Targeted imaging of urothelium carcinoma in human bladders by an ICG pHLIP® peptide ex vivo: Beyond the Abstract

In modern medicine, we increasingly find ourselves at the interface of technological advances and scientific breakthroughs.  As techniques and instrumentation become ever more precise, research into specific disease processes progressively focuses on unique microscopic and molecular features that might lend themselves as therapeutic target.  Interestingly the mechanisms behind the molecules at work in the study at hand rely on basic cancer biology principles, namely that of tumor acidity and disease microenvironment.  

In the present study our group showed the utility of intravesical instillation of the ICG pHLIP® (ICG is a FDA approved near infrared fluorescent dye and pHLIP® is a pH (Low) Insertion Peptide, which targets tumor acidity) construct for bladder tumor identification and staging.  The molecule was also able to identify dysplastic tissue which may represent a premalignant lesion.  If premalignant lesions could be identified in a reliable and actionable fashion this might offer the opportunity of preventing disease progression and subsequent patient morbidity.  Furthermore, in an era of rising healthcare costs for both patients and institutions, early detection and prevention may represent significant savings in treatment and follow up surveillance costs.   

There are many potential novel applications for this molecule moving forward.  As described in the manuscript, our utilization of ICG as the molecule bound to pHLIP® is in many ways a proof of principle.  Having demonstrated the preferential avidity of pHLIP for bladder cancer cells over normal tissue, it is our intent to utilize the pHLIP® molecule to deliver alternative agents such as chemotherapeutics in future experiments.  Additionally, our collaborators have demonstrated the feasibility of using pHLIP® in PET imaging for accurate tumor identification and characterization1. While the current study was performed on ex-vivo specimens, preliminary data on toxicity of the molecule are encouraging and a natural next step will be immediate preoperative intravesical instillation for patients undergoing transurethral bladder tumor resections to aid in tumor identification and perhaps even allow for real time tumor staging.

As a pilot study, our publication requires further validation and investigation in a larger population of patients.  Further efforts will focus on the prospects for intravenous administration of this or similar constructs for targeted fluorescence, contrast or drug delivery. Current foci for investigation at our institution include IRB approved projects applying the ICG pHLIP® construct to upper tract urothelial and renal cell neoplasms for tumor identification and staging purposes.  Preliminary results are encouraging as we optimize specimen preparation regimens.

With the dubious honor of having the highest per capita incidence of bladder cancer in the nation, Rhode Island represents a unique patient population.  We thank the patients who participated in this study and those who will assist in studies to come.  With the application of this and other burgeoning technologies, we hope to improve the quality of care delivered to bladder cancer patients both locally and abroad.  

Written by: Joseph M Brito, Yana K Reshetnyak, and Dragan Golijanin

1. Demoin et al. PET Imaging of Extracellular pH in Tumors with (64)Cu- and (18)F-Labeled pHLIP Peptides: A Structure-Activity Optimization Study  Bioconjug Chem. 2016, 27(9), 2014-2023.