Synthesis and composition of photodynamic therapeutic agents for the targeted treatment of cancer
Inventors
Kularatne, Sumith A. • Gagare, Pravin
Assignees
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Publication Number
US-12144874-B2
Publication Date
2024-11-19
Expiration Date
Abstract
The present invention describes new compounds that are useful for image-guided surgery and photodynamic therapy. In particular the compounds may be targeted to the nucleus or the mitochondria after compounds were delivered to diseased tissues such as cancer using a ligand that target receptor that express on the diseased tissue and followed by receptor mediated endocytosis and provide effective activity against cancer cells as well as other disorders. Methods and compositions for use of the same are described.
Core Innovation
The invention relates to interventional procedures that contract biological tissue using a compound having amino acid L, linker L/ to improve pharmacokinetic properties, linker L// configured to release an organelle-targeted photodynamic therapeutic (PDT) agent, organelle-targeting agent X, and photodynamic therapeutic agent Y. The composition is configured so that, upon administration and distribution within biological tissue, illumination with excitation light absorbable by the compound produces reactive oxygen species (ROSs).
The method allows time for the compound to distribute within the biological tissue, guides a flexible probe to the biological tissue, and illuminates the tissue with excitation light of a wavelength absorbable by the compound. The composition produces ROSs thereby inducing cell death and necrosis of diseased cells and destroying the biological tissue. The organelle-targeted PDT framework includes nucleus-targeted PDT production by organelle/DNA-binding modifications of BPheid-a and folate-receptor-targeted organelle-targeted PDT using flexible probes/endoscopes and image-guided interventional procedures.
The specification includes modified BPheid-a PDT agents and related organelle-targeted variants, with chemical structures and synthetic schemes for compounds derived from BPheid-a/BPheid-derived compounds. The described rationale connects organelle targeting, especially nucleus-targeted variants, with improved delivery characteristics compared with prior clinical PDT agents having poor water solubility, poor targeting, poor fluorescence, and poor elimination.
Claims Coverage
The claims coverage identifies two independent claims. The inventive features center on a compound with amino acid L, pharmacokinetic-improving linker L/, releasable linker L//, organelle-targeting agent X, and photodynamic therapeutic agent Y, together with an interventional procedure using tissue distribution, flexible probe guidance, and excitation-light activation to generate ROS and destroy diseased tissue.
Organelle-targeted PDT compound with amino acid L and linkers
A compound having amino acid L, where L/ is a linker to improve pharmacokinetic properties and L// is a linker configured to release an organelle-targeted photodynamic therapeutic (PDT) agent.
Organelle-targeting agent X and photodynamic therapeutic agent Y
X is an organelle-targeting agent and Y is a photodynamic therapeutic agent selected from the group consisting of the photodynamic therapeutic agents, with excitation light absorbable by the compound producing reactive oxygen species (ROSs) thereby inducing cell death and necrosis of diseased cells and destroying the biological tissue.
Interventional procedure using distribution, flexible probe guidance, and illumination
Allowing time for the compound to distribute within the biological tissue; guiding a flexible probe to the biological tissue; and illuminating the tissue with an excitation light of a wavelength absorbable by the compound.
Administering the compound for interventional procedure
Administering, to a human or animal subject, the compound having the formula with amino acid L, linkers for pharmacokinetic properties and possible release of an organelle-targeted PDT agent, organelle-targeting agent X, and photodynamic therapeutic agent Y, followed by distribution, flexible probe guidance, and excitation-light activation.
Organelle targeting within diseased cells
X targets an organelle within a diseased cell and optionally targets the PDT agent to the mitochondria or the nucleus of the diseased cell.
The claims cover use of an organelle-targeted PDT composition defined by amino acid L, linkers for pharmacokinetic improvement and release, organelle-targeting agent X, and photodynamic therapeutic agent Y, in an interventional procedure that relies on distribution, flexible-probe guidance, and excitation-light illumination to produce ROS and induce cell death and necrosis.
Stated Advantages
Improved pharmacokinetic properties via a linker configured to improve pharmacokinetic properties.
Organelle-targeted photodynamic therapeutic (PDT) agent released from a linker and directed by an organelle-targeting agent.
Addresses prior clinical PDT agents having poor water solubility, poor targeting, poor fluorescence, and poor elimination.
Improved activity from organelle targeting, especially nucleus-targeted variants.
Inducing cell death and necrosis of diseased cells and destroying the biological tissue through ROS production.
Allowing time for the compound to distribute within the biological tissue prior to illumination.
Documented Applications
Interventional procedures on contracting biological tissue of a human or animal subject using an organelle-targeted PDT approach with flexible probe guidance and excitation light.
Organelle targeting for treating diseased cells by targeting an organelle within a diseased cell, including optional targeting to the mitochondria or the nucleus.
Folate-receptor-targeted organelle-targeted PDT in image-guided interventional procedures using flexible probes/endoscopes, including nucleus-targeted PDT.
Preclinical evaluation including KB cell EC50/IC50 comparison of targeted versus non-targeted agents and xenograft imaging and laser PDT regimens.
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