Scission-enhanced nuclear imaging and treatment
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Solution Overview
Problem
Current nuclear imaging and radiotherapeutic methods face challenges with long-circulating radionuclide-labeled affinity ligands, leading to radiotoxicity, limited imaging frequency, and suboptimal target-to-background ratios due to the need for renal protection programs and complex pre-targeting strategies.
Innovation Solution
Development of bioorthogonal conjugates with releasable trans-cyclooctene linkers that allow for precise, rapid cleavage and elimination of radionuclides using a tetrazine antidote, enabling reduced radiotoxicity and enhanced imaging capabilities through multiplexed nuclear imaging and improved target-to-background ratios.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If radionuclide-labeled affinity ligands are used for nuclear imaging and therapy, then diagnostic and therapeutic capabilities are achieved, but radiotoxicity increases and imaging frequency is limited
Solution Approach 1:
The conjugate is divided into separable components: the affinity ligand remains bound to the target while the radionuclide can be released and eliminated. This segmentation allows the diagnostic/therapeutic function to be performed while the harmful radionuclide is removed, resolving the contradiction between maintaining capability and reducing radiotoxicity
Solution Approach 2:
The radionuclide is deliberately discarded from the conjugate after serving its diagnostic or therapeutic purpose. The tetrazine antidote triggers release of the radionuclide, which is then eliminated from the body, allowing repeated imaging without cumulative radiotoxicity while preserving the affinity ligand for future use
2Reliability
If long-circulating radionuclide-labeled affinity ligands are used, then target binding capability is maintained, but target-to-background ratio deteriorates
Solution Approach 1:
The system transitions from a static conjugate to a dynamic system where the radionuclide can be released on demand. The circulatory form maintains target binding, while the released form is rapidly eliminated, creating dynamic control over background signal and improving target-to-background ratio
Solution Approach 2:
The system enables periodic imaging by releasing radionuclides between scans. The affinity ligand circulates and binds to targets, then radionuclides are periodically released and eliminated, allowing repeated imaging cycles with improved contrast between target and background
3Object-affected harmful factors
If pre-targeting strategies are used to reduce radiotoxicity, then radiation exposure is reduced, but system complexity increases
Solution Approach 1:
The system merges the affinity ligand and radionuclide into a single conjugate that can be administered as one agent, eliminating the need for separate pre-targeting steps. The built-in release mechanism using tetrazine antidote provides the same radiotoxicity reduction as pre-targeting but with simpler administration
Solution Approach 2:
The conjugate contains its own release mechanism through the labile linker that responds to tetrazine. The system self-regulates radionuclide release without requiring complex external control systems or multiple administration steps, reducing overall system complexity while maintaining radiotoxicity reduction
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The solution achieves instantaneous and complete radionuclide cleavage (>99%), reducing radiotoxicity, allowing for more frequent imaging and improved diagnostic accuracy by rapidly eliminating radionuclides, thereby enhancing therapeutic efficacy and imaging quality.
Implementation Method 1
the tetrazine ('Tz') antidote engages in inverse electron demand Diels-Alder ('IEDDA') reaction with the TCO fragment within the linker, which cleaves the radionuclide-chelator complex from the affinity ligand
Data Source
AI summary
The present disclosure provides compounds and methods for “scission-enhanced” nuclear imaging and treatment (“SENIT”). In one example, the disclosure provides a conjugate where an affinity ligand (e.g., an antibody) is connected to a radionuclide (e.g., a DOTA-chelated 68Ga) using a “click-to-release” bioorthogonal linker (e.g., a linker containing a releasable trans-cyclooctene moiety in its structure). As described herein, the imaging and theranostic methods of this disclosure advantageously allow for rapid corporeal elimination of radionuclides once imaging or theranostic treatment is completed.