Method of treatment for solid tumors containing hypoxia and/or stroma features
Inventors
Sau, Samaresh • Iyer, Arun K. • Alsaab, Hashem
Assignees
Publication Number
US-12083187-B2
Publication Date
2024-09-10
Expiration Date
2038-12-28
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Abstract
Advancements in solid tumor (e.g., renal cell carcinoma) treatments and imaging are described. The advancements are based on nanoformulations that: (i) overcome deliverability issues associated with anti-cancer compounds; (ii) have increased targeted delivery to tumors, and hypoxic cores of tumors due to the presence of targeting ligands; (iii) have increased delivery to the hypoxic cores of tumors due to engineered shapes; (iv) provide synergistic treatment combinations; and/or (v) overcome cancer cell resistance to therapeutic treatments.
Core Innovation
The invention presents a rod-shaped encapsulated nanoparticle, oligomicelle, or nanomicelle that comprises a CARP-1 functional mimetic (CFM-4.16), a carbonic anhydrase-IX (CAIX) targeting ligand, a folate receptor targeting ligand, and one or more selected polymers, such as DBCO-conjugated vitamin E TPSG, SMA-TPGS, HP-β-CD, SBE-β-CD, PC, ceramide, poloxamer 407, and PLA-PEG. The formulations can include a nanoformulation encapsulated with chemotherapeutic agents and can be administered as a pharmaceutical composition for the treatment of solid tumors exhibiting hypoxia and/or stromal components.
The technical problem addressed is the limited effectiveness of current therapies for solid tumors, especially renal cell carcinoma (RCC), due to drug resistance, poor deliverability of anti-cancer compounds, suboptimal tumor targeting, and insufficient penetration into hypoxic tumor cores. Existing therapies often fail to overcome resistance mechanisms, resulting in inadequate treatment options for patients with refractory or metastatic disease.
The innovation described overcomes these limitations by providing nanoformulations that offer increased targeted delivery to tumors, especially hypoxic cores, using surface targeting ligands for tumor specificity and engineered shapes for enhanced penetration. The inclusion of CARP-1 functional mimetic CFM-4.16 enables efficient induction of tumor cell apoptosis and works synergistically with other therapeutic agents such as kinase inhibitors. The formulations can be used for both therapeutic and diagnostic purposes, including imaging-guided surgery and early detection, due to the ability to couple imaging agents to the nanoparticle platform.
Claims Coverage
The claims contain several inventive features centered on targeted nanoformulations utilizing specific ligands and polymers for treating solid tumors, especially those exhibiting hypoxia and stroma features.
Rod-shaped encapsulated nanoparticle with dual targeting ligands and defined polymers
A rod-shaped encapsulated nanoparticle, oligomicelle, or nanomicelle comprising: - CARP-1 functional mimetic (CFM-4.16) - A carbonic anhydrase-IX (CAIX) targeting ligand - A folate receptor targeting ligand - One or more polymers selected from the group consisting of DBCO-conjugated vitamin E TPSG, SMA-TPGS, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD), phosphatidylethanolamine (PC), ceramide, poloxamer 407, and PLA-PEG.
Composition with specified nanoparticle for pharmaceutical use
A pharmaceutical composition comprising the encapsulated nanoparticle, oligomicelle, or nanomicelle as described, for use in treating solid tumors.
Method of treating solid tumors using targeted nanoformulation
A method comprising administering the pharmaceutical composition containing the rod-shaped encapsulated nanoparticle, oligomicelle, or nanomicelle to a subject having a solid tumor.
Imaging composition containing targeted nanoformulation
An imaging composition comprising the encapsulated nanoparticle, oligomicelle, or nanomicelle containing the dual targeting ligands and selected polymers.
Method for visualizing a solid tumor using the imaging composition
A method comprising visualizing a solid tumor in a subject using the imaging composition containing the encapsulated nanoparticle, oligomicelle, or nanomicelle.
Method of treating a subject with hypoxic and/or stromal solid tumor using nanoparticle
A method of treating a subject with a solid tumor exhibiting hypoxia and/or stromal components, comprising administering the encapsulated nanoparticle, oligomicelle, or nanomicelle with the specified features.
In summary, the inventive features cover rod-shaped, ligand-targeted nanoparticles with defined compositions for dual targeting (CAIX and folate receptor), their pharmaceutical and imaging uses, and methods for treating and visualizing solid tumors exhibiting hypoxia and/or stromal characteristics.
Stated Advantages
Overcomes deliverability issues associated with anti-cancer compounds by enabling efficient encapsulation and intravenous administration.
Provides increased targeted delivery to tumors and hypoxic tumor cores due to the presence of targeting ligands for specific tumor surface proteins.
Enhances delivery to hypoxic cores of tumors through engineered non-spherical or rod-shaped nanoparticles.
Allows synergistic treatment combinations to improve cancer therapy outcomes.
Overcomes cancer cell resistance to therapeutic treatments, including drug resistance encountered in solid tumors such as RCC.
Enables imaging for early diagnosis, care management, and imaging-guided surgery due to the coupling of imaging agents to the nanoformulation.
Demonstrates high bioavailability, stability, and sustained release properties, improving the efficiency of therapeutic payload delivery.
Reduces non-specific organ uptake and enhances tumor specificity by utilizing dual-targeting ligands and antifouling linkers.
Documented Applications
Treatment of solid tumors exhibiting hypoxia and/or stromal components, including renal cell carcinoma, using the described nanoformulations.
Administration for both prophylactic and therapeutic treatment of solid tumors to overcome drug resistance.
Use of the nanoformulation as a pharmaceutical composition for intravenous administration in animal models and humans.
Imaging of solid tumors (such as RCC) for visualization, early diagnosis, and imaging-guided surgery using nanoformulations conjugated with imaging dyes.
Use in a wide variety of cancer types, including carcinoma, sarcoma, lymphoma, melanoma, mesothelioma, adenocarcinoma, and many other solid tumors as explicitly listed.
Delivery of chemotherapeutic agents, such as kinase inhibitors, in encapsulated nanoparticles for enhanced tumor targeting and efficacy.
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