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AssigneesMemorial Sloan Kettering Cancer Center, Cornell University
InventorsMichelle S. Bradbury, Steven Saeid Zanganeh, Brian Madajewski, Luis Felipe Campesato, Taha Marghoub, Michael Overholtzer, Michael R. McDevitt, Ulrich Wiesner
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Described herein are methods of treating cancer by inducing favorable effects on tumor microenvironment (e.g., including macrophage polarization, cytokine profile, and/or immunophenotype) via administration of nanoparticles (e.g., silica-based ultra-small nanoparticles and nanoparticle conjugates such as nanoparticle drug conjugates). In certain embodiments, the methods may be used in concert with, or as part of, checkpoint inhibition therapy (e.g., anti-PD1) or radiotherapy, or a combination of both radiotherapy and checkpoint inhibitor therapy.
A method of treatment of a subject (e.g., a subject having been diagnosed with cancer), the method comprising administering a composition comprising ultrasmall (e.g., no greater than 20 nm in diameter, e.g., no greater than 10 nm in diameter) nanoparticles (e.g., a silica-containing, e.g., silica-based nanoparticle) to activate a tumor microenvironment (e.g., macrophages, T cells, and/or antigen-presenting cells (APCs, such as dendritic cells)).
The method of any one of the preceding claims, wherein the nanoparticle comprises a radiolabel (e.g., 225Actinium).
The method of any one of the preceding claims, wherein the nanoparticle comprises 1 to 25 targeting ligands (e.g., 2 to 20 ligands, 5 to 15 ligands, 5 to 10 ligands, or about 6-8 ligands).
The method of any one of the preceding claims, wherein the nanoparticle comprises a heterogeneous surface characterized by one or more of (i) to (iv) as follows:
The method of any one of the preceding claims, wherein the nanoparticle has a hydrodynamic diameter no greater than 10 nm (e.g., wherein the hydrodynamic diameter is in a range from 1 nm to 10 nm).
The method of any one of the preceding claims, wherein the nanoparticle comprises a silica core.
The method of any one of the preceding claims, wherein the nanoparticle comprises a polyethylene glycol (PEG) shell.
The method of any one of the preceding claims, wherein the nanoparticles have a silica composition such that ferroptosis is not induced (e.g., ferroptosis is switched “off”).
The method of any one of the preceding claims, wherein the nanoparticles have a silica composition such that ferroptosis may be induced (e.g., ferroptosis is not switched “off”).
The method of any one of the preceding claims, wherein the nanoparticle comprises a chelator.
The method of any one of the preceding claims, wherein the nanoparticle is non-toxic to normal tissue.
The method of any one of the preceding claims, wherein the nanoparticles are internalized (e.g., phagocytosed) within one or more cell types (e.g., macrophages, tumor cells, THP-1 cells) of the microenvironment.
The method of any one of the preceding claims, wherein the tumor is a cancer.
The method of any one of the preceding claims, wherein local concentration of nanoparticles within the microenvironment of the tumor is in a range from about 0.013 nmol/cm3 to about 86 nmol/cm3 or from about 0.013 nmol/cm3 to about 0.14 nmol/cm3 or from about 8 nmol/cm3 to about 86 nmol/cm3 (e.g., wherein an administered dose (e.g., by IV) has particle concentration from about 100 nM to about 60 μM, or wherein an administered dose has particle concentration less than 150 nM (e.g., less than 100 nM, e.g., less than 50 nM, less than 10 nM, less than 5 nM).
The method of any one of the preceding claims, wherein the activation of the microenvironment of the tumor comprises a change (e.g., an increase) in at least one M1 macrophage polarization marker.
The method of any one of the preceding claims, wherein the activation of the microenvironment of the tumor comprises a change (e.g., a decrease) in at least one M2 macrophage polarization marker.
The method of any one of the preceding claims, wherein the activation of the tumor microenvironment causes a change (e.g., an increase) in one or more cytokines and/or cytolytic proteins.
The method of any one of the preceding claims, wherein the composition is administered in multiple doses (e.g., at fixed intervals, e.g., every 1, 2, 3, 5, or 10 days).
The method of any one of the preceding claims, wherein the method comprises administering a macromolecule (e.g., a protein).
The method of any one of the preceding claims, wherein the method comprises activating the tumor microenvironment in the absence of ferroptosis.
The method of any one of the preceding claims, wherein the method comprises administering one or more regulators of ferroptosis.
A composition for use in the method of any one of the preceding claims, the composition comprising ultrasmall nanoparticles having the following attributes:
A composition (e.g., a pharmaceutical composition) for use in a medicament, the composition comprising ultrasmall nanoparticles having the following attributes:
A treatment comprising a therapeutically effective amount of a composition (e.g., wherein the composition comprises a tumor microenvironment activating nanoparticle with a ligand for targeting MC1-R) for use in a method of treating cancer in a subject.
A method of treating cancer in a subject, the method comprising:
Dependencies are inferred from the claim text.