal stability, and macrophage uptake and subsequent viability. The two-color PFC-NE was administered to Leprdb/db and wild-type mice by tail vein injection, and in vivo tracking of the nanoemulsion was performed using both NIRF imaging and confocal microscopy to assess its biodistribution within phagocytic macrophages along the peripheral sensory apparatus of the hindlimb. Results In vitro experiments show two-color PFC-NE demonstrated high fluorescent and colloidal stability, and that it was readily incorporated into RAW 264.7 macrophages. In vivo tracking revealed distribution of the two-color nanoemulsion to macrophages within most tissues of Leprdb/db and wild-type mice which persisted for several weeks, however it did not cross the blood brain barrier. Reduced fluorescence was seen in sciatic nerves of both Leprdb/db and wild-type mice, implying that the nanoemulsion may also have difficulty crossing an intact blood nerve barrier. Additionally, distribution of the nanoemulsion in Leprdb/db mice was reduced in several tissues as compared to wild-type mice. This reduction in biodistribution appears to be caused by the increased number of adipose tissue macrophages in Leprdb/db mice. Conclusions The nanoemulsion in this study has the ability to identify phagocytic macrophages in the Leprdb/db model using both NIRF imaging and fluorescence microscopy. Presented nanoemulsions have the potential for carrying lipophilic drugs and/or fluorescent dyes, and target inflammatory macrophages in diabetes. Therefore, we foresee these agents becoming a useful tool in both imaging inflammation and providing potential treatment in diabetic peripheral neuropathy.

scholarly journals Targeted Nanoparticles for Fluorescence Imaging of Folate Receptor Positive Tumors

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1651
Author(s):  
Aimee J. Marko ◽  
Ballav M. Borah ◽  
Kevin E. Siters ◽  
Joseph R. Missert ◽  
Anurag Gupta ◽  
...  
Keyword(s):  
Folic Acid ◽  
Fluorescence Imaging ◽  
Near Infrared ◽  
Folate Receptor ◽  
Cyanine Dye ◽  
Target Specificity ◽  
Nir Fluorescence ◽  
Positive Breast Cancer

This report presents the synthesis and folate receptor target-specificity of amino-functionalized polyacrylamide nanoparticles (AFPAA NPs) for near-infrared (NIR) fluorescence imaging of cancer. For the synthesis of desired nano-constructs, the AFPAA NPs (hereafter referred to as NPs) were reacted with a NIR cyanine dye (CD) bearing carboxylic acid functionality by following our previously reported approach, and the resulting conjugate (NP-CD) on further reaction with folic acid (FA) resulted in a new nano-construct, FA-NP-CD, which demonstrated significantly higher uptake in folate receptor-positive breast cancer cells (KB+) and in folate receptor over-expressed tumors in vivo. The target-specificity of these nanoparticles was further confirmed by inhibition assay in folate receptor-positive (KB+) and -negative (HT-1080) cell lines. To show the advantages of polyacrylamide (PAA)-based NPs in folate receptor target-specificity, the CD used in preparing the FA-NP-CD construct was also reacted with folic acid alone and the synthetic conjugate (CD-FA) was also investigated for its target-specificity. Interestingly, in contrast to NPs (FA-NP-CD), the CD-FA conjugate did not show any significant in vitro or in vivo specificity toward folate receptors, showing the advantages of PAA-based nanotechnology in delivering the desired agent to tumor cells.

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