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Prediction of optimal contrast times post-imaging agent administration to inform personalized fluorescence-guided surgery.

ABSTRACT: Fluorescence guidance in cancer surgery (FGS) using molecular-targeted contrast agents is accelerating, yet the influence of individual patients' physiology on the optimal time to perform surgery post-agent-injection is not fully understood. Develop a mathematical framework and analytical expressions to estimate patient-specific time-to-maximum contrast after imaging agent administration for single- and paired-agent (coadministration of targeted and control agents) protocols. The framework was validated in mouse subcutaneous xenograft studies for three classes of imaging agents: peptide, antibody mimetic, and antibody. Analytical expressions estimating time-to-maximum-tumor-discrimination potential were evaluated over a range of parameters using the validated framework for human cancer parameters. Correlations were observed between simulations and matched experiments and metrics of tumor discrimination potential (p < 0.05). Based on human cancer physiology, times-to-maximum contrast for peptide and antibody mimetic agents were <200 min, >15 h for antibodies, on average. The analytical estimates of time-to-maximum tumor discrimination performance exhibited errors of <10 % on average, whereas patient-to-patient variance is expected to be greater than 100%. We demonstrated that analytical estimates of time-to-maximum contrast in FGS carried out patient-to-patient can outperform the population average time-to-maximum contrast used currently in clinical trials. Such estimates can be made with preoperative DCE-MRI (or similar) and knowledge of the targeted agent's binding affinity.

SUBMITTER: Sadeghipour N

PROVIDER: S-EPMC7667427 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Prediction of optimal contrast times post-imaging agent administration to inform personalized fluorescence-guided surgery.

Sadeghipour Negar N Rangnekar Aakanksha A Folaron Margaret M Strawbridge Rendall R Samkoe Kimberley K Davis Scott S Tichauer Kenneth K

Journal of biomedical optics 20201101 11

<h4>Significance</h4>Fluorescence guidance in cancer surgery (FGS) using molecular-targeted contrast agents is accelerating, yet the influence of individual patients' physiology on the optimal time to perform surgery post-agent-injection is not fully understood.<h4>Aim</h4>Develop a mathematical framework and analytical expressions to estimate patient-specific time-to-maximum contrast after imaging agent administration for single- and paired-agent (coadministration of targeted and control agents ...[more]

PMID: 33200596

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Project description:PurposeNon-specific uptake and retention of molecular targeted agents and heterogeneous tissue optical properties diminish the ability to differentiate between tumor and normal tissues using molecular targeted fluorescent agents. Paired-agent imaging (PAI) can increase the diagnostic ability to detect tumor tissue by mitigating these non-specific effects and providing true molecular contrast by co-administration of an untargeted control imaging agent with a targeted agent. This study evaluates the suitability of available clinically translatable untargeted agents for the translation of PAI in fluorescence-guided surgery using an affibody-based targeted imaging agent (ABY-029).ExperimentalDESIGN: Three untargeted agents that fluoresce near 700 nm and exhibit good clinical safety profiles (methylene blue, IRDye 700DX, and IRDye 680LT) were tested in combination with the clinically tested IRDye 800CW-labeled anti-epidermal growth factor receptor (EGFR) affibody molecule, ABY-029 (eIND 122,681). Properties of the untargeted agent important for human use and integrity of PAI were tested: (1) plasma protein binding; (2) fluorescence signal linearity in in vitro whole blood dilution; (3) in vivo pharmacokinetic matching to targeted agent in negative control tissue; and (4) in vivo diagnostic accuracy of PAI vs single agent imaging (SAI) of ABY-029 alone in orthotopic oral head and neck squamous cell carcinomas.ResultsIRDye 680LT outperformed IRDye 700DX and methylene blue with the highest signal linearity (R2 = 0.9998 ± 0.0002, 0.9995 ± 0.0004, 0.91 ± 0.02, respectively), the highest fluorescence yield in whole blood at 1 μM (104.42 ± 0.05, 103.68 ± 0.09, 101.9 ± 0.2, respectively), and the most closely matched ABY-029 pharmacokinetics in EGFR-negative tissues (binding potential error percentage = 0.31% ± 0.37%, 10.25% ± 1.30%, and 8.10% ± 5.37%, respectively). The diagnostic ability of PAI with ABY-029 and IRDye 680LT outperformed conventional SAI with an area-under-the-receiver-operating-characteristic curve (AUC) value of 0.964 vs. 0.854, and 0.978 vs. 0.925 in the Odyssey scanning system and Pearl wide field imaging system, respectively.ConclusionPAI is a highly promising methodology for increasing detection of tumors in fluorescence-guided surgery. Although not yet clinically approved, IRDye 680LT demonstrates promise as an untargeted agent when paired with ABY-029. The clinical translation of PAI to maximize tumor excision, while minimizing normal tissue removal, could improve both patient survival and life quality.

Dataset Information

Prediction of optimal contrast times post-imaging agent administration to inform personalized fluorescence-guided surgery.

Publications

Prediction of optimal contrast times post-imaging agent administration to inform personalized fluorescence-guided surgery.

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