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Intra-operative ureter visualization using a novel near infrared fluorescent dye Sakkarapalayam M. Mahalingam, Fernando Dip, Marco Castillo, Mayank Roy, Steven D Wexner, Raul J Rosenthal, and Philip S. Low Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00427 • Publication Date (Web): 06 Jul 2018 Downloaded from http://pubs.acs.org on July 10, 2018

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Molecular Pharmaceutics

Intra-operative ureter visualization using a novel near infrared fluorescent dye Sakkarapalayam M. Mahalingam1,3 Fernando Dip2,3, Marco Castillo2, Mayank Roy2, Steven D. Wexner2, Raul J. Rosenthal2,4, and Philip S. Low1,4

1

Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette,

Indiana 47907, United States 2

Section of Minimally Invasive Surgery, Department of General Surgery, Cleveland Clinic Florida, 2950 Cleveland Clinic Boulevard, Weston, FL 33331, USA 3

These authors contributed equally to this publication.

4

To whom correspondence should be addressed.

Corresponding Authors E-mail: [email protected] ; [email protected]

Conflict of Interest: This work was supported in part by a grant from On Target Laboratories. Dr. Philip Low is a co-founder and a member of the Board of Directors of On Target Laboratories.

ACS Paragon Plus Environment

Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract Ureters can be accidentally severed during pelvic surgeries, significantly prolonging the times in the OR to allow for complete repair of damaged ureters and leading to significant morbidities associated with consequent ureter obstruction and possible kidney dysfunction. In an effort to prevent these complications, light-emitting stents and urine-excreted dyes have been introduced to illuminate the ureter during surgery. However, problems with mechanical insertion, ureter spasm, image contrast, and localized injection have limited interest in their clinical applications. We report here the synthesis and characterization of a new near-infrared (NIR) fluorescent dye (UreterGlow) that can injected systemically but is excreted primarily through the renal system, allowing ureter imaging with an NIR fluorescence camera. Following intravenous injection of 0.1 mg/kg UreterGlow, we have monitored the flow of UreterGlow through the proximal, medial and distal segments of the ureters. The timing of ureter visualization was calculated from the time of injection of the drug. The null hypothesis was that: “Visualization of the ureter in pigs is possible 60 minutes after administration of UreterGlow’ using an NIR camera”. UreterGlow displayed excitation and emission maxima of λex = 800 nm and λem = 830 nm in phosphate buffered saline, pH 7.4, and could be imaged in the urinary tract in mice. Shortly after injection of UreterGlow into Yorkshire pigs, peristalsis of the ureter could be observed. The distal ureter could be visualized under NIR illumination after 60 minutes with constant fluorescence in all five pigs for >2 hours. The same ureters could not be seen using visible light (X2, p=0.0001). Because both excitation and emission of UreterGlow occurs at >30 nm longer wavelength than most tumor-imaging fluorescent dyes, it should be possible to distinguish ureter fluorescence from tumor fluorescence with this dye.

Keywords: ureteric injury, UreterGlow, urologic surgery, ﬂuorescence-guided surgery

Introduction Iatrogenic ureteral injury (IUI) constitutes a serious complication for gynecologic, colorectal and urologic surgeries, which collectively account for ~75% of all ureter injuries1. Identification of


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ureters in surgical procedures can be difficult due to the proximity of ureters to vascular structures and other organs in the abdomen and pelvis, and its location in the posterior peritoneum1. Not surprisingly, IUI occurs in ~0.3% of all gynecologic procedures2,3 and 0.2% to 4.5% of colorectal surgeries4. IUI is also not uncommon during laparoscopic and robotic surgeries5. Centers with low volume pelvic cases have a slightly higher incidence of IUI6. Certain patient factors such as previous surgery or radiotherapy, obesity, inflammatory processes, and ureter anatomical abnormalities can also render the ureter more prone to injury4-7. Devastating long term complications can be associated with IUI. including chronic fistula, kidney failure, peritonitis and the need for autotransplantation6,8.

To date, there is no definitive cost-effective method for identifying the ureters during surgery. Stents have been reported to facilitate ureteric localization and injury identification, but they have not decreased the incidence of IUI nor have they proven to be cost effective4,9,10. Their use is also associated with increased incidents of hematuria, oliguria, ureteric perforation4,11, length of hospital stay and increased time in the operating room (up to 44 min)10,12. Lighted ureteral stents have also been proposed as an alternative to other types of stenting. However, they are costly and can cause similar complications to regular stents13–15. Attempts have also been made to intra-operatively visualize ureters under visible and NIR light using various contrast agents such as methylene blue, fluorescein, indocyanine green, IR800ZW, ZW800-1, and CW800-CA16,17,18. Unfortunately, these methods have had limited success because of problems with image contrast, ureter spasm, intra-ureter injection, duration of fluorescence signal, or background fluorescence. In an effort to develop a safe, effective, convenient and inexpensive fluorescent ureter imaging agent, we have synthesized a highly water-soluble NIR dye conjugate of glucosamine (UreterGlow). The aim of this study was to evaluate the intra-operative visualization of ureters in Yorkshire pigs using near-infrared fluorescence after intravenous administration of UreterGlow. Materials and Methods Experimental Section:



Materials. 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) was obtained from Genscript Inc. (Piscataway, New Jersey). Diisopropylethylamine (DIPEA), dimethylsulphoxide (DMSO), glucosamine and all other reagents were purchased from Sigma Aldrich and S0456 from Few Chemicals. Synthesis of UreterGlow: As shown in Scheme 1, the chloro near-infrared dye (S0456) was reacted with 2-(4mercaptophenyl) acetic acid (90% yield, 95% purity), and the resulting compound was coupled to glucosamine in the presence of HATU and DIPEA in DMSO for 12 h to yield the final conjugate, UreterGlow. The crude product was purified by preparative reverse-phase highperformance liquid chromatography (yield of 68% and final purity of 96%) with a gradient mobile phase consisting of 20 mM ammonium acetate buffer and 5% to 80% acetonitrile over 30 min (xTerra C18; Waters; 10 μm; 19 × 250 mm). Elution of the conjugate was monitored at 280 nm, and identities of eluted compounds were analyzed by liquid chromatography−mass spectrometry (see Supporting Information). UreterGlow was synthesized by conjugation of the thiol group of the aromatic thiophenol shown in Scheme 1 to the commercially available near-infrared dye (S0456) to furnish the intermediate, MA0424. MA0424 was then rendered more water soluble and less efficiently scavenged by the liver by further coupling it to glucosamine, yielding the final adduct in 80% overall yield which we named UreterGlow. The glucose is not released or metabolized under physiological conditions. Fluorescence Imaging and Analysis of Mice ND4 Swiss Webster mice were injected via tail vein with UreterGlow near IR dye. Mice were imaged at 2, 4, and 6 h post injection using a Caliper IVIS Lumina II Imaging station coupled with an ISOON5160 Andor Nikon camera equipped with Living Image Software Version 4.0. The settings were as follows: lamp level, high; excitation, 745 nm; emission, ICG; epi illumination; binning (M) 4; FOV, 12.5; f-stop, 4; acquisition time, 1 s. Pigs were imaged with the IMAGE1 S Dynamic Camera Architecture from KARL STORZ [Tuttlingen, Germany]. The camera’s near infrared components - H3-Z FI camera head, D-Light P


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light source, and ICG laparoscope - were used throughout the procedures with either NIR or white light illumination. Switching between white light and NIR light illumination was accomplished via a foot switch. Animal Procedures: ND4 Swiss Webster mice were purchased from Harlan Laboratories (Indianapolis, IN), maintained on normal rodent chow and housed in a sterile environment on a standard 12 h light and dark cycle for the duration of the study. All animal procedures were approved by the Purdue Animal Care and Use Committee in accordance with NIH guidelines. After ICUC approval from Miami University, five adult female Yorkshire pigs (weight 25 – 35kg) were used according to committee guidelines for the surgeries. The pigs were placed in left lateral position and secured to the operating table. A 10-mm trocar was introduced in the midline superior to the umbilicus, and pneumoperitoneum was established with CO2. One 5-mm trocar was placed under laparoscopic guidance inferior to the umbilicus. At the end of the experiment, all pigs were euthanized according to approved protocols. During laparoscopy, retroperitoneum was illuminated with xenon light. UreterGlow was intravenously administrated at a dose of 0.1 mg/kg. Kidney, ureter and the bladder were included in the images. The ureter was traced along its entire length. The whole procedure was video recorded, and static images were taken at 5 minute intervals. Illumination was switched frequently between xenon and near infrared light sources. Timing of ureter visualization with UreterGlow was calculated from the time of injection of the drug. Tissue was mobilized around the distal ureter to determine if there might be any difference in ureter imaging. All static images of xenon and NIR illuminated tissues were stored in TIFF format and analyzed using Image J software. Statistical analysis was performed and represented as Chi square. Results: Synthesis and characterization of ureter specific NIR dye UreterGlow (Scheme 1) Examination of the fluorescence properties of UreterGlow revealed excitation and emission maxima of λex = 800 nm and λem = 830 nm in phosphate buffered saline, pH 7.4 (Figure 1 A, B). These emission parameters were found to be independent of λex and pH between pH 3.5 and



10 (Figure 1C, 2). The conjugate was determined to be highly soluble and stable in aqueous solution over this same pH range, suggesting it could be useful for ureter imaging in vivo. O HO SO3 H

O 3S

O

SO3H

O3 S Cl

HO S

N

N

N

N SH HO3 S

DMSO

SO 3H

SO 3H

HO3S

S0456

MA0424

OH HO

O

HN

OH OH

O OH

SO3H

O 3S O

OH

S HO

NH 2

N

N

OH

HATU, DIPEA, DMSO

SO3 H

HO3 S

UreterGlow

Scheme 1. Synthesis of UreterGlow.

Figure 1. Excitation and emission spectra of 1 μM UreterGlow in PBS pH 7.4 (A) and human urine pH 5.5 (B). Emission spectra of UreterGlow were measured in sodium carbonate buffers between pHs 3.5 and 10 (C). Because visualization of ureters is often important during abdominal surgeries (e.g. colon cancer surgery, hysterectomy, ovarian cancer surgery, etc.) where accidental severance of ureters can occur, it seemed prudent to design the fluorescence properties of a ureter imaging agent to be distinguishable from fluorescent probes commonly used to image malignant lesions to be removed. Because IR800CW, ZW800-1, LS288, and OTL38 are under investigation for imaging tumors and other pathologic tissues,

19-21

we undertook to design a ureter imaging


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agent whose fluorescence would not be confused with the fluorescence of these probes. As shown in Table I, when dissolved in phosphate buffered saline, pH 7.4, at 100 nM concentration, each of the above probes exhibits excitation and emission spectra near 775 nm and 800 nm, respectively. In contrast, UreterGlow displays an excitation (800 nm) and emission (830 nm) maximum that can be easily distinguished with proper filters from the aforementioned dyes.

Table 1. Photophysical properties of UreterGlow, OTL38, ICG, IR800CW, ZW800-1, and LS288 in phosphate buffered saline. NIR Dye16–21 IR800CW LS288 ZW800 ICG OTL38 MA0424/ UreterGlow

λex (nm) 780 770 770 780 776 800

λem (nm) 795 785 788 802 796 830


λ (nm) 15 15 18 22 20 30


Figure 2. Emission spectra of 1 μM UreterGlow in PBS under near-IR laser excitation at wavelengths increasing in 10 nm increments from 700 nm to 800 nm. In Vivo Imaging and Biodistribution To determine whether UreterGlow might be cleared through the renal system, mice were injected with UreterGlow and imaged over a subsequent 6 h period. As shown in Figure 3, UreterGlow could be imaged under NIR illumination in both the liver and kidneys for the entire 6 h, but little or no fluorescence could be seen in any other organ or tissue after 1 h postinjection. Because UreterGlow could also be found in the feces and urine, we interpret these data to suggest that UreterGlow is cleared from the blood via both liver and kidneys, with little retention in other tissues.

Figure 3. Evaluation of UreterGlow (10 nmol) accumulation in the internal tissues and organs of ND4 Swiss Webster mice. (A) Organs and tissues were dissected 2, 4, and 6 h after UreterGlow injection and imaged for NIR fluorescence. Organs from top to bottom: 1) heart, 2) lungs, 3) liver, 4) spleen, 5) kidneys, 6) stomach, 7) small intestine, 8) large intestine and 9) muscle. (B) Evaluation of UreterGlow in

the kidneys reveals its continuous excretion is similar at 2, 4, and 6 h after injection.


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Large animal study Five Yorkshire pigs were also injected intravenously with 0.1 mg/kg UreterGlow and imaged with both white and near infrared (NIR) light using appropriate cameras. Ureter identification was not possible under white light illumination (xenon lamp) in any of the pigs. Activation of the NIR fluorescent imaging system, however, afforded clear visualization of the glowing ureters within 15 minutes of injection, allowing facile observation of ureter peristalsis (Figure 4). By 30 minutes post-injection, the distal ureter could be visualized with constant fluorescence upon NIR excitation, but no visualization was possible with xenon lamp (visible light) excitation. This difference in ureter contrast was highly significant when images were compared using J-image software (X2 [1, N=5] =72.76, p=0.0001) (Figure 5). Importantly, the ureters were visible with NIR light up to 2 hours in all five pigs, and there was no background fluorescence to compromise its visualization. Hence, we fail to reject the null hypothesis. Yorkshire pigs have little peri-ureteral fat, and consequently, the efficiency of penetration of NIR light through fatty tissues could not be evaluated. Biliary excretion was noted 15 minutes after injection of the dye, and it did not interfere with fluorescence of the ureters. No immediate serious toxicities were found after injection of the dye.

Figure 4. A) Ureters could not be visualized with visible light (xenon lamp). B) Visualization of peristalsis with UreterGlow upon illumination with NIR light.



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Figure 5. A) Ureters could not be visualized with visible light (xenon lamp). B) Both the bladder (B) and ureter (U) could be visualized for >2 hours after administration of UreterGlow upon illumination with NIR light.

Discussion Visualization of ureters is important during abdominal and pelvic surgery to avoid ureteric injury, as injury can add considerable time, cost and morbidity. Methylene blue has been injected intravenously ~45 min before surgery and shown to illuminate ureters for up to 60 min post-injection22. However, because its fluorescence is weak and its emitted light is unable to penetrate solid tissues, its application to ureter imaging has been limited23,24.

Sodium

fluorescein has also been used in previous studies, because it fluoresces brightly, is inexpensive, and has minimal side effects25,26. However, fluorescein can potentially stain normal tissues, fluoresces at a wavelength where tissue autofluorescence occurs27, and emits light that is not transparent to normal tissues28, resulting in poor contrast and potential misidentification of the ureters27. While illuminated stents have more recently been inserted through the urethra and into the ureters to facilitate ureter visualization during surgery, the cost of this procedure is high ($1500 to $3500)4,11 and the associated trauma can be severe. NIR fluorescent dyes constitute the most promising tools for intra-operative ureter localization. Although indocyanine green (ICG) is an NIR dye approved for human use, it is not excreted through the kidneys, so it has to be administered in retrograde fashion using a ureteral catheter. Visualization of ureters has successfully been achieved in this manner, but potential complications can arise similar to those seen with stents29–31. While IR800CW and ZW800-1


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have both been found to image ureters in animals following intravenous injection18, their application in human cancer surgeries may be limited by their short half-lives of excretion and the use of the same NIR dyes to image tumor tissues (i.e. buried ureters and malignant lesions that fluoresce identically may be difficult to distinguish). Because UreterGlow excretes over a period of >2 hours in the pig, excites and emits at an easily distinguishable wavelength from all common tumor imaging dyes, and can be administered subcutaneously or intravenously, we suggest that it should satisfy the ureter imaging requirements for most abdominal surgeries17,18,30–32. A limitation with the use of some fluorescent dyes for ureter imaging lies in their poor quantum yields at acidic urine pHs, causing ureter fluorescence to vary depending on physiologic and pathologic conditions35. To assure that UreterGlow would be equally fluorescent at all urine pHs, we examined the pH sensitivity of the UreterGlow in solutions buffered at all possible urine pHs. As noted in Fig. 1C, UreterGlow exhibited constant fluorescence emission at all pHs between 3.5 and 10.0, suggesting its intensity will not change with fluctuations in urine pH. This property will allow visualization of the ureters even in patients whose urine pH is altered, such as in patients taking diuretics or even in patients with intraoperative lactic acidosis 36,37. This study has a few limitations that should be mentioned. Visualization in the pig was not limited by the peri-ureteral fat that is often prominent in overweight and obese patients38. The agent also has yet to be tested in humans to establish its safety and efficacy. However, this is the first step towards achieving these goals. Fluorescent ureterography was possible intraoperatively with UreterGlow in Yorkshire pigs. At least 30 minutes is needed in order to reduce ureteric peristalsis and identify the ureter with NIR fluorescence light. UreterGlow offers good ureter visualization with little or no background fluorescence in proximal tissues and a distinct emission spectrum from the NIR dyes commonly used to image tumors. Visualization was possible for >2 hours after injection of the drug, suggesting it should be useful in reducing ureter damage during most abdominal surgeries.

ASSOCIATED CONTENT Supporting Information



The Supporting Information includes the chemical characterization of UreterGlow and is available free of charge on the ACS Publications website at http://pubs.acs.org. Acknowledgments The authors gratefully acknowledge support from the Purdue University Center for Cancer Research, P30CA023168 and a grant from On Target Laboratories LLC.

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272x152mm (96 x 96 DPI)


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Intra-operative ureter visualization using a novel ... - ACS Publications

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