Polymeric Micelles as Carriers for Nerve-Highlighting Fluorescent Probe Delivery

Hackman, Kayla M.; Doddapaneni, Bhuvana Shyam; Barth, Connor W.; Wierzbicki, Igor H.; Alani, Adam W.G.; Gibbs, Summer L.

doi:10.1021/acs.molpharmaceut.5b00582

Cited by 25 publications

(30 citation statements)

References 28 publications

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“…Tumor and adipose tissue pair imaging was performed using a custom-built wide field imaging system consisting of a QImaging EXi Blue monochrome camera (Surrey, British Columbia, CA) for fluorescence detection with a removable Bayer filter for collecting co-registered color images 46 - 48 . A PhotoFluor II light source (89 North, Burlington, VT) was focused onto the field of view (FOV, 34 mm × 45 mm) through a liquid light guide and used unfiltered for white light illumination.…”

Section: Methodsmentioning

confidence: 99%

Optimizing fresh specimen staining for rapid identification of tumor biomarkers during surgery

Barth¹,

Schaefer²,

Rossi³

et al. 2017

Theranostics

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Rationale: Positive margin status due to incomplete removal of tumor tissue during breast conserving surgery (BCS) is a prevalent diagnosis usually requiring a second surgical procedure. These follow-up procedures increase the risk of morbidity and delay the use of adjuvant therapy; thus, significant efforts are underway to develop new intraoperative strategies for margin assessment to eliminate re-excision procedures. One strategy under development uses topical application of dual probe staining and a fluorescence imaging strategy termed dual probe difference specimen imaging (DDSI). DDSI uses a receptor-targeted fluorescent probe and an untargeted, spectrally-distinct fluorescent companion imaging agent topically applied to fresh resected specimens, where the fluorescence from each probe is imaged and a normalized difference image is computed to identify tumor-target distribution in the specimen margins. While previous reports suggested this approach is a promising new tool for surgical guidance, advancing the approach into the clinic requires methodical protocol optimization and further validation.Methods: In the present study, we used breast cancer xenografts and receiver operator characteristic (ROC) curve analysis to evaluate a wide range of staining and imaging parameters, and completed a prospective validation study on multiple tumor phenotypes with different target expression. Imaging fluorophore-probe pair, concentration, and incubation times were systematically optimized using n=6 tissue specimen replicates per staining condition. Resulting tumor vs. normal adipose tissue diagnostic performance were reported and staining patterns were validated via receptor specific immunohistochemistry colocalization. Optimal staining conditions were tested in receptor positive and receptor negative cohorts to confirm specificity.Results: The optimal staining conditions were found to be a one minute stain in a 200 nM probe solution (area under the curve (AUC) = 0.97), where the choice of fluorescent label combination did not significantly affect the diagnostic performance. Using an optimal threshold value determined from ROC curve analysis on a training data set, a prospective study on xenografts resulted in an AUC=0.95 for receptor positive tumors and an AUC = 0.50 for receptor negative (control) tumors, confirming the diagnostic performance of this novel imaging technique.Conclusions: DDSI provides a robust, molecularly specific imaging methodology for identifying tumor tissue over benign mammary adipose tissue. Using a dual probe imaging strategy, nonspecific accumulation of targeted probe was corrected for and tumor vs. normal tissue diagnostic potential was improved, circumventing difficulties with ex vivo tissue specimen staining and allowing for rapid clinical translation of this promising technology for tumor margin detection during BCS procedures.

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Section: Methodsmentioning

confidence: 99%

Optimizing fresh specimen staining for rapid identification of tumor biomarkers during surgery

Barth¹,

Schaefer²,

Rossi³

et al. 2017

Theranostics

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“…At four hours post-injection 38, 40, 41, the rabbits were euthanized, and the spinal cord, sciatic nerve and surrounding tissues were then exposed and imaged in the FIS.…”

Section: Methodsmentioning

confidence: 99%

Rapid fluorescence imaging of spinal cord following epidural administration of a nerve-highlighting fluorophore

Liu¹,

Gu²,

Zhu³

et al. 2017

Theranostics

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Iatrogenic spinal cord injury (SCI) is the most devastating complication of spine surgery, which usually results in permanent and serious disabilities of patients. Improvement of the visualization and discrimination of the spinal cord is critical for accuracy and safety during surgery; however, to date, there is no suitable technology to fulfill this clinical need. Here, we first show an efficient and rapid fluorescence imaging of the spinal cord in rabbit by epidural administration of a nerve-highlighting fluorophore, i.e. (E, E)-1,4-bis(p-aminostryl)-2-methoxy benzene (BMB). The BMB is firstly encapsulated into polymeric micelles to form a BMB-micelle (BMB-m) formulation with well-dispersion in normal saline solution. After epidural administration of BMB-m, BMB is transported by the flow of cerebrospinal fluid (CSF) and binds to the peripheral region of the white matter thus facilitating rapid staining of the spinal cord. Furthermore, this BMB imaging technology also holds great potential for visually monitoring the integrity of the spinal cord in real time and promptly identifying acute SCI during spine surgery.

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“…Color and fluorescence images of tumor and normal tissue pairs were collected using a previously described custom-built wide field imaging system, 28 detailed briefly as follows. The macroscopic fluorescence imaging system consisted of a QImaging EXi Blue monochrome camera (Surrey, British Columbia, California) with a removable Bayer filter and a PhotoFluor II light source (89 North, Burlington, Vermont).…”

Section: Ddsi Macroscopic Imagingmentioning

confidence: 99%

Diagnostic performance of receptor-specific surgical specimen staining correlates with receptor expression level

et al. 2019

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Intraoperative margin assessment is imperative to cancer cure but is a continued challenge to successful surgery. Breast conserving surgery is a relevant example, where a cosmetically improved outcome is gained over mastectomy, but re-excision is required in >25% of cases due to positive or closely involved margins. Clinical translation of margin assessment modalities that must directly contact the patient or required administered contrast agents are time consuming and costly to move from bench to bedside. Tumor resections provide a unique surgical opportunity to deploy margin assessment technologies including contrast agents on the resected tissues, substantially shortening the path to the clinic. However, staining of resected tissues is plagued by nonspecific uptake. A ratiometric imaging approach where matched targeted and untargeted probes are used for staining has demonstrated substantially improved biomarker quantification over staining with conventional targeted contrast agents alone. Our group has developed an antibody-based ratiometric imaging technology using fluorescently labeled, spectrally distinct targeted and untargeted antibody probes termed dual-stain difference specimen imaging (DDSI). Herein, the targeted biomarker expression level and pattern are evaluated for their effects on DDSI diagnostic potential. Epidermal growth factor receptor expression level was correlated to DDSI diagnostic potential, which was found to be robust to spatial pattern expression variation. These results highlight the utility of DDSI for accurate margin assessment of freshly resected tumor specimens.

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Polymeric Micelles as Carriers for Nerve-Highlighting Fluorescent Probe Delivery

Cited by 25 publications

References 28 publications

Optimizing fresh specimen staining for rapid identification of tumor biomarkers during surgery

Optimizing fresh specimen staining for rapid identification of tumor biomarkers during surgery

Rapid fluorescence imaging of spinal cord following epidural administration of a nerve-highlighting fluorophore

Diagnostic performance of receptor-specific surgical specimen staining correlates with receptor expression level

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