Engineering NIR Probes to Enhance Affinity and Clinical Workflow Compatibility for Prostate Cancer Imaging
Abstract
Abstract Positive surgical margins following radical prostatectomy increase the risk of biochemical recurrence and subsequent disease progression. Fluorescence‐guided surgery (FGS) using targeted contrast agents has shown clinical benefits for several cancer types. However, current prostate cancer targeted imaging probes exhibit long pharmacokinetic (PK) profiles, necessitating extended waiting periods or repeated hospital visits, limiting their integration into standard clinical workflow. To overcome this critical clinical compatibility challenge, we developed an innovative tri‐compartment, chemistry‐driven probe design strategy. Specifically, we developed a congeneric library of near infrared (NIR) water soluble fluorescent probes incorporating: 1) a glutamic acid‐urea‐lysine (EuK) ligand targeting prostate specific membrane antigen (PSMA); 2) a NIR heptamethine cyanine fluorophore optimized for enhanced PSMA binding via secondary binding site interactions; and 3) distinct PK modulators residing outside the PSMA binding pocket to promote rapid off‐target tissue clearance. While molecular docking scores, photophysical properties and live‐cell staining results showed similar overall performance, probes bearing PK modulators produced stronger tumor‐specific fluorescence and accumulation in vivo than the control probe lacking a PK modulator. This effort enabled identification of a lead probe with robust tumor targeting and accelerated off‐target clearance, providing optimal tumor‐specific signal and contrast in a timeframe, fully compatible with robotic‐assisted radical prostatectomy (RARP) timelines.
Article Details
Authors (17)
Gauri S. Malankar
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Dani A. Szafran
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Gourav Kumar
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Joshua Pace
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Mackenzie Devereux
Cancer Early Detection Advanced Research Center Oregon Health & Science University Portland Oregon 97201 USA
Kai Tao
Michelle Gomes
Cancer Early Detection Advanced Research Center Oregon Health & Science University Portland Oregon 97201 USA
William S. Greer
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Cody C. Rounds
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Anas M. Masillati
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Seseel Gergis
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Hayden Ledvina
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Kyle J. Milnes
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Melissa H. Wong
Mark J. Niedre
Department of Bioengineering Northeastern University Boston Massachusetts 02115 USA
Summer L. Gibbs
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA
Lei G. Wang
Department Biomedical Engineering Oregon Health & Science University Portland Oregon 97201 USA