Synthesis and composition of photodynamic therapeutic agents for the targeted treatment of cancer
Inventors
Kularatne, Sumith A. • Gagare, Pravin • Myers, Carrie H.
Assignees
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Publication Number
US-10676487-B2
Publication Date
2020-06-09
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 provides folate-targeted organelle-specific photodynamic therapeutic agents for treating FR-positive cancers and related diseased cells. The compounds include a pteroyl/folate ligand linked to an amino-acid-based pharmacokinetic linker, and the linker is used to improve pharmacokinetic properties. The architecture is configured to deliver an organelle-targeted PDT agent to specific intracellular organelles in diseased cells, including the nucleus or mitochondria.
The organelle targeting is implemented by an organelle-targeting agent X, and the PDT payload Y is an organelle-targeted photodynamic therapeutic agent selected from photodynamic drug conjugates and bacteriopheophorbide-a (BPheid-a) and analogues. The PDT payload may be released inside diseased cells by a linker configured to release the organelle-targeted PDT agent, including a releasable linker such as a disulfide. The compounds and related constructs are described as having high water solubility and improved pharmacokinetic properties relative to non-targeted PDT approaches.
The photodynamic therapeutic payload is characterized in terms of optical performance and reactive oxygen species generation. The compounds are described as having strong fluorescence for image-guided surgery and near-infrared fluorescence imaging, and as exhibiting high PDT efficacy with reduced off-target effects. The photodynamic action is described through singlet oxygen and/or reactive oxygen species generation that induces tumor and cell damage.
Claims Coverage
The claim coverage centers on a compound formula directed to an organelle-targeted, release-capable PDT conjugate, and a method of photodynamic therapy for biological tissue expressing a folate receptor. The inventive features include an amino-acid-based PK linker, an optional release linker, an organelle-targeting agent, and a specified photodynamic therapeutic agent, with dependent refinements adding optical constraints and organelle targeting to mitochondria.
Amino-acid-based pharmacokinetic linker configured to improve pharmacokinetic properties
L is an amino acid and L is a linker to improve pharmacokinetic properties.
Release linker for organelle-targeted PDT payload
L// is a linker configured to release an organelle-targeted photodynamic therapeutic agent.
Organelle-targeting agent for organelle delivery
X is an organelle-targeting agent.
Photodynamic therapeutic agent selected from a specified group
Y is a photodynamic therapeutic agent selected from the specified group.
Molar extinction coefficient constraint on the PDT agent
The compound has εmax of about 50,000 to about 100,000 M−1 cm−1.
Absorption and emission maxima range for the PDT agent
Y has absorption and emission maxima of about 680 nm to about 800 nm.
Mitochondria targeting of the PDT agent
The organelle-targeting agent targets the PDT agent to the mitochondria of the diseased cell.
Amino acid linker selected by charge class and backbone type
The amino acid or amino acid derivative is selected from an alpha amino acid, a homo amino acid, a beta amino acid, a positively charged amino acid, a negatively charged amino acid, and derivatives thereof.
Folate receptor-expressing tissue photodynamic therapy causing cell death and necrosis
A method of photodynamic therapy for biological tissue expressing a folate receptor by contacting with a composition, allowing distribution and clearance, and illuminating with excitation light absorbable by the compound to generate ROS that induce cell death and necrosis and destroy the tissue.
Coverage centers on a compound formula with an amino-acid PK linker and an optional release linker for an organelle-targeted PDT payload. The claims further define the organelle-targeting agent, the specified PDT agent, optical constraints for Y, mitochondria targeting, and a folate receptor-expressing tissue photodynamic therapy method that generates ROS causing cell death, necrosis, and tissue destruction.
Stated Advantages
Improved pharmacokinetic properties relative to non-targeted PDT approaches.
High water solubility.
Strong fluorescence suitable for image-guided surgery and near-infrared fluorescence imaging.
High PDT efficacy.
Reduced off-target effects.
Photodynamic action generating reactive oxygen species and singlet oxygen to induce cell death and necrosis.
Low dark toxicity.
Tumor-to-background signal.
Improved potency of modified mitochondrial-targeted and nucleus-targeted PDT agents compared to non-targeted BPheid-a.
Documented Applications
Photodynamic therapy of biological tissue expressing a folate receptor using the claimed compound or composition, with ROS generation leading to cell death, necrosis, and destruction of the tissue.
Image-guided surgery and near-infrared fluorescence imaging using strong fluorescence from the compounds.
In vitro cell studies and imaging using KB/HeLa and related cell contexts, including laser studies and fluorescence imaging.
In vivo tumor-related contexts described as exhibiting tumor growth cures in representative studies.
In vivo fluorescence imaging (IVIS) and therapeutic studies in KB tumor-bearing mice using fluorescence overlays and time-course imaging together with laser-treated tumor growth cure/no recurrence.
Cell viability/survival experiments for folate-drug conjugate dosing followed by laser exposure.
Tissue-focused therapeutic and diagnostic application contexts for PDT agents directed to tissues expressing the folate receptor, including imaging-guided surgery concepts.
Representative tumor-type evaluation using in vitro and in vivo PDT evaluation in KB cells and tumor xenografts.
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