WO2017189849A1 - Compositions de nanoparticules comprenant des antagonistes du récepteur de l'adénosine et méthodes d'utilisation - Google Patents

Compositions de nanoparticules comprenant des antagonistes du récepteur de l'adénosine et méthodes d'utilisation Download PDF

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WO2017189849A1
WO2017189849A1 PCT/US2017/029841 US2017029841W WO2017189849A1 WO 2017189849 A1 WO2017189849 A1 WO 2017189849A1 US 2017029841 W US2017029841 W US 2017029841W WO 2017189849 A1 WO2017189849 A1 WO 2017189849A1
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nanoparticle composition
nanoparticle
tgf
administering
inhibitor
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Steven F. Josephs
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Immunicom, Inc.
Therinject, Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin

Definitions

  • Nanoparticle Compositions Comprising Adenosine Receptor Antagonists and Methods of Use
  • the present disclosure relates to nanoparticulate compositions and their use in inhibiting immunosuppressive pathways.
  • the present disclosure relates to nanoparticulate compositions comprising adenosine pathway inhibitors in combination with inhibitors of the TGF signaling pathway and their use in ameliorating tumor-mediated immunosuppressive activity.
  • Tumor growth has been indicated to be dependent on immunosuppression activity within the tumor microenvironment including two major immunosuppressive pathways: 1) the purinergic pathway involving adenosine signaling particularly through the A2A and A2B receptors and 2) TGF signaling.
  • Tumors typically have high levels of both adenosine and TGF , both of which suppress multiple immune cell types that are part of the anti-tumor immune responses.
  • Adenosine is a natural response signal that keeps potential runaway inflammatory responses in check.
  • TGFP is a multifunctional cytokine that acts to suppress inflammation and undue cell proliferation.
  • TGFP has been indicated to be involved in tissue differentiation, development, hematopoiesis, and tissue remodeling and repair.
  • TGF-pi is a central component of wound healing, stimulates matrix molecule deposition and angiogenesis, and has been indicated as a mediator of pathologic scarring in fibrotic disorders.
  • TGFP plays also significant role in cancers. Massague J. Cell. 134(2):215-30 (2008).
  • Figures 1 shows a depiction of an adenosine signaling pathway.
  • Figure 2A shows a graph of tumor volume versus days post injection in injected tumors with a blank (PBS), a nanoparticle with no drug (NP), and nanoparticle with adenosine antagonist SCH58621 (NP-SCH).
  • Figure 2B shows a graph of tumor volume versus days post injection in non- injected tumors on the contralateral side of the injected tumor side shown in Figure 2 A.
  • Figure 3 shows a graph of particle concentration versus particle size for an exemplary nanoparticle composition.
  • Figure 4 shows a graph of counts versus zeta potential for an exemplary nanoparticle composition.
  • Figure 5A shows a graph overlay of absorption versus wavelength of an A2A antagonist (SCH58261) and a TGF inhibitor (SB431542).
  • Figure 5B shows a graph of absorption versus wavelength plot for a nanoparticle composition comprising a selective A2A antagonist (SCH58261) and a selective TGF inhibitor (SB431542).
  • SCH58261 selective A2A antagonist
  • SB431542 selective TGF inhibitor
  • Figure 6A shows an HPLC trace of SB431542.
  • Figure 6B shows an HPLC trace of SCH58261.
  • Figure 7 shows an HPLC trace of an extract from nanoparticles embedded with both SCH58261 (peak retention time of 15.884 minutes) and SB431542 (peak retention time of 9.288 minutes).
  • Figure 8 A shows a graph of tumor volume versus days post tumor graft in treated (injected) tumors with blank nanoparticles not containing drug ( ⁇ -blank), nanoparticles containing SB431542, a TGF inhibitor (TI-07B), nanoparticles containing SCH58261, an adenosine A2A receptor antagonist, (TI-07H) and, nanoparticles containing both SB431542 and SCH58261, i.e., the combination of a TGF-beta inhibitor and an A2A receptor antagonist, (TI-07).
  • TI-07B TGF inhibitor
  • SCH58261 an adenosine A2A receptor antagonist
  • Figure 8B shows a graph of tumor volume versus days post tumor graft in untreated tumors on the contralateral side of the injected tumor side shown in Figure 8A.
  • Figure 9 shows a bar graph of tumor volumes for injected and uninjected tumors at Day 18 following tumor cell engraftment. Summary
  • embodiments herein relate to nanoparticle compositions comprising an adenosine receptor antagonist, a TGF inhibitor a permeation enhancer, and a poly(lactic-co-glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • adenosine receptor antagonist e.g., a TGF inhibitor a permeation enhancer
  • PLGA poly(lactic-co-glycolic acid) copolymer
  • embodiments herein relate to methods of treating a disease or disorder characterized by immunosuppression comprising administering to a mammalian subject a nanoparticle composition comprising an adenosine receptor antagonist, a TGF inhibitor, a permeation enhancer, and a poly(lactic-co-glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • a nanoparticle composition comprising an adenosine receptor antagonist, a TGF inhibitor, a permeation enhancer, and a poly(lactic-co-glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • PLGA poly(lactic-co-glycolic acid)
  • embodiments herein relate to methods of treating cancer comprising administering to a mammalian subject a nanoparticle composition comprising an adenosine receptor antagonist, a TGF inhibitor, a permeation enhancer, and a poly(lactic-co- glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • a nanoparticle composition comprising an adenosine receptor antagonist, a TGF inhibitor, a permeation enhancer, and a poly(lactic-co- glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • PLGA poly(lactic-co- glycolic acid) copolymer
  • embodiments herein relate to methods of treating cancer or a disease or disorder characterized by immunosuppression comprising administering to a mammalian subject a first nanoparticle composition comprising an adenosine receptor antagonist and co- administering a second nanoparticle composition comprising a TGFP inhibitor, wherein the first and second nanoparticle compositions each comprise a permeation enhancer and a poly(lactic-co-glycolic acid) (PLGA) copolymer as a matrix.
  • PLGA poly(lactic-co-glycolic acid)
  • Embodiments herein provide nanoparticle compositions that may inhibit one or both of the adenosine and TGFP pathways implicated in immunosuppression. When delivered into tumors, these compositions may provide an approach to cancer treatment. Without being bound by theory, it is believed that blocking the activity of either the purinergic pathway involving adenosine signaling and/or TGF signaling using small molecule inhibitors inhibits the immunosuppressive signals of these pathways and results in the slowing of tumor growth through stimulation of anti-tumor immune responses.
  • the exemplary nanoparticles disclosed herein are tailored to enhance their uptake into myeloid derived cells including macrophages and dendritic cells that are inactivated in the presence of TGFP and adenosine.
  • the use of small molecule inhibitors in combination to block both adenosine and TGFP may have distinct advantages over each as monotherapies due to their synergistic activity.
  • the use of the compositions disclosed herein to counter immunosuppressive effects in tumors is expected to be particularly useful in combination with other anti-cancer therapies.
  • Figure 1 shows how adenosine has been indicated to interact with four G-coupled protein receptors Ai, A2A, A2B and A3.
  • the adenosine receptors (AiAR, A 2A R, A 2B AR and A 3 AR) are coupled to adenylate cyclase (AC) through G proteins (G x ).
  • the A 2 A and A 2 B ARS are coupled through Gs while Ai and A3 are coupled through Gi to either activate or inhibit the production of cyclic AMP (cAMP), respectively.
  • cAMP cyclic AMP
  • PKA Protein Kinase A
  • Epac guanine exchange protein
  • a 2 B and A3 are coupled to Phospholipase C (PLC) through Gq where activation results in the production of Diacylglycerol (DAG) which activates PKC and Inositol 1,4,5-trisphosphate (IP 3 ) which mobilizes calcium from intracellular stores.
  • DAG Diacylglycerol
  • IP 3 Inositol 1,4,5-trisphosphate
  • the A ⁇ R is coupled to the potassium (K + ) efflux through Go- Both PKA and Epac-1 have been found in macrophages, a specific target cell for the nanoparticle formulations discussed herein (Ballinger M. et al. PLoS One.
  • adenosine attenuates inflammatory responses.
  • Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage (e.g. in inflammatory or ischemic tissue), these concentrations are quickly elevated (600-1,200 nM).
  • the function of adenosine is primarily that of cytoprotection preventing tissue damage during instances of hypoxia, ischemia, and seizure activity.
  • Activation of A 2A receptors produces a constellation of responses that in general can be classified as antiinflammatory.
  • Adenosine activity contributes to immunosuppression in tumors through enhanced upregulation of Ecto Enzyme activity CD39 and CD73 which converts AMP to adenosine.
  • Table 1 lists multiple adenosine function that when translated to the tumor microenvironment are pro-tumorigenic. Table 1. Pro-tumor Effects of Adenosine Signaling
  • IFN- ⁇ IFN- ⁇ , RANTES, IL-12P 70 , IL-2, IL-2 receptor a chain (CD25), IL- ⁇
  • compositions herein comprise an adenosine receptor antagonist; in some instances the adenosine receptor is selected from the group of caffeine, theophylline, 8-phenyl theophylline, SCH58261, istradefylline, pyrazolo[4,3-e]-l ,2,4-triazolo[l,5-c] pyrimidines or substituted derivatives thereof (e.g., methoxy biaryl or quinoline
  • the adenosine receptor antagonist comprises an A2A-type antagonist and/or an A2B-type antagonist.
  • the A2A-type antagonist and/or an A2B-type antagonist is selected from the group consisting of [3,4- dihydropyrimidin-2(lH)-one chemotype e.g.
  • the adenosine receptor antagonist is an A2A-type antagonist
  • the A2A-type antagonist is selected from the group consisting of caffeine, theophylline, 8-phenyl theophylline, SCH58261, istradefylline, pyrazolo[4,3-e]- l ,2,4-triazolo[l,5-c ] pyrimidines orsubstituted derivatives thereof (e.g., methoxy biaryl or quinoline substitutions), SCH412348, SCH420814, fused heterocyclic pyrazolo[4,3-e]- l ,2,4-triazolo[l,5-c ] pyrimidines or substituted derivatives thereof (e.g., tetrahydyroisoquinoline or azaisoquinoline derivatives), aryl piperazine substituted 3H- [l,2,4]-triazolo[5,li
  • selective A2A antagonists include, without limitation, ZM241385 (4-
  • Transforming Growth Factor Beta (1, 2, and 3) are highly pleiotropic cytokines that virtually all cell types secrete. TGF molecules are proposed to act as cellular switches that regulate processes such as immune function, proliferation, and epithelial-mesenchymal transition. Targeted deletions of these genes in mice show that each isoform has some non- redundant functions: 1) is involved in hematopoiesis and endothelial differentiation; 2) affects development of cardiac, lung, craniofacial, limb, eye, ear, and urogenital systems; and 3) influences palatogenesis and pulmonary development.
  • TGF 1, 2, and 3 have been found to be largely interchangeable in an inhibitory bioassay. TGF knockout mice die around 4 weeks of age due to extensive inflammatory cell infiltrates.
  • TGF ligands are initially synthesized as precursor proteins that undergo proteolytic cleavage.
  • the bioactive cytokine molecule is a dimer composed of a polypeptide chain that is cleaved from a precursor by enzymes such as furins and other convertases.
  • the mature segments form active ligand dimers via a disulfide -rich core consisting of the characteristic 'cysteine knot'.
  • Signaling begins with binding to a complex of the accessory receptor betaglycan (also known as RIII) and a type II serine/threonine kinase receptor termed RII.
  • the active TGF dimer signals by bringing together two pairs of receptor serine/threonine kinases known as the type I and type II receptors, respectively.
  • the type II receptors phosphorylate and activate the type I receptors (either ALK-1 or RI (also called ALK-5)) that then propagate the signal by phosphorylating Smad transcription factors.
  • Receptors of the TGF branch of the cytokine family phosphorylate Smads 2 and 3, whereas those of the other branch such as BMP receptors phosphorylate Smads 1, 5, and 8.
  • Use of other signaling pathways that are Smad-independent allows for distinct actions observed in response to in different contexts.
  • the receptor substrate Smads shuttle to the nucleus and form a complex with Smad4, a binding partner common to all Rsmads. Shi Y. et al. Cell. 113:685-700 (2003).
  • Smads receptor substrate Smads
  • a common TGF stimulus can activate or repress hundreds of target genes at once.
  • Variant signaling branches and Smad-independent pathways coexist with the canonical Smad pathway in the response to TGF .
  • Seven type I receptors and five type II receptors paired in different combinations provide the receptor system for the entire TGF family. Alterations and frame shifts are found at the level of the TGF receptors in cancer.
  • TGFP As an immunosuppressive cytokine, TGFP inhibits the development, proliferation, and function of both the innate and the adaptive arms of the immune system.
  • Targets of TGFP include CD4 + effector T cells (Thl and Th2), CD8 + cytotoxic T cells (CTLs), dendritic cells, NK cells, and macrophages. Additionally, TGFP stimulates the generation of regulatory T cells (Treg), which inhibit effector T cell functions, and IL 17 -producing Thl7 cells, which regulate NK cells and macrophages.
  • the formulations that have been developed here are to inhibit the effects of TGFP in dendritic cells and macrophages after they engulf the particles from which the TGFP inhibitor released to block the TGFP receptor from the effects of TGFp. These cells are thus protected from the immunosuppressive effects of TGFP and retain the ability to stimulate anti-cancer immune responses.
  • TGFP is a potent inducer of Epithelial-mesenchymal transition (EMT).
  • EMT Epithelial-mesenchymal transition
  • Cells undergoing EMT lose expression of E-cadherin and other components of epithelial cell junctions. Instead, they produce a mesenchymal cell cytoskeleton and acquire motility and invasive properties.
  • TGFP in the tumor environment primes cells for metastasis through the angiopoietin-like 4 (ANGPTL4) expression pathway.
  • ANGPTL4 angiopoietin-like 4
  • TGFP can also enhance cell motility by cooperating with HER2 signals, as observed in breast cancer cells overexpressing HER2.
  • TGFP stimulates the generation of myofibroblasts from mesenchymal precursors.
  • Myofibroblasts have features of fibroblasts and smooth muscle cells and are highly motile. Their presence in tumor stroma, partly as what are called “cancer- associated fibroblasts,” facilitates tumor development.
  • Glioma cell cultures proliferate in response to TGFP through the induction of platelet-derived growth factor B (PDGF-B) through epigenetic processes.
  • PDGF-B platelet-derived growth factor B
  • the nanoparticle preparations described herein are fabricated to target the myeloid derived phagocytic cells that can function with direct anti-tumor effects such as 1) engulfing tumor cells directly or 2) by priming anti-tumor immune responses through antigen presentation as antigen presenting cells (APC). Preserving these functions in the tumor microenvironment is independent of the loss of the tumor-suppressive arm of the tumor cells.
  • TGFpi immunostaining in infiltrating breast carcinoma has long been associated with metastasis.
  • TGFP high levels of TGFP in the tumor microenvironment influence primary tumor cells toward metastatic potential.
  • mice where TGFP levels are increased by radiation or chemotherapy the use of blockers prevents lung metastasis.
  • TGFP stimulates expression of ANGPTL4 which functions to disrupt vascular endothelial cell junctions, to increase permeability of lung capillary walls and facilitates seeding of pulmonary metastases. Since the elevation of TGF levels is immunosuppressive to macrophages and dendritic cells, the targeting of these specific cells with the deliverty of TGF inhibitors through the formulations disclosed herein is intended to reverse these effects.
  • TGFP In addition to the role of TGFP in local tumor invasion, growing evidence implicates TGFP in the promotion of distal metastasis. Metastasis proceeds through a series of steps whereby cancer cells enter the circulatory system, disseminate to distal capillary beds, enter a parenchyma by extravasation, adapt to the new host microenvironment, and eventually grow into lethal tumor colonies in those distal organs. Fidler IJ. Nat. Rev. Cancer 3:453-8 (2003); Gupta GP. et al. Cell 127:679-95 (2006).
  • Metastasis follows characteristic organ distribution patterns that reflect distinct colonization aptitudes of cancer cells from different origins, different tumor-efferent circulation patterns, and distinct compatibilities between disseminated cells and the organ that they encounter. Beyond the proliferative, survival, and invasive functions of a malignant state, metastasis requires extravasation and colonization functions that come into play once malignant cells disseminate. Such functions may be acquired in the primary tumor but become selected mainly during seeding and colonization distal metastases. Studies in model systems have described a broad range of potential and sometimes contradictory TGF effects on metastasis.
  • Bone metastases are a significant problem in late stage breast cancer patients. Following their mobilization into marrow, cancer cells trigger osteoclasts to release which further influences cytokine release which which in turn enhances metastatic invasiveness. Kingsley L.A. et al. Mol. Cancer Ther. 6:2609-17 (2007).
  • Two genes that modulate bone metastases in ER " breast cancer cells are interleukin-11 (IL-11) and connective tissue growth factor (CTGF). These are TGF target genes.
  • IL-11 interleukin-11
  • CTGF connective tissue growth factor
  • Induction of IL-11 and CTGF expression by TGF is mediated by the Smad pathway (Kang Y. et al. Proc Natl Acad Sci U S A. 102: 13909- 14 (2005)) and has been confirmed in malignant cells isolated from patients with metastatic breast cancer. Gomis RR. et al. Cancer Cell 10:203-14 (2006).
  • TGFP also induces IL-10 and IL-6 expression where IL-10 provides positive feedback for TGFP expression.
  • ER ⁇ breast tumors that are positive for both the TGFP gene response signature and lung metastasis signature (LMS) are associated with the highest risk of relapse through lung metastases. Minn AJ. et al. Nature 436:518-24 (2005). Patients with these signatures showing enhanced function may be selective candidates for TGFP blocking therapy.
  • TGFP signaling by overexpressing the inhibitor Smad7 or a dominant-negative form of the TGFP receptor inhibits the formation of osteolytic metastases by human breast cancer (Yin J.J. et al. J. Clin. Invest. 103: 197-206 (1999)), melanoma (Javelaud D. et al. Cancer Res. 67:2317-24 (2007)) and renal carcinoma cell line xenografts. ( Kominsky SL. et al. J. Bone Miner. Res.
  • TGFP parathyroid hormone-related protein
  • TGF RANK ligand
  • RTKL RANK ligand
  • Administration of anti-PTHrP neutralizing antibodies inhibits TGFP-dependent osteolytic bone metastasis in mice.
  • the role of TGF in metastatic colony expansion may not be limited to bone metastasis.
  • a majority of metastases to lung, liver, and brain in breast cancer patients stain positive for phospho-Smad2, suggesting a widespread activation of this pathway in metastasis by locally released TGF .
  • TGF may facilitate tumor reinitiation through an aberrant induction of ID1 expression.
  • Inhibitors of the TGFP pathway developed to date encompass several classes. They include antisense oligonucleotides, inhibitors of ligand-receptor interactions such as anti-TGFp antibodies (Morris JC. et al. PLoS One 9:e90353 (2014)), anti-receptor antibodies, TGFP-trapping receptor ectodomain proteins, and small-molecule inhibitors that target TGFP receptor kinases. A few anti-TGFp compounds have shown efficacy in preclinical studies and several of these compounds are being evaluated in clinical trials. Arteaga CL. Curr. Opin. Genet. Dev. 16:30-7 (2006); Bierie B. et al. Nat. Rev. Cancer 6:506-20 (2006).
  • TGFP blockers have not been reported to increase spontaneous tumor development in animal models with one possible exception.
  • carcinomas Such lesions are believed to be derived from pre-malignant foci that normally remain suppressed in the absence of antibody. Indeed, when antibody treatment is discontinued, the carcinomas resolve.
  • TGFP pathway in tumors such as glioma, melanoma, and renal cell carcinoma is based on the rationale that TGFP exerts strong
  • blocking TGFP function may empower the immune system against tumors.
  • Blocking TGFP action may also have additional tumor-specific benefits.
  • TGFP inhibition in gliomas may curtail the production of autocrine survival factors, such as PDGF.
  • Blocking TGFP in ER ⁇ breast cancer might prevent primary or metastatic tumors from seeding and reseeding metastasis. Nam JS. et al. Cancer Res. 68:3835-43 (2008).
  • blocking TGFP might interrupt the cycle of TGFP-induced osteoclastogenic factors and halt tumor growth.
  • TGF TGF-induced inflammatory and autoimmune reactions
  • targeting TGF receptor function may contribute to alternatively enhanced activity through compensatory mechanisms by other activators of the Smad pathway, reminicent to what occurs in patients with inactivating mutations in TGFBRI or TGFBR11. Loeys BL. et al. N. Engl. J. Med. 355:788-98 (2006).
  • Antagonists of the Adenosine A2A receptor inhibit tumor growth.
  • Nanoparticles herein comprising adenosine antagonists mediate effective antitumor responses.
  • the nanoparticles developed herein have facilitated delivery and uptake into APCs of anti-immunosuppressive small molecules to engender systemic anti-tumor immune responses. It has been indicated that transient suppression of TGF would be sufficient for protective tumor immunity through reduction of Tregs. Conroy H. et al. Cancer Immunol Immunother. 2012;61(3):425-31.
  • the nanoparticles herein may provide a "tumor vaccine approach" through delivery of the combination of TGF inhibitor and adenosine antagonist into even one or a small number of tumors resulting in systemic immune surveillance response in metastatic tumors such as breast cancer. This concept is supported by data described the Examples shown herein below.
  • nanoparticle compositions comprising an adenosine receptor antagonist, a permeation enhancer, a TGF inhibitor, and a poly(lactic-co- glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • Adenosine receptor antagonist refers to any of the adenosine antagonist subtypes, and includes any combinations of subtypes.
  • the Examples below show results with selective A2A receptor antagonists. However, those skilled in the art will appreciate that A2A antagonists may still have some inhibitory effect on the other adenosine receptors and vice versa.
  • nanoparticle formulations with A2B antagonists or the combination of A2A and A2B antagonists may be combined with TGF .
  • the adenosine receptor antagonist comprises an A 2 A-type antagonist and/or an A 2 B-type antagonist. In some embodiments, the adenosine receptor antagonist comprises A2A-type antagonist. In some embodiments, the A2A-type antagonist comprises SCH58621 of formula I:
  • the adenosine receptor antagonist is present in an amount in a range from about 0.02% to about 0.5% by total weight of the composition, including any subrange in between such as 0.05 to 0.25% by total weight of the composition, or 0.1 to 0.2% by total weight of the composition.
  • the TGF- ⁇ inhibitor is selected from, but not limited to the group consisting of SB431542 (4-[4-(l,3-benzodioxol-5-yl)-5-(2-pyridinyl)-lH-imidazol-2- yl]benzamide), SB525334 ( 6-[2-(l,l-Dimethylethyl)-5-(6-methyl-2-pyridinyl)-lH-imidazol- 4-yl]quinoxaline), Ki26894 (Kirin Brewery Company, Gunma, Japan, (Ehata et al Cancer Sci 98): 127-133), LY364947 (4-[3-(2-Pyridinyl)-lH-pyrazol-4-yl]-quinoline), SD-208 (2-(5- Chloro-2-fluorophenyl)-4-[(4-pyridyl)amino]pteridine), SD-093 (2-(2-fluor
  • the TGF inhibitor comprises SB431542 of formula II:
  • the TGF inhibitor is present in an amount in a range from about 0.02% to about 0.5% by total weight of the composition.
  • Nanoparticle compositions here comprise a permeation enhancer.
  • a "permeation enhancer” is a compound that aids in delivery of the nanoparticles into the target cells. That is, they enhance the ability of the nanoparticles to cross the cell membrane and enter the cell.
  • the permeation enhancer is selected from the group consisting of chitosan material, a fatty acid, a bile salt, a salt of fusidic acid, a polyoxyethylenesorbitan, a sodium lauryl sulfate, polyoxyethylene-9-lauryl ether (LAURETHTM-9), EDTA, citric acid, a salicylate, a caprylic glyceride, a capric glyceride, sodium caprylate, sodium caprate, sodium laurate, sodium glycyrrhetinate, dipotassium glycyrrhizinate, glycyrrhetinic acid hydrogen succinate, a disodium salt, an acylcarnitine, a cyclodextrin, a phospholipid, and mixtures or combinations thereof.
  • the permeation enhancer comprises chitosan.
  • chitosan or othe permeation enhancer is present in an amount in a range from about 1 % to about 20% by total weight of the composition.
  • the nanoparticle compositions have a zeta potential in a range from about -30 mvolts to about +30 mvolts, such zeta potential being modifiable by altering the amount of permeation enhancer chitosan.
  • biodegradable polymers suitable as matrices for the nanoparticles include, without limitation, a polyester, a lactic acid polymer, homopolymers of lactic acid or glycolic acid (e.g., poly lactic acid (PLA), poly gly colic acid (PGA)), poly-s-caprolactone (PCL), poly(anhydrides), poly(amides), poly(urethanes), poly(carbonates), poly(acetals), poly (ortho-esters), poly(glycolide-co-trimethylene carbonate), poly(dioxanone),
  • PLA poly lactic acid
  • PGA poly gly colic acid
  • PCL poly-s-caprolactone
  • PCL poly(anhydrides), poly(amides), poly(urethanes), poly(carbonates), poly(acetals), poly (ortho-esters), poly(glycolide-co-trimethylene carbonate), poly(dioxanone),
  • PAEMA 2 (dimethylamino)ethyl methacrylate
  • DMAEMA polyethylene glycol
  • HPMA N-(2-hydroxypropyl)methacrylamide
  • PBLA poly(beta-benzyl-L-aspartate)
  • PBLA poly(hydroxybutyrate-co valerate)
  • a size of the nanoparticle is in a range from about 50 nm to about 2,000 nm. In some embodiments, a size of the nanoparticle is in a range from about 50 nm to about 1,000 nm. In some embodiments, a size of the nanoparticle is in a range from about 100 nm to about 1,000 nm. In some embodiments, a size of the nanoparticle is in a range from about 200 nm to about 1,000 nm. In some embodiments, a size of the nanoparticle is in a range from about 50 nm to about 500 nm. In some embodiments, a size of the nanoparticle is in a range from about 100 nm to about 500 nm.
  • nanoparticles have a size in a range with from about 400 nm to about 800 nm. Consistent with the term "nanoparticle”as used in the art, such term refers to a particle having an average diameter of about 0.5 nm to about 1 micron. In some embodiments, the nanoparticle has an average diameter of about 5 nm to about 950 nm, about 50 nm to about 900 nm, about 100 nm to about 800 nm, about 150 nm to about 750 nm, about 200 nm to about 700 nm, about 300 nm to about 600 nm, or about 400 nm to about 500 nm.
  • the nanoparticles may comprise a dye.
  • dyes may include, without limitation, lipophilic tracer dyes such as DiD dye (l,l '-dioctadecyl- 3,3, 3", 3"- tetramethylindodicarbocyanine), DiO dye (3,3'- dioctadecyloxacarbocyanine), DiA dye (4-(4- (dihexadecylamino)styryl)-N- methylpyridinium ), Dil dye ((2Z)-2-[(E)-3-(3,3-dimethyl-l- octadecylindol-l-ium-2- yl)prop-2-enylidene]-3,3-dimethyl-l-octadecylindole; perchlorate; CAS No.
  • DiR dye (l,l '-dioctadecyl-3,3,3',3'- tetramethylindotricarbocyanine), which are commercially available from Life Technologies.
  • the dyes described herein can have various emission wavelengths.
  • One of skill in the art will appreciate that the dyes described herein have various purposes including but not limited to particle identification, size determination, tracking, and quantification in vitro and in vivo.
  • nanoparticle compositions herein have been developed to selectively block both the adenosine and TGF- ⁇ (TGF-beta I, TGF-beta II)
  • the combination of these pathway inhibitors may be more effective than either inhibitor alone as a tumor therapeutic.
  • the combined nanoparticle formulation of TGF and Adenosine pathway inhibitors may be of general use as an immunologically based cancer therapy with the potential to induce protective anti-tumor immunity.
  • the adenosine receptor antagonist is present in an amount in a range from about 0.02% to about 0.5% by total weight of the composition.
  • the TGF- ⁇ inhibitor is selected from, but not limited to the group consisting of SB431542 (4-[4-(l,3-benzodioxol-5-yl)-5-(2-pyridinyl)-lH-imidazol-2- yljbenzamide), SB525334 ( 6-[2-(l,l-Dimethylethyl)-5-(6-methyl-2-pyridinyl)-lH-imidazol-
  • nanoparticle compositions may also comprise a targeting moiety.
  • the targeting moiety may be selected from the group consisting of a tumor-targeting moiety, a viral-specific moiety, a bacteria-specific moiety, and a cell- targeting moiety.
  • the targeting moiety may be a cell-targeting moiety and may be selected from the group consisting of a phagocytic cell-targeting moiety, a natural killer cell-targeting moiety, a T-cell targeting moiety, a B-cell targeting moiety, a glial cell targeting moiety, a myeloid cell targeting moiety, an epithelial cell targeting moiety, a macrophage-targeting moiety, a tumor cell-targeting moiety, and a dendritic cell-targeting moiety.
  • the macrophage or dendritic cell targeting moiety is chitosan.
  • nanoparticle compositions herein may form part of a pharmaceutical composition comprising the nanoparticles described herein.
  • Such pharmaceutical composition comprising the nanoparticles described herein.
  • compositions may be formulated for parenteral, intravenous, intradermal, subcutaneous, oral, inhalation, transdermal, transmucosal, rectal and intratumoral administration.
  • a disease or disorder characterized by immunosuppression comprising administering to a mammalian subject a nanoparticle composition comprising an adenosine receptor antagonist, a TGF inhibitor a permeation enhancer, and poly(lactic-co-glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • the disease or disorder may be an inflammatory condition or an autoimmune condition.
  • methods of treating cancer comprising administering to a mammalian subject a nanoparticle composition comprising an adenosine receptor antagonist, a TGF inhibitor a permeation enhancer, and poly(lactic-co-glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • a nanoparticle composition comprising an adenosine receptor antagonist, a TGF inhibitor a permeation enhancer, and poly(lactic-co-glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • Neoplasia, tumor, cancer and malignancy treatable in accordance with the methods herein include solid cellular mass, hematopoietic cells, or a carcinoma, sarcoma (e.g. lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma,
  • sarcoma e.g. lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma
  • lymphoma rhabdomyosarcoma or fibrosarcoma
  • lymphoma leukemia, adenoma, adenocarcinoma, melanoma
  • glioma glioblastoma
  • meningioma neuroblastoma
  • retinoblastoma astrocytoma
  • oligodendrocytoma mesothelioma, reticuloendothelial
  • lymphatic or haematopoietic e.g., myeloma, lymphoma or leukemia
  • Neoplasia, tumor, cancer and malignancy treatable in accordance with the methods herein can be present in or affect a lung (small cell lung or non-small cell lung cancer), thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pituitary gland, thyroid, lymph, gastrointestinal (mouth, esophagus, stomach, duodenum, ileum, jejunum (small intestine), colon, rectum), genito-urinary tract (uterus, ovary, cervix, endometrial, bladder, testicle, penis, prostate), kidney, pancreas, liver, bone, bone marrow, lymph, blood, muscle, skin or stem cell neoplasia, tumor, cancer, or malignancy.
  • adenosine receptor and TGF pathways are implicated in the activity of either the purinergic pathway involving adenosine signaling and/or TGF signaling.
  • the use of small molecule inhibitors inhibits the immunosuppressive signals of these pathways and forms the basis for treatment of a variety of conditions including, without limitation, cancer.
  • methods directed to cancer treatment may further comprise administering a chemotherapeutic agent to the subject.
  • chemotherapeutic agent classes useful with the nanoparticle compositions include, without limitation, anthracyclines, platinum drugs, intercalating chemotherapeutic agents, topoisomerase poisons,
  • cyclophosphamide drugs and mixtures thereof.
  • chemotherapeutic agents include, without limitation, daunomycin, Cytoxan, cytarabine, melphalan, adriamycin, colchicine, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, mitoxantrone, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, interferons, camptothecin and derivatives thereof, phenesterine, taxanes and derivatives thereof (e.g., paclitaxel and derivatives thereof, taxotere and derivatives thereof), topetecan, vinblastine, vincristine, tamoxifen, piposulfan, nab-5404, nab-5800, nab-5801, Irinotecan, HKP, Ortat
  • the chemotherapeutic agent is also composition comprising nanoparticles, either separately or together with the A2A anatagonist and TGF inhibitor.
  • the chemotherapeutic agent may be an antagonist of other factors that are involved in tumor growth, such as EGFR, ErbB2, ErbB3, ErbB4, or TNF. In some such embodiments, it may be beneficial to also administer one or more cytokines to the individual.
  • the therapeutic agent is a growth inhibitory agent.
  • methods designed for the treatment of cancer may also further comprise administering radiation therapy.
  • methods herein employ an adenosine receptor antagonist that comprises SCH58621 of formula I:
  • the permeablizing agent comprises chitosan or derivatives of chitosan.
  • inventions herein describe nanoparticle compositions in which the adenosine receptor antagonist and TFG inhibitor are present in the same nanoparticle matrix, it is also possible to deliver them in separate nanoparticles.
  • methods of treating a disease or disorder characterized by immunosuppression comprising administering to a mammalian subject a first nanoparticle composition comprising an adenosine receptor antagonist and co-administering a second nanoparticle composition comprising a TGF inhibitor, wherein the first and second nanoparticle compositions each comprise a permeation enhancer and a poly(lactic-co-glycolic acid) (PLGA) copolymer as a matrix.
  • PLGA poly(lactic-co-glycolic acid)
  • both administering and co-administering steps are peformed simultaneously.
  • the first nanoparticle and second nanoparticle are disposed in a single oral capsule. In other embodiments, the first
  • nanoparticle composition is disposed in a first oral capsule and the second nanoparticle composition is disposed in a second oral capsule.
  • Oral delivery is not limited to capsule delivery and this is merely exemplary.
  • Other oral adminstration routes may include tablets, syrups, and the like.
  • the administering and co-administering steps are performed intravenously. In some embodiments, the administering and co-administering steps are performed subcutaneously. In some embodiments the administering and co-administering steps are performed by intratumoral injection.
  • the disclosure provides a pharmaceutical composition comprising the particles described herein. In some embodiments of all aspects, the composition is formulated for parenteral, intravenous, intradermal, subcutaneous, oral, inhalation, transdermal, transmucosal, rectal, intrathecal and intratumoral administration. In some embodiments in the adjuvant can be delivered p.o, i.p. s.c, i.v., i.t. (intrathecal) into spinal fluid, sublingual, lung inhalation, nasal administration, suppositories, eye drops or other means of administration.
  • a nanoparticle compositions in the manufacture of a medicament for the treatment of cancer, an inflammatory condition, or an autoimmune condition, the nanoparticle composition comprising an adenosine receptor A2A antagonist, an adenosine receptor A2B antagonist, a TGF-beta inhibitor, a permeabilizing agent; and a poly(lactic-co-glycolic acid) (PLGA) copolymer as a matrix for the nanoparticle composition.
  • PLGA poly(lactic-co-glycolic acid)
  • Nanoparticle (NP) formulations were fabricated using 50:50 poly (lactide-co- glycolide) (PLGA 50:50) and chitosan (15% wt:wt) to enhance both mucosal penetration and uptake into phagocytic cells, specifically macrophages and dendritic cells.
  • concentration of adenosine inhibitor SCH58621 in this Example was 1 microgram per milligram of PLGA polymer.
  • Tumor injections were done using 100 microliter volumes per injection at an overall concentration of 65 nM SCH58261 based on the amount of drug within the nanoparticles being administered (see Figure 2).
  • Anti-tumor effects of an exemplary nanoparticle composition were assessed by directly injecting tumors with NPs containing an A2A antagonist alone (SCH58261 (the nanoparticle-drug composition designated "SCH-NP" at 65 nM)).
  • SCH58261 the nanoparticle-drug composition designated "SCH-NP” at 65 nM
  • Such treatment resulted in inhibition of the growth of syngeneic 4T1 breast cancer in Balb/c mice as disclosed by Hammerl D. et al., "Intratumoral injection of microparticles containing the A2A receptor antagonist SCH58261 slow tumor growth and metastasis more effectively than system drug administration," Abstract in Purinergic Signal. 1019 (2016). "Tumor cells were injected into both right and left breast fat pads and allowed to grow for 5 days.
  • Figures 2A and 2B show the effects of NPs containing SCH58261 (NP-SCH) on the growth and metastasis of treated and untreated 4T1 breast cancer cells.
  • SCH concentrations were calculated as if the drug were free in solution in a volume of 100.
  • Figure 2A shows tumor progression in injected tumors and
  • Figure 2B shows tumor progression in uninjected contralateral tumors.
  • the NP-SCH were significantly slowed in tumor growth.
  • Adenosine A2A Receptor Antagonist and a TGF-beta Inhibitor.
  • PLGA-particles were prepared by modification of the method of Ravi Kumar. Ravi Kumar MN. et al. Biomaterials 25: 1771-1777 (2004) to include an adenosine antagonist and a TGF-beta inhibitor. Solutions of 5 mg/mL each of SCH58261, an A2A receptor antagonist (Baraldi PG. et al. J. Med. Chem. 37: 4329-4337 (1994).), and SB431542, a TGF- beta inhibitor (Inman GJ. et al. Mol. Pharmacol. 62: 65-74 (2002).), were made in DMSO.
  • the amount of 200 mg of PLGA (50:50) was dissolved in 10 mL of ethyl acetate after which was added 0.05 mL of each drug solution alone or in combination and 0.1 mL of DiD dye (Invitrogen) in DMSO.
  • An aqueous solution was prepared by mixing 9 mL sterile water (SW) with 15 mg of chitosan and 15 microliters of acetic acid. After dissolving the chitosan, 1 mL of 1% Poly- vinyl Alcohol (PVA) in SW was added. The ethyl acetate solution was poured into the aqueous solution and vigorously mixed by high-speed vortexing for 3 minutes.
  • SW sterile water
  • PVA Poly- vinyl Alcohol
  • Microparticle characterization An aliquot of 250 microliters of the final suspension (stock) was vacuum dried in a tared 1.5 mL microtube and the dry weight of the nanoparticles was determined. The dried nanoparticles were dissolved in 1 mL of DMSO. To determine the drug concentration, the sample was centrifuged at 1000 x g for 1 min and the absorbances at 285 and 336 nm were determined on the supernatant. The concentration of SCH58261 was calculated by dividing the absorbance at 285 nm by 0.061 to obtain the concentration in ⁇ g/mL and multiplied by 4 to determine the stock concentration of drug.
  • Nanocomposix using a Malvern Nanosight unit and a Malvern Zetasizer repectively, after diluting the stock nanoparticles in water to 0.1 mg/mL of polymer ( Figures 3 and 4).
  • Figure 3 shows the averaged size distribution of nanoparticles comprising SCH58261 and SB431542.
  • the stock nanoparticles of Lot 16005 were diluted in water to 0.1 mg/mL and size measurements were performed using Nanosight technology (Nanocomposix, San Diego, CA).
  • the mean particle size was 533.4 nm + 118.2 nm.
  • the particle concentration was 3.19 x 10 9 + 3.28 x 10 8 particles/mL.
  • Figure 4 shows the zeta potential measurement of nanoparticles.
  • the stock nanoparticles of Lot 16005 were diluted in sterile water to 0.1 mg/mL of polymer and the zeta potential was measured using a Malvern Zetasizer (Nanocomposix, San Diego, CA). A plot of the particle counts vs apparent zeta potential is shown. The zeta potential was measured to be 18.4 + 5.89 mV.
  • FIGS 5A/5B show the UV spectra of SCH58261 and SB431542, respectively.
  • the nanoparticles (0.250 mL of stock) were dried and dissolved in DMSO and centrifuged at 1000 x g for 1 minute.
  • the UV spectra were obtained on the supernatants using a reference of non-drug containing nanoparticles prepared in the same way.
  • the Top Panel shows the UV spectra of nanoparticles containing each individual drug in an overlay of SB431542 (dotted line) and SCH58261 (solid line).
  • SCH58261 has strong absorbance at 285 nm in a region where SB431542 is transparent while SB438542 absorbs at 336 in a region where SCH58261 is transparent.
  • the bottom panel shows the UV spectrum nanoparticles (Lot24b) containing the combination of both SCH58261 and SB431542.
  • FIGURE 6 shows an HPLC trace of SB431542 (left panel) and SCH58261 (right panel) using an Agilent Zorbax GF-250 9.4 x 250 mm column equilibrated to 30°C.
  • Stock drug solutions of 5 mg/mL in DMSO were diluted 1:500 in Ethanol:Water:Glacial Acetic Acid (20:75:5)(EWA) and run at 1 niL/min in EWA as the mobile phase.
  • the retention times for SB431542 and SCH58261 were 9.178 and 16.011 min respectively.
  • Figure 7 shows an HPLC trace of an extract from nanoparticles embedded with both SCH58261 (peak retention time of 15.884 minutes) and SB431542 (peak retention time of 9.288 minutes).
  • Particles were vacuum dried and dissolved in DMSO.
  • Two volumes of Ethanol:Water:Glacial Acetic Acid (20:75:5::vol:vol:vol) (EWA) were added to 1 volume of the DMSO solution and then mixed by shaking. The precipitates were removed by centrifugation at 10,000 x g for 5 min and the supernantant collected and filtered through a 0.2 PTFE filter.
  • the amount of 50 microliters of the supernatant was run using an Agilent Zorbax GF250, 9.4 x 250 mm column equilibrated to 30°C at a flow rate of 1 niL/min. EWA was used as the mobile phase.
  • the retention times of SB431542 and SCH58261 (labeled peaks at 9.288 and 15.884 minutes, respectively) were consistent with the original stocks as shown in FIGURE 5.
  • Figures 8A/8B indicate the enhanced anti-tumor activity of nanoparticles containing both an adenosine A2A receptor antagonist and a TGF-beta inhibitor.
  • the amount of 5 x 10 4 Lewis Lung Carcinoma cells was injected into both flanks of syngeneic C57/B16 mice.
  • nanoparticle-drug preparations 100 nM drug or BLANK
  • Two additional injections were performed on days 14 and 17. Tumor growth was monitored by caliper measurements over the indicated number of days.
  • the nanoparticle preparations were TI- BLANK, a non-drug containing control; TI-07B, nanoparticles containing SB431542 (a TGF- beta inhibitor); TI-07H, nanoparticles containing SCH58261 (an adenosine A2A receptor antagonist) and TI-07, nanoparticles containing both SB431542 and SCH58261 (the combination of a TGF-beta inhibitor and an A2A receptor antagonist).
  • the combination formulation, TI-07 resulted in enhanced anti-cancer effects regarding tumor growth. As in Figures 2A/B, it is remarkable that the untreated tumors on the contralateral side still responded to the treatment as effectively as the intratumorally injected side.
  • Figure 8A and 8B show a slowing of the tumor growth with TI-07 (asterisks *) starting at day 14 (day of 2nd injection).
  • a slowing of tumor growth in Figure 8B (asterisk *) is consistent with a generalized anti-tumor immune response.
  • Figure 9 shows a bar graph tumor volumes for TI-07 and controls on day 18 of Figure 6.
  • Lewis Lung Carcinoma tumors were generated as described in Figure 6 with two tumors per mouse, one tumor on the left and one tumor on the right flank of each mouse. The left flank tumors of each mouse were injected while the right flank tumors were uninjected.
  • the data show significant suppression of tumor growth with TI-07 the combination of SB431542, the TGFb inhibitor, and SCH58261, the adensonine A2A receptor antagonist, compared to the controls.

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Abstract

L'invention concerne une composition de nanoparticules qui comprend un antagoniste du récepteur de l'adénosine, un inhibiteur de TGFβ dans une matrice copolymère d'acide poly(lactique-co-glycolique) (PLGA) pour la composition de nanoparticules ainsi qu'un amplificateur de perméation. Ladite composition de nanoparticules est utilisée dans des méthodes de traitement du cancer et de maladies ou de troubles caractérisés par une immunosuppression.
PCT/US2017/029841 2016-04-27 2017-04-27 Compositions de nanoparticules comprenant des antagonistes du récepteur de l'adénosine et méthodes d'utilisation WO2017189849A1 (fr)

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US10702476B2 (en) 2017-08-14 2020-07-07 Phosphorex, Inc. Microparticle formulations of adenosine receptor antagonists for treating cancer
US20190046448A1 (en) * 2017-08-14 2019-02-14 Phosphorex, Inc. Microparticle formulations of adenosine receptor antagonists for treating cancer
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US20210071137A1 (en) * 2017-11-24 2021-03-11 Sumitomo Chemical Company, Limited Production method for cell mass including neural cells/tissue and non-neural epithelial tissue, and cell mass from same
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CN113521074A (zh) * 2020-04-17 2021-10-22 南京圣和药业股份有限公司 一种包含喹啉类TGF-β1抑制剂的组合物及其用途
CN115969801A (zh) * 2023-03-21 2023-04-18 劲方医药科技(上海)有限公司 用于癌症的药物组合物及其制备方法
CN115969801B (zh) * 2023-03-21 2023-08-25 劲方医药科技(上海)有限公司 用于癌症的药物组合物及其制备方法

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