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WO2024209267A2 - Modulateurs de l'absorption de nanoparticules - Google Patents

Modulateurs de l'absorption de nanoparticules Download PDF

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Publication number
WO2024209267A2
WO2024209267A2 PCT/IB2024/000175 IB2024000175W WO2024209267A2 WO 2024209267 A2 WO2024209267 A2 WO 2024209267A2 IB 2024000175 W IB2024000175 W IB 2024000175W WO 2024209267 A2 WO2024209267 A2 WO 2024209267A2
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Prior art keywords
liposome
inhibitor
subject
target cell
uptake
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PCT/IB2024/000175
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English (en)
Inventor
Takahiro Yamauchi
Naoko HOSONO
Hiroaki ARAIE
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Jazz Pharmaceuticals Ireland Limited
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Publication of WO2024209267A2 publication Critical patent/WO2024209267A2/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

Definitions

  • AML Acute myeloid leukemia
  • CPX-351 (Trade name: Vyxeos®), is an advanced liposomal formulation of cytarabine and daunorubicin encapsulated at a 5: 1 molar ratio, which is found to be maximally synergistic and minimally antagonistic in vitro (Tardi et al., LeukRes., 33(1): 129-39 (2009)). That is, at some molar ratios of cytarabine: daunorubicin the combination is additive, at others it is far more effective and in some ratios the combination is actually worse.
  • Liposomal encapsulation markedly increases the plasma half-life of cytarabine and daunorubicin and leads to greater drug accumulation within the bone marrow comparing with free cytarabine and daunorubicin (Feldman et al. LeukRes. 36(10): 1283-9 (2012); Lim et al., LeukRes. 34(9): 1214-23 (2010)).
  • the liposomal integrity of CPX-351 in circulation ensures that there is minimal free drug release, as well as simultaneous co-delivery of the two drugs at the optimal molar ratio. This co-delivery strategy eliminates the problem of differential biodistribution and metabolism.
  • liposomes encapsulating one or more therapeutic agents administered with an inhibitor of a selected cellular pathway to a subject in need thereof, each in a therapeutically useful dosage results in a significant increase in uptake of the liposome by cells relative to the uptake seen in an identical cell without administration of the inhibitor.
  • the inhibitor is an inhibitor of Scavenger Receptor BI (SR-BI). Incorporating such an inhibitor in a therapeutically useful dosage results in a significant increase in uptake of the liposome by cells expressing SR-BI relative to the uptake seen in an identical cell without administration of the inhibitor.
  • SR-BI Scavenger Receptor BI
  • SR-BI implicated in HDL uptake into cells, was recently recognized as mediating uptake of certain liposomes in leukemia cells (Di et al., Drug Dev. Ind. Pharm. 45(l):21-26 (2019)).
  • an increase in liposome uptake upon contacting SR-BI with a known inhibitor of SR-BI is a surprising result as one of ordinary skill in the art would expect the uptake of the liposome to decrease upon inhibiting SR-BI.
  • the disclosure sets forth a method of increasing the cellular uptake of a liposome encapsulating one or more therapeutic agents by a target cell expressing SR-BI.
  • the method includes administering the liposome to the target cell and also administering to the target cell an amount of the inhibitor of SR-BI sufficient to increase uptake by the cell of the liposome (e.g., '‘a therapeutically effective amount”).
  • the target cell is diseased and either underexpresses or overexpresses SR-BI relative to an identical undiseased cell.
  • the formulations of the instant invention leverage this over-, under-expression to effect enhanced delivery of the liposome to the cell.
  • a method of treating a disease in a subject in need of such treatment includes administering to the subject a therapeutically effective amount of a liposome encapsulating one or more therapeutic agents effective in treating the disease, ameliorating the symptoms of the disease, etc., and an amount of an inhibitor of SR-BI selected such that the cellular uptake by a target cell of the subject is increased relative to the cellular uptake of the liposome by the same target cell in the absence of the inhibitor of SR-BI.
  • a method of treating cancer in a subject in need of such treatment e.g., leukemia, e.g., acute myeloid leukemia.
  • the method includes administering to the subject a therapeutically effective dosage of a liposome encapsulating one or more cancer chemotherapeutic agents and an amount of a SR-BI inhibitor selected such that the cellular uptake by a target cell of the subject is increased relative to the cellular uptake of the liposome by the same target cell in the absence of the inhibitor of SR-BI.
  • the inhibitor of SR-BI is effective at increasing the uptake of the liposome by the target cell at a first higher dosage of the SR-BI inhibitor but either has no effect on uptake or reverses the effect and reduces the uptake at a lower dosage of the SR-BI inhibitor.
  • the delivery is enhanced by administering an inhibitor of SR-BI in an amount selected such that the uptake by a target cell of the subject is increased relative to the cellular uptake of the liposome by the same target cell in the absence of the inhibitor of SR-BI, thereby reducing delivery to non-target cells.
  • the enhanced delivery to the target cell leads to less off target delivery than when the inhibitor is not present.
  • An exemplary alteration of the side effect profile includes a diminishment or amelioration of at least one undesirable side effect of the therapeutic agent on the subject to whom it is administered.
  • An exemplary 7 method of the invention is useful to reduce cellular resistance to a one or more liposome encapsulated therapeutic agents, e.g., cytarabine, daunorubicin and combinations thereof.
  • the method comprises administering to a drug resistant target cell an inhibitor of SR-BI in an amount selected such that the cellular uptake of the liposome encapsulated therapeutic agent(s) by the target cell is increased relative to the cellular uptake of the liposome encapsulated agent(s) by the same target cell in the absence of the inhibitor of SR-BI, or the cellular efflux of the liposome encapsulated therapeutic agent(s) (or deencapsulated therapeutic agent(s)) is less than the efflux of the agent(s) relative to the same target cell in the absence of the inhibitor of SR-BI.
  • a pharmaceutical formulation for carrying out one or more of the methods set forth above.
  • the pharmaceutical formulation includes a liposome encapsulating one or more therapeutic agents and a SR-BI inhibitor selected such that the cellular uptake of the liposome by a target cell is increased relative to the cellular uptake of the liposome by the same target cell in the absence of the inhibitor of SR-BI.
  • the presence of the inhibitor in the formulation reduces delivery to non-target cells.
  • the liposome includes one or more cancer chemotherapeutic agents.
  • the chemotherapeutic agents are cytarabine and daunorubicin.
  • the cytarabine and daunorubicin are encapsulated in the liposome in a constant 5: 1 ratio.
  • An exemplary 7 liposome is CPX-351.
  • a pharmaceutical formulation comprising therapeutically effective amounts of a liposome and an inhibitor of SR-BI in an amount selected such that the cellular uptake of the liposome by a cell of the subject is increased relative to the cellular uptake of the liposome by the same cell of the subject in the absence of the inhibitor of SR-BI.
  • a pharmaceutical formulation comprising therapeutically effective amounts of CPX-351 and an inhibitor of SR- BI in an amount selected such that the cellular uptake of the liposome by a cell of the subject is increased relative to the cellular uptake of the liposome by the same cell of the subject in the absence of the inhibitor of SR-BI.
  • the CPX-351 and inhibitor of SR-BI are combined in a pharmaceutically acceptable carrier.
  • a combination of a liposome comprising cytarabine and an equilibrative nucleoside transporter (ENT) (e.g., ENT1) inhibitor in therapeutically useful dosages results in a significant increase in uptake of liposome-encapsulated cytarabine bycells expressing ENT (e.g., ENT1) relative to the uptake of unencapsulated cytarabine in the presence of the ENT inhibitor seen in an identical cell.
  • ENT equilibrative nucleoside transporter
  • the disclosure sets forth a method of combination therapy of a proliferative disorder, e.g., cancer, e.g.. leukemia, e.g., acute myeloid leukemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a liposome comprising cytarabine and an amount of an ENT inhibitor effective to enhance uptake of liposome-encapsulated cytarabine by a target cell exhibiting the genotype and/or phenotype associated with the proliferative disease relative to the uptake of unencapsulated cytarabine in the presence of the ENT inhibitor by an identical cell.
  • a proliferative disorder e.g., cancer, e.g.. leukemia, e.g., acute myeloid leukemia
  • the method comprising administering to a subject in need thereof a therapeutically effective amount of a liposome comprising cytarabine and an amount of an ENT inhibitor effective to enhance uptake of
  • the method of the invention utilizing the ENT inhibitor alters the side effect profile of the therapeutic agent.
  • An exemplary alteration of the side effect profile includes a diminishment or amelioration of at least one undesirable side effect of the therapeutic agent on the subject to whom it is administered.
  • the enhanced delivery to the target cell leads to less off target delivery than when the inhibitor is not present.
  • a method of treating acute myeloid leukemia in a subject in need of such treatment comprising administering a therapeutically relevant dose of CPX- 351 to the subject.
  • Administration of CPX-351 in this patient population is correlated with lower cardiotoxicity than administration of standard 7+3 therapy.
  • FIGURE 2 The uptake of CPX-351 into leukemia cell lines evaluated by flow cytometry, (b) The uptake of CPX-351 in HL-60/AD treated with MK571. (c) The growth inhibition curve in HL-60/AD. Control and HL-60/AD treated with MK571 were incubated with various concentrations of CPX-351 for 72 h, and the ICso was then determined by using the XTT assay, (d) The uptake of CPX-351 in K562/ADM treated with tariquidar. (e) The growth inhibition curve in K562/ADM.
  • FIGURE 3 Inhibition of the CPX-351 uptake pathway by the addition of chlorpromazine, 5-(N-ethyl-N-isopropyl)-Amiloride (EIPA), or low-dose blocks lipid transport-1 (LD-BLT-1, 400 nM).
  • EIPA 5-(N-ethyl-N-isopropyl)-Amiloride
  • LD-BLT-1 low-dose blocks lipid transport-1
  • *** p 0.004.
  • K562. *p ⁇ 0.001. ** p 0.0018.
  • the mean ⁇ SE for at least 3 independent experiments is shown for each value.
  • FIGURE 4 Enhancement of the CPX-351 uptake by the addition of high-dose blocks lipid transport-1 (HD-BLT-1, 40 pM) alone or in combination with chlorpromazine, 5-(N- ethyl-N-isopropyl)-Amiloride (EIPA), or incubation at 4°C.
  • lipid transport-1 HD-BLT-1, 40 pM
  • EIPA 5-(N- ethyl-N-isopropyl)-Amiloride
  • EIPA 5-(N- ethyl-N-isopropyl)-Amiloride
  • FIGURE 5 Patient specimen analysis, (a) the expression of scavenger receptor class B type 1 (SR-BI). (b) the uptake of CPX-351 alone or in combination with high-dose blocks lipid transport- 1 (HD-BLT-1, 40 pM).
  • SR-BI scavenger receptor class B type 1
  • FIGURE 7 Inhibition of DNA synthesis by CPX-351. ***P ⁇ 0.001.
  • the present disclosure provides new combination formulations of a liposome encapsulating one or more therapeutic agents, and an inhibitor of a selected cellular pathway.
  • the inhibitor is an inhibitor of Scavenger Receptor BI (SR-BI).
  • combination therapies with these formulations, and methods of using the new formulations and combination therapies to treat disease.
  • the present disclosure also sets forth new methods of determining whether therapy with a liposome encapsulated therapeutic or a combination therapy with this liposome and inhibitor is appropriate for a particular subject in need of treatment for a disease.
  • Liposomes are closed vesicles having at least one lipid bilayer surrounding an aqueous core.
  • the intra-liposomal space and lipid layer(s) can entrap a wide variety' of substances including drugs, cosmetics, diagnostic reagents, genetic material and bioactive compounds. Since non-toxic lipids act as the basis for liposomes, they generally exhibit low toxicity. The low toxicity coupled with the ability of liposomes to increase the plasma circulation lifetime of agents gives rise to liposomes as vehicles particularly useful for delivering pharmaceutically active agents. In many cases, liposome-delivered drugs result in superior clinical efficacy paired with reduced toxicity.
  • SR-BI is recognized as a receptor mediating the uptake of HDL into cells and was recently recognized as mediating uptake of liposomes in leukemia cells (Di et al., Drug Dev. Ind. Pharm. 45(l):21-26 (2019)).
  • SR-BI is a member of the CD36 superfamily. Each member contains a large extra cellular domain flanked by two membrane - spanning (ML279) domains with short amino and carboxy - terminal intracellular tails.
  • CD36 family members maintain about 30 % sequence identity. They can differ in subcellular localization and ligand preference. For example. CD36/SCARB3 can bind HDL but is incapable of efficient uptake of HDL cholesterol via selective lipid uptake.
  • Inhibitors of SR-BI are recognized compounds. See, e.g., U.S. Pat. No. 9,884,851; Raldue et al. Tox. Letters 175(1-3): 1-7 (2007).
  • the diabetic dmg glyburide an inhibitor of the sulfonylurea receptors SURI and SUR2, was also found to have activity at SR-BI, though it was a relatively weak inhibitor of cholesterol efflux.
  • researchers at Sankyo discovered that the protected piperazines R-138329 and R- 154716 increased HDL-cholesterol in both mice and hamsters, presumably by inhibiting SR-BI-mediated uptake of HDL
  • a p38 MAP kinase inhibitor (ITX-5061) was reported to have similar in vivo effects and appears to be a moderate inhibitor of SR-BI- mediated cholesterol uptake. See, e.g., U.S. Pat. No, 9,884,851.
  • Inhibitors of SR-BI as a class are exemplified by Block Lipid Transport- 1 and related compounds.
  • Block Lipid Transport- 1 In researching the mechanism by which liposomes are taken up by cells, the inventors unexpectedly discovered that inhibitors of SR-BI, as exemplified by BLT-1, at selected dosages increase the uptake of liposomes by cells.
  • the present disclosure also provides new combination formulations of a liposome comprising cytarabine and an ENT inhibitor. Also provided are combination therapies with these formulations, and methods of using the new formulations and combination therapies to treat disease. Supporting these various embodiments is the discovery that an exemplary ENT inhibitor, at selected dosages in combination with a liposome comprising cytarabine, enhances uptake of liposome-encapsulated cytarabine by target cells compared to the combination of unencapsulated cytarabine and an ENT inhibitor.
  • ENTs are polytopic integral membrane proteins that mediate physiologic nucleoside transport across cellular membranes (Boswell-Casteel and Hays, Nucleosides Nucleotides Nucleic Acids , 36(1): 7-30 (2017)).
  • ENT inhibitors include, but are not limited to, S-(4- nitrobenzyl)-6-thioinosine (NBMPR), dilazep, dipyridamole, and rapadocin (Rehan et al., SLAS Discovery, 24(10): 953-968 (2019)).
  • the ENT inhibitor comprises a modified nucleoside. In some embodiments, the ENT inhibitor comprises adenosine. In some embodiments, the ENT inhibitor comprises a modified adenosine. In some embodiments, the ENT inhibitor comprises a derivative and/or analog of adenosine. In some embodiments, the ENT inhibitor comprises a nucleoside modified with a thionitrobenzyl moiety. In some embodiments, the ENT inhibitor comprises a purine moiety. In an exemplary embodiment, the ENT inhibitor comprises NMBPR.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by how the value is measured or determined- e.g., the limitations of the measurement system, or the degree of precision required for a particular purpose. For example, “about” can mean within 1 or within 2 standard deviations, as per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, and more preferably up to 5% of a given value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” means an acceptable error range for the particular value should be assumed.
  • CPX-351 refers to a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5: 1 molar ratio.
  • the liposome is formulated with DSPC/DSPG/Chol at a about a 7:2: 1 ratio.
  • Liposome refers to closed vesicles having at least one lipid bilayer surrounding an aqueous core.
  • the intra-liposomal space and lipid layer(s) can entrap a wide variety of substances including drugs, cosmetics, diagnostic reagents, genetic material and bioactive compounds.
  • An exemplary liposome of use in the compositions and methods provided herein includes no more than about 20% cholesterol.
  • the liposome further comprises from about 1% to about 20% DSPG.
  • the liposome comprises one or more additional lipid. See. e g., U.S. Pat. No, 8.518,437, incorporated herein by reference in its entirety for all purposes.
  • the liposome is formulated from DSPC/DSPG/Chol in a ratio of about 7 to about 2 to about 1.
  • therapeutic agent or “drug” as used herein refers to chemical moieties used in a variety of therapeutic, including pharmaceutical applications.
  • the term "subject" refers to an animal, such as a mammal, bird, or fish.
  • the subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans.
  • the subject is a human, for example a human that has been or will be the object of treatment, observation or experiment.
  • therapeutically effective amount refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a subject in need of such treatment.
  • the therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity' of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art.
  • the therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
  • Patient doses for administration of either or both the liposome and the SR-BI inhibitor ty pically range from about 1 mg/day to about 10,000 mg/day, more ty pically from about 10 mg/day after adding suitable auxiliaries, if desired, to obtain tablets to about 1,000 mg/day, and most typically from about 50 to about 500 mg/day.
  • ty pical dosages can range from about 0.01 to about 150 mg/kg/day, more ty pically from about 0.1 to about 15 mg/kg /day, and most typically from about 1 to about 10 mg/kg/day, for example 5 mg/kg /day or 3 mg/kg/day. Adjusting the dosages to obtain a desired ratio of SR- BI inhibitor and liposome is within the skill of the ordinarily skilled clinician or researcher.
  • an exemplary “therapeutically effective amount” is an amount that increases the uptake of the liposome by the target cell to w hich the liposome and inhibitor are administered.
  • an exemplary “therapeutically effect amount” is an amount that enhances uptake of liposome-encapsulated cytarabine by the target cell relative to the uptake of unencapsulated cytarabine in the presence of the ENT inhibitor.
  • the patient doses for these agents are similar to those for the SR-BI inhibitor.
  • Target cell refers to a cell to which a liposome and an inhibitor are administered, and which uptakes the liposome.
  • SR-BI and/or ENT are administered.
  • An exemplary' target cell expresses SR-BI and/or ENT.
  • An exemplary target cell is a diseased cell exhibiting the genotype and/or phenotype of the disease.
  • An exemplary diseased cell over- or under-expresses SR-BI and/or ENT.
  • a target cell can also be a “normal” cell not exhibiting neither the genotype nor the phenotype of the disease.
  • the normal target cell is used as reference point for comparison to determine if cellular uptake is greater or lesser in the diseased cell.
  • Such comparisons are of use in determining whether a subject is an appropriate candidate for combination therapy with a liposome and an inhibitor of SR-BI and/or ENT, and/or an appropriate dosage level of either or both of these agents for the candidate.
  • Treatment includes one or more of: preventing a disease or disorder (i.e., causing the clinical symptoms of the disease or disorder not to develop); inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e.. causing relief from or regression of clinical symptoms).
  • the term encompasses situations where the disease or disorder is already being experienced by a subject, as well as situations where the disease or disorder is not currently being experienced but is expected to arise.
  • the term covers both complete and partial reduction or prevention of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder.
  • compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
  • the compounds disclosed and/or described herein may prevent a disease or disorder from developing or lessen the extent of a disease or disorder that may develop.
  • SR-BI refers to Scavenger Receptor B, type 1, which mediates the transfer of lipids between high density lipoproteins (HDL) and cells.
  • ⁇ ‘Inhibitor of SR-BI” refers to any member of a class of agents that function to inhibit SR-BI mediated cholesterol uptake by a cell to which the inhibitor is administered, as exemplified by BLT-1.
  • '‘BLT-1” refers to Block Lipid Transport-1, a thiosemicarbazone copper chelator, which is a SR-BI inhibitor.
  • ENT refers to Equilibrative Nucleoside Transporter, such as ENTL ENT2, ENT3, and ENT4, which are polytopic integral membrane proteins that mediate physiologic nucleoside transport across cellular membranes.
  • ENT inhibitor refers to any member of a class of agents that function to inhibit ENT mediated nucleoside transport across a cell membrane of a cell to which the inhibitor is administered, as exemplified by NBMPR.
  • a liposome encapsulating one or more therapeutic agents administered with an inhibitor of Scavenger Receptor BI (SR-BI) to a target cell expressing SR-BI results in a significant increase in uptake of the liposome by the target cell relative to the uptake seen in an identical target cell without administration of the inhibitor.
  • SR-BI Scavenger Receptor BI
  • a method of increasing the cellular uptake of a liposome encapsulating one or more therapeutic agents in a target cell expressing SR-BI includes administering the liposome to the cell and an amount of the inhibitor of SR-BI sufficient to increase uptake by the target cell of the liposome (e.g., "a therapeutically effective amounf ’).
  • Exemplary inhibitors of SR-BI including BLT-1, are known in the art, as are methods for assaying their activity' towards cells expressing this target, and methods for preparing and testing new inhibitors. See, e.g., U.S. Pat. No. 9,994,851.
  • the inhibitor of SR-BI is effective at increasing the uptake of the liposome by the target cell at a first dosage of the inhibitor.
  • An exemplar ⁇ ' first dosage is higher than a lower second dosage at which the cell shows no increase in uptake, an uptake less than that seen at the first dosage, or a lower degree of uptake than the target cell without administration of the inhibitor of SR-BI.
  • the target cell is an abnormal cell (e.g., diseased) and underexpresses or overexpresses SR-BI relative to an identical normal cell.
  • the formulations of the instant invention leverage this over-, under-expression to effect enhanced delivery of the liposome to the cell.
  • the liposome comprises at least 1 mol % distearoyl phosphatidylglycerol (DSPG) or distearoyl phosphatidylinositol (DSPI).
  • DSPG distearoyl phosphatidylglycerol
  • DSPI distearoyl phosphatidylinositol
  • the liposome comprises about 20 mol % or less of cholesterol.
  • the liposome comprises distearoylphosphatidyritiline (DSPC).
  • the liposome comprises DSPC, DSPG and Cholesterol.
  • An exemplary ratio of DSPC/DSPG/Cholesterol is about a 7:2: 1 molar ratio.
  • a method of treating a disease in a subject in need of such treatment includes administering to the subject a therapeutically effective amount of a liposome encapsulating one or more therapeutic agents effective in treating the disease, ameliorating the symptoms of the disease, etc., and an amount of an inhibitor of SR-BI selected such that the uptake of the liposome by a target cell of the subject is increased relative to the cellular uptake of the liposome by the same target cell in the absence of the inhibitor of SR-BI.
  • the disease is a proliferative disease, e.g., cancer.
  • the disease is a hematological disease, e.g., a hematological proliferative disorder.
  • the disease is leukemia, e.g., acute myeloid leukemia (AML).
  • the uptake of the liposome by a target cell is enhanced by administering, in addition to the liposome, an inhibitor of SR-BI.
  • the inhibitor is administered in an amount selected such that the uptake of the liposome by a target cell of the subject is increased relative to the cellular uptake of the liposome by the same target cell in the absence of the inhibitor.
  • An exemplary alteration of the side effect profile includes reducing the incidence or severity of one or more adverse events associated with administration of a therapeutically effective amount of the liposome.
  • An exemplary 7 alteration of the side effect profile includes a diminishment or amelioration of at least one undesirable side effect of the therapeutic agent on the subject to whom it is administered.
  • An exemplary' method of the invention is useful to reduce cellular resistance to one or more liposome encapsulated therapeutic agents, e.g., cytarabine, daunorubicin and combinations thereof.
  • the method comprises administering to a drug resistant target cell an inhibitor of SR-BI in an amount selected such that the cellular uptake of the liposome encapsulated therapeutic agent(s) by the target cell is increased relative to the cellular uptake of the liposome encapsulated agent(s) by the same target cell in the absence of the inhibitor of SR-BI. or the cellular efflux of the liposome encapsulated therapeutic agent(s) (or deencapsulated therapeutic agent(s)) is less than the efflux of the agent(s) relative to the same target cell in the absence of the inhibitor of SR-BI.
  • a method of combination therapy of a proliferative disorder e g., cancer, e.g., leukemia, e.g., acute myeloid leukemia.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a liposome encapsulating one or more therapeutic agents useful in treating the proliferative disease and a therapeutically effective amount of an inhibitor of BLT-1.
  • the liposome and inhibitor are administered substantially simultaneously or sequentially in either order (i.e. , inhibitor followed by liposome, or liposome followed by inhibitor).
  • the liposome and the inhibitor of SR-BI are administered sequentially in separate pharmaceutical formulations or combined into a single pharmaceutical formulation and administered in this format.
  • a method of this disclosure utilizes a liposome encapsulating one or more cancer chemotherapeutic agents.
  • the chemotherapeutic agents are cytarabine and daunorubicin.
  • the cytarabine and daunorubicin are encapsulated in the liposome in a 5: 1 ratio and the liposome comprises DSPC/DSPG/Cholesterol at about a 7:2: 1 ratio.
  • An exemplary liposome is CPX- 351.
  • a method of enhancing delivery of CPX-351 into an intracellular compartment of a target cell comprises administering to a subject in need thereof a therapeutically effective amount of CPX-351 and a therapeutically effective amount of a SR-BI inhibitor (e.g., BLT-1).
  • the therapeutic agents are administered sequentially in separate pharmaceutical formulations or combined into a single pharmaceutical formulation and administered in this format.
  • the amount of BLT-1 administered is effective to enhance uptake of CPX-351 by the cell, providing enhanced delivery' of CPX-351 to this compartment.
  • the delivery of the liposome to the intracellular compartment of the target cell is enhanced relative to the delivery to the same compartment of the same target cell in the absence of the inhibitor.
  • a method of altering the side effect profile of at least one therapeutic agent encapsulated in a liposome comprises administering to a subject in need thereof a therapeutically effective amount of the liposome and a therapeutically effective amount of SR-BI inhibitor.
  • the amount of the SR-BI inhibitor administered is effective to enhance uptake of the liposome by a target cell, providing enhanced delivery of the liposome to the target cell, thereby decreasing the amount of liposome delivered to a non-target cell and altering the side effect profile of the at least one therapeutic agent.
  • the at least one therapeutic agent is selected from cytarabine, daunorubicin and a combination thereof.
  • the inhibitor of SR-BI is BLT-1.
  • a method of determining whether administering a liposome encapsulating at least one therapeutic agent is an appropriate therapy for a selected subject in need of treatment with the at least one therapeutic agent comprises determining whether the target cell of the subject has an expression level of SR-BI greater or less than a pre-selected SR-BI expression level threshold; and if the SR- BI expression level is above this threshold identifying the subject as a candidate for therapy with the liposome.
  • the method above identifies a candidate for combination therapy with the liposome and an inhibitor of SR-BI.
  • the expression of SR-BI in the target cell is below the predetermined threshold.
  • the liposome comprises at least 1 mol % distearoyl phosphatidylglycerol (DSPG) or distearoyl phosphatidylinositol (DSPI).
  • the liposome comprises about 20 mol % or less of cholesterol.
  • the liposome comprises distearoylphosphatidylcholine (DSPC).
  • the liposome comprises DSPC, DSPG and Cholesterol.
  • the liposome comprises DSPC. DSPG and Cholesterol at a molar ratio of about 7:2: 1. In various embodiments, the liposome is CPX-351. In various embodiments, the inhibitor of SR-BI is BLT-1.
  • the method further comprises determining an appropriate dosage level for a liposome based on determining the expression level of SR-BI in a target cell of the subject to which the liposome is to be administered. For example, those subjects expressing a high level of SR-BI on the target cell may require a lower dosage of the liposome than those with a lower SR-BI expression on the principle that the cellular uptake of the liposome will be greater in those target cells expressing more SR-BI.
  • the dosage level is assessed taking into account the administration of combination therapy for the subject using a liposome and a SR-BI inhibitor.
  • the liposome is CPX-351.
  • the inhibitor of SR-BI is BLT-1.
  • a combination of a liposome comprising cytarabine and an equilibrative nucleoside transporter (ENT) (e.g., ENT1) inhibitor in therapeutically useful dosages results in a significant increase in uptake of liposome-encapsulated cytarabine by cells expressing ENT (e.g., ENT1) relative to the uptake of unencapsulated cytarabine in the presence of the ENT inhibitor seen in an identical cell (e.g.. “a therapeutically effective amount”).
  • ENT equilibrative nucleoside transporter
  • the disclosure sets forth a method of combination therapy of a disease in a subject in need of such treatment.
  • the method includes administering to a subject in need thereof a therapeutically effective amount of a liposome comprising cytarabine and an amount of an ENT inhibitor effective to enhance uptake of liposome- encapsulated cytarabine by a target cell exhibiting the genotype and/or phenotype associated with the proliferative disease relative to the uptake of unencapsulated cytarabine in the presence of the ENT inhibitor by an identical cell.
  • the disease is a proliferative disease, e.g., cancer.
  • the disease is a hematological disease, e.g., a hematological proliferative disorder.
  • the disease is leukemia, e.g., acute myeloid leukemia (AML).
  • the disclosure sets forth a method of enhancing delivery of a therapeutic agent into an intracellular compartment of a target cell in the presence of an ENT inhibitor.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a liposome comprising the therapeutic agent and a therapeutically effective amount of the ENT inhibitor, wherein uptake of the therapeutic agent by the target cell is enhanced relative to the uptake of unencapsulated therapeutic agent in the presence of the ENT inhibitor by an identical cell, thereby providing enhanced deliver)' of the therapeutic agent to the intracellular compartment.
  • the disclosure sets forth a method of enhancing deliver ⁇ ' of cytarabine into an intracellular compartment of a target cell in the presence of an ENT inhibitor, the method comprising administering to a subject in need thereof a therapeutically effective amount of a liposome comprising cytarabine and a therapeutically effective amount of the ENT inhibitor, wherein uptake of liposome-encapsulated cytarabine by the target cell is enhanced relative to the uptake of unencapsulated cytarabine in the presence of the ENT inhibitor by an identical cell, thereby providing enhanced deliver)' of the cytarabine to the intracellular compartment.
  • the method of the invention utilizing the ENT inhibitor alters the side effect profile of the therapeutic agent.
  • An exemplary alteration of the side effect profile includes a diminishment or amelioration of at least one undesirable side effect of the therapeutic agent on the subject to whom it is administered.
  • the enhanced deliver ’ to the target cell leads to less off target deliver)' than when the inhibitor is not present.
  • the liposome further comprises daunorubicin.
  • liposome comprises CPX-351.
  • the target cell is a blood cell. In some embodiments, the target cell is a leukemia cell.
  • the target cell is an abnormal cell (e.g., diseased) and underexpresses or overexpresses ENT relative to an identical normal cell.
  • abnormal cell e.g., diseased
  • the ENT inhibitor is NBMPR.
  • the liposome and the ENT inhibitor are administered sequentially in separate pharmaceutical formulations.
  • the liposome and the ENT inhibitor are combined into a single pharmaceutical formulation and administered to the subject in this format.
  • the liposome comprises at least 1 mol % distearoyl phosphatidylglycerol (DSPG) or distearoyl phosphatidylinositol (DSPI).
  • DSPG distearoyl phosphatidylglycerol
  • DSPI distearoyl phosphatidylinositol
  • the liposome comprises about 20 mol % or less of cholesterol.
  • the liposome comprises distearoylphosphatidylcholine (DSPC).
  • DSPC distearoylphosphatidylcholine
  • the liposome comprises DSPC, DSPG and Cholesterol.
  • An exemplary ratio of DSPC/DSPG/Cholesterol is about a 7:2: 1 molar ratio.
  • a method of treating acute myeloid leukemia in a subject in need of such treatment comprising administering a therapeutically relevant dose of CPX-351 to the subject and an inhibitor of SR-BI.
  • Administration of CPX-351 in this patient population is correlated with lower cardiotoxicity than administration of standard 7+3 therapy.
  • the SR-BI inhibitor is BLT-1.
  • a pharmaceutical formulation comprising therapeutically 7 effective amounts of a liposome including at least one encapsulated therapeutic agent, and an inhibitor (e.g., an inhibitor of SR-BI and/or ENT).
  • the liposome and inhibitor are in a pharmaceutically acceptable carrier, diluent, etc.
  • the pharmaceutical formulation includes a liposome encapsulating one or more therapeutic agents and a SR-BI inhibitor selected such that the cellular uptake of the liposome by a target cell is increased relative to the cellular uptake of the liposome by the same target cell in the absence of the inhibitor of SR-BI.
  • the presence of the inhibitor in the formulation reduces delivery to non-target cells.
  • the polymer-conjugated lipid is 1,2-distearoyl-rac-glycero- 3- methoxypoly(ethylene glycol) or l,2-dimyristoyl-rac-glycero-3-methoxypoly(ethylene glycol). In some embodiments, the polymer-conjugated lipid is l,2-distearoyl-rac-glycero-3- methoxy poly (ethylene glycol). In some embodiments, the polymer-conjugated lipid is DSG-PEG2000. In some embodiments, the lipid bilayer further comprises a second lipid. In some embodiments, the second lipid is a phospholipid.
  • the lipid bilayer comprises dihydrosphingomyelin (DHSM), cholesterol, and DSG-PEG2000. In some embodiments, the lipid bilayer comprises DHSM/cholesterol/DSG-PEG2000 at a molar ratio of about 53:45:2. In some embodiments, the lipid bilayer comprises distearoyl phosphatidyl choline (DSPC), cholesterol, and DSG- PEG2000. In some embodiments, the lipid bilayer comprises DSPC/cholesterol/DSG- PEG2000 at a molar ratio of about 57:38:5.6.
  • DHSM dihydrosphingomyelin
  • DSPC distearoyl phosphatidyl choline
  • the lipid bilayer comprises DSPC/cholesterol/DSG- PEG2000 at a molar ratio of about 57:38:5.6.
  • the liposome comprises about 20 mol% or less of cholesterol.
  • the liposome has a mean diameter between about 50 nm and about 250 nm. In some embodiments, the liposome has a mean diameter between about 50 nm and about 150 nm. In some embodiments, the liposome has a mean diameter between about 50 nm and about 120 nm. In some embodiments, the liposome has a mean diameter between about 50 nm and about 100 nm. In some embodiments, the liposome has a mean diameter of about 80 nm. In some embodiments, the liposome has a mean diameter between about 80 nm and about 150 nm. In some embodiments, the liposome has a mean diameter of about 120 nm.
  • the liposomal composition has a poly dispersity 7 index (PDI) between about 0.001 and about 0.5. In some embodiments, the liposomal composition has a poly dispersity index (PDI) between about 0.001 and about 0.3. In some embodiments, the liposomal composition has a poly dispersity index (PDI) between about 0.001 and about 0.1. In some embodiments, the liposomal composition has a poly dispersity index (PDI) between about 0.1 and about 0.3. In some embodiments, the liposomal composition has a poly dispersity index (PDI) between about 0.1 and about 0.5. In some embodiments, the liposomal composition has a poly dispersity index (PDI) between about 0.3 and about 0.5.
  • the concentration of delivery vehicles in the pharmaceutical formulations can vary widely, such as from less than about 0.05%, usually at or at least about 2-5% to as much as 10 to 30% by weight and will be selected primarily by fluid volumes, viscosities, and the like, in accordance with the particular mode of administration selected. For example, the concentration may be increased to lower the fluid load associated with treatment. Alternatively, delivery vehicles composed of irritating lipids may be diluted to low concentrations to lessen inflammation at the site of administration. For diagnosis, the amount of delivery vehicles administered will depend upon the particular label used, the disease state being diagnosed and the judgment of the clinician.
  • the pharmaceutical compositions of the present invention are administered intravenously. Dosage for the delivery vehicle formulations will depend on the ratio of drug to lipid and the administrating physician's opinion based on age, weight, and condition of the patient.
  • the liposomal composition further comprises a therapeutic agent external to the one or more liposomes.
  • the inhibitor of SR-BI and/or ENT is external to the liposome.
  • the formulation comprises a therapeutically effective amount of CPX-351 and a therapeutically effective amount of an inhibitor (e.g., an inhibitor of SR-BI and/or ENT).
  • an inhibitor e.g., an inhibitor of SR-BI and/or ENT.
  • the formulation includes the SR-BI inhibitor Block Lipid Transport-1 (BLT-1) and a liposome containing at least one encapsulated therapeutic agent.
  • BLT-1 Block Lipid Transport-1
  • the formulation includes NBMPR and a liposome comprising at least one encapsulated therapeutic agent.
  • the formulation includes NBMPR and a liposome comprising cytarabine.
  • the formulation comprises a combination of CPX-351 and NBMPR in a pharmaceutically acceptable carrier, diluent, etc.
  • kits comprising a first vessel containing a therapeutically effective amount of a liposome comprising at least one therapeutic agent encapsulated therein, and a second vessel comprising a therapeutically effective amount of an inhibitor of SR-BI.
  • the kit further comprises instructions for the clinician for administering the liposome and SR-BI inhibitor to a subject in need of treatment with these agents.
  • the instructions optionally detail a procedure to prepare the liposome and/or inhibitor of SR-BI, in a therapeutically effective amount, prior to administering the combination to the subject.
  • kits which include, in separate containers, a first composition comprising delivery vehicles stably associated with at least a first therapeutic agent and, in a second container, a second composition comprising delivery vehicles stably associated with at least one second therapeutic agent.
  • the containers can then be packaged into the kit.
  • the kit also includes instructions as to the mode of administration of the compositions to a subject, at least including a description of the ratio of amounts of each composition to be administered.
  • the kit is constructed so that the amounts of compositions in each container is pre-measured so that the contents of one container in combination with the contents of the other represent the correct ratio.
  • the containers may be marked with a measuring scale permitting dispensation of appropriate amounts according to the scales visible.
  • the containers may themselves be useable in administration; for example, the kit might contain the appropriate amounts of each composition in separate syringes. Formulations which comprise the pre-formulated correct ratio of therapeutic agents may also be packaged in this way so that the formulation is administered directly from a syringe prepackaged in the kit.
  • the present disclosure sets forth new methods, compositions and kits. Supporting these various embodiments is the discovery that an exemplary inhibitor of SR-BI, Block Lipid Transport-1, in a therapeutically effective dose (HD-BLT-1) administered in conjunction with a liposome encapsulating one or more therapeutic agents results in a significant increase in uptake of the liposome, and hence the therapeutic agent(s) by cells expressing Scavenger Receptor Bl (SR-BI). This result is surprising in view of the fact that administration of BLT-1 at lower dosages (LD-BLT-1) induces the opposite effect, decreasing cellular uptake of the liposome.
  • SR-BI Scavenger Receptor Bl
  • compositions and methods of the invention are exemplified by the combination of the liposome CPX-351, a liposome encapsulating cytarabine and daunorubicin, and the SR-BI inhibitor BLT-1.
  • the methods, compositions and principles of the instant disclosure are, however, not limited to this exemplary embodiment.
  • compositions and methods exemplified by the combination of the liposome CPX-351, a liposome encapsulating cytarabine and daunorubicin, and the ENT inhibitor NBMPR.
  • the methods, compositions and principles of the instant disclosure are, however, not limited to this exemplary embodiment.
  • the present disclosure also provides a method of treating a selected patient population with AML, with CPX-351, resulting in therapeutic efficacy with lower cardiotoxicity than would otherwise be expected.
  • the patient population includes subject over the age of 60.
  • Combination of cytarabine and daunorubicin is the standard induction chemotherapy in patients treated with AML.
  • the clinical efficacy of the combination how ever, has been limited in the older population.
  • the clearance and metabolism of the two drugs are different, such that when the free drugs are co-administered, the molar ratio at the pharmacologic site of action will vary over time, resulting in intracellular molar ratios that may be additive, synergistic or antagonistic.
  • a method of treating acute myeloid leukemia in a subject in need of such treatment comprising administering a therapeutically relevant dose of CPX- 351 to the subject.
  • markers of cardiotoxicity due to CPX-351 are lower in patients falling into this age group vs. these markers in patients in this age group to whom standard 7+3 therapy is administered.
  • HL-60 human promyelocytic leukemia cells (ATCC, VA, USA: CCL-240) was cultured in RPMI-1640 media with 20% fetal bovine serum (FBS, Cat# 173012; NICHIREI BIOSCIENCES INC, Tokyo, Japan) and maintained in a 5% CO 2 - humidified atmosphere at 37°C.
  • FBS fetal bovine serum
  • K562 chronic myelogenous leukemia cells (JCRB Cell Bank, Osaka, Japan: JCRB0019), K562/ADM adriamycin resistant derivative of K562 cell line due to expressing P-gly coprotein (JCRB Cell Bank: JCRB 1002), THP-1 human acute monocytic leukemia cells (JCRB Cell Bank: JCRB01 12.1), and HL-60/ AD cytarabine and daunorubicin resistant derivative of HL-60 cell line due to expressing multidrug resistance-associated protein (MRP) established in our laboratory 25 , were cultured in RPMI-1640 media with 10% FBS and maintained in a 5% CO2-humidified atmosphere at 37°C.
  • MRP multidrug resistance-associated protein
  • CPX-351 handling The formulation of CPX-351 liposome for injection was a sterile, pyrogen-free, purple, lyophilized product provided in 50 mL vials, each containing 100 units where 1 unit is equivalent to 1.0 mg of cytarabine and 0.44 mg of daunorubicin (as base). The product was reconstituted with 19 mL of ultrapure water and gently swirled for 10 minutes at room temperature. Working aliquots of the reconstituted product were stored frozen at -20°C.
  • CPX-351 was mixed with FBS in a 1: 1 volume ratio and incubated at room temperature for 90 minutes. Following incubation, the samples were centrifuged for 15 minutes at 14,000 rpm, followed by resuspension of the pellet in phosphate-buffered saline (PBS). This procedure was repeated three times to wash the sample and remove unbound proteins.26 The protein pellets were then subjected to tryptic digestion using an In-Solution Tryptic Digestion and Guanidination Kit (Thermo Fisher Scientific, Bremen, Germany) according to the manufacturer's instructions.
  • PBS phosphate-buffered saline
  • Liquid chromatography - tandem mass spectrometry (LC-MS/MS) analysis was performed on an Orbitrap Elite hybrid ion trap-Orbitrap mass spectrometer (Thermo Fisher Scientific) equipped with a nanoelectrospray ion source.
  • Raw data files were analyzed using Proteome Discover (version 1.4.0.288; Thermo Fisher Scientific) and searched against the UniProt database (UniProtKB 2022_01 results).
  • a well-established label-free technique was used to determine the absolute concentration of proteins via the utilization of the average MS signal response of the most optimal two or three ionizing peptides to a given protein. (Silva JC, Gorenstein MV, Li GZ, Vissers JP, Geromanos SJ. Absolute quantification of proteins by LCMSE: a virtue of parallel MS acquisition. Mol Cell Proteomics. 2006:5(1): 144-156.).
  • SR-BI scavenger receptor class B type 1
  • LRP1 low -density 7 lipoprotein receptor-related protein 1
  • SR-BI antibody Miltenyi Biotec, Bergisch Gladbach, Germany
  • APC-conjugated LRP1 antibody Miltenyi Biotec
  • human IgGl isotype control antibody Miltenyi Biotec
  • LDLR low-density 7 lipoprotein receptor
  • PE-conjugated anti-LDLR antibody C7 clone; Novus Biologicals, Littleton, CO.
  • mice IgG2b isotype control Novus Biologicals
  • mouse IgG2b isotype control Novus Biologicals
  • Flow cytometry for cellular uptake of CPX-351 Uptake of CPX-351 into each leukemia cell lines w as measured using flow cytometry, utilizing the fluorescence of free daunorubicin. Cells were resuspended to a density 7 of 1 x 106 cells/mL in 1 mL of FBS alone. Then, CPX-351 was added to these cells to a final concentration of 19.5 pM in daunorubicin equivalents. After two hours of incubation (37 °C. 5% CO2), cells were washed with PBS and analyzed by BD FACS Canto II at an excitation wavelength of 480 nm and an emission wavelength of 590 nm. The intracellular daunorubicin content was determined by the median fluorescence intensity of gated leukemic cells, normalized by the corresponding negative controls, and expressed in AU ⁇ SE. 27,28
  • MK-571 50 pM, Cayman Chemical, Ann Arbor, MI, USA
  • an MRP inhibitor was added to HL- 60/ AD and incubated for 30 minutes (37 °C, 5% CO2).
  • Tariquidar 1 pM, Selleck Chemicals, Houston, TX, USA
  • a P-glycoprotein inhibitor was added to K562/ADM and incubated for 10 minutes (37 °C, 5% CO2).
  • CPX-351 was added to these cells to a final concentration of 3.9 pM in daunorubicin equivalents. After four hours of incubation (37 °C. 5% CO2), cells were washed with PBS and analyzed by BD FACS Canto II using the previously described method.
  • Peripheral blood or bone marrow specimens were obtained from patients with newly diagnosed or relapsed/refractory AML. This study was conducted in accordance with the Declaration of Helsinki, and informed consent w as obtained from all patients. The protocol was approved by the Institutional Review Board of the University of Fukui School of Medical Sciences. The blood or bone marrow specimens were separated on a Ficoll gradient.
  • the abundant proteins that comprise the protein corona of CPX-351 identified using the average MS signal response of the three best ionizing peptides are listed in Table 1. Those identified using the average MS signal response of the two best ionizing peptides are listed in Table 2.
  • the protein corona of CPX-351 liposomes was primarily composed of apolipoproteins, including apolipoproteins A-II (relative ratio: 47.34% ⁇ SE: 6.7) and A-I (5.25% ⁇ 0.52), which are ligands for SR-BI, 37 ’ 38 and apolipoprotein C-III (21.71% ⁇ 1.17), which binds to LDLR and LRP1.
  • Table 1 The abundant proteins identified in the protein corona of CPX-351 via the utilization Table 2
  • LDLR was expressed in THP-1 (4.1 AU ⁇ 0.06) but was diminished in HL-60 (1.5 AU ⁇ 0.08) and K562 (1.2 AU ⁇ 0.03) (Figure IB).
  • LRP1 was expressed in THP-1 (1.7 AU ⁇ 0.05), but not in HL-60 or K562 ( Figure 1C).
  • IC50 of CPX-351 was significantly higher in both HL-60/AD (7120 nM in cytarabine equivalents, p ⁇ 0.01) and K562/ADM (512.7 nM in cytarabine equivalents, p ⁇ 0.01) compared to their respective parental cells (Table 3).
  • MK-571 an MRP inhibitor
  • HL-60/AD significantly increased the intracellular CPX-351 in HL-60/AD (9.1 AU ⁇ 0.07) compared to the control (3.1 AU ⁇ 0.2, p ⁇ 0.01) ( Figure 2B), and correspondingly decreased the IC50 in HU-60/ AD (478.3 nM in cytarabine equivalents) compared to the control (7120 nM, p ⁇ 0.01) ( Figure 2C).
  • HD-BLT-1 also significantly increased the uptake of CPX-351 in resistance cells, HL-60/ AD and K562/ADM, by more than twofold compared to control cells, with increases of 434.4% and 214.2%, respectively (p ⁇ 0.01, respectively) (Figure 4D-E).
  • Sample 2 was a 64-year-old man who experienced relapse of AML with complex karyotype (FAB: M0, WHO: AML, not otherwise specified) after receiving standard induction and consolidation chemotherapy, and was resistant to azacitidine.
  • Sample 3 w as a 72-year-old woman with newly diagnosed FLT3/ITD-positive AML (FAB: M5, WHO: AML with NPM1 mutation).
  • the expression of SR-BI was highest in sample 3. followed by sample 1 and sample 2 ( Figure 5A).
  • the uptake of CPX-351 was highest in sample 3, followed by sample 1 and sample 2.
  • the addition of HD-BLT-1 significantly increased the uptake of CPX-351 by more than twofold in sample 1 and sample 3, but did not alter uptake in sample 2 ( Figure 5B).
  • SR-BI-mediated uptake pathway may be a key mechanism by which CPX-351 is internalized in leukemia cells.
  • SR-BI expression in HL- 60/ AD and K562/ADM was at least as high as in their respective parental cell lines, but CPX- 351 uptake was significantly lower.
  • MK571 to HL-60/ AD and tariquidar to K562/ADM significantly increased CPX-351 uptake and significantly decreased IC50. suggesting that MRP and P -glycoprotein expression may be the resistance mechanism for CPX-351.
  • HD-BLT-1 was added, CPX-351 uptake increased more than twofold in all different cell lines, including resistant cells.
  • Apolipoproteins have been shown to bind to lipoprotein receptors, such as SR-BI and LDLR, which are frequently observed in a variety of pathological conditions, including melanoma, lymphoma, hepatocellular carcinoma, and atherosclerosis. 41 This apolipoprotein-rich characteristic of nanoparticles may enable them to be recognized by cells that overexpress apolipoprotein receptors.
  • SR-BI is the primary receptor responsible for the selective internalization of cholesteryl esters from high- density lipoprotein (HDL) molecules, which consists of apolipoproteins A-I and A-II. 45,46 SR-BI has recently gained attention for its role in cancer development. 47 High expression of SR-BI has been observed in various types of cancer cells including choriocarcinoma cells, malignant epithelial cells, prostate cancer cells, breast cancer cells, and hepatoma cells.
  • HDL high- density lipoprotein
  • SR-BI high expression of SR-BI has been linked to poor prognosis in breast 48 , lung 49 , renal cell cancer 50 , and neuroblastoma. 51 However, the expression and significance of SR-BI in leukemia have not yet been fully analyzed. In this study, all the cell lines used expressed SR- BI. Recently, various nanomedicine carrying therapeutic agents targeting cancer cells with high expression of SR-BI have been tested. 52 ' 54
  • SR-BI has been demonstrated to possess the ability to form a hydrophobic tunnel within cell membranes, allowing for the selective uptake of hydrophobic molecules which bypass lysosomal processing.
  • BLT-1 a selective inhibitor of SR-BI, can bind to the cysteine 384 residue of SR-BI, inhibiting the transfer of cholestery l esters.
  • BLT- 1 is highly specific to the SR-BI pathway and does not interfere with receptor-mediated endocytosis or other forms of intracellular vesicular traffic. 33 In addition to inhibiting the uptake of cholesteryl esters via SR-BI, BLT-1 has the unique characteristic of increasing SR- BI's binding affinity 7 for HDL in a dose-dependent manner, resulting in enhanced HDL binding. 33 34
  • HD-BLT-1 also increased CPX-351 uptake in patient samples, but not in a sample with low SR-BI expression.
  • HD-BLT-1 may enhance the binding of CPX-351 to SR-BI, activating other endocytic pathway s such as macropinocytosis in addition to CME, leading to an increased uptake of CPX-351 in leukemia cells.
  • Macropinocytosis has recently received significant attention as a potential method of selective drug delivery 7 to cancer cells, as it is uniquely expressed by some cancer cells in comparison to healthy cells of the same ty pe.
  • cancer cells with mutant KRAS activate macropinocytosis to actively take up nutrients such as glucose, lipids, and albumin to meet their energetic requirements for survival and proliferation.
  • HDL particles reconstituted with apolipoprotein E3 have been found to activate macropinocytosis and are efficiently taken up by glioblastoma cells.
  • SR-BI binds apolipoprotein A-I and All, a main component of the protein corona of CPX-351
  • the enhancement of the binding between CPX-351 and SR-BI through the addition of HD-BLT-1 may increase uptake through the activation of macropinocytosis.
  • SR-BI can serve as a potential biomarker for CPX-351 therapy and that the combination of HD-BLT-1 and nanoparticle formulations can enhance therapeutic efficacy in treatment.
  • DNR drug sensitivities of daunorubicin
  • HL-60 cells w ere pre-incubated for 30 min with or without 1 pM NBMPR, and then treated with daunorubicin (DNR) for further 72 h. Subsequently, the cell growth inhibition (IC50) was determined by using the XTT assay. DNR inhibited the growth of HL-60 cells to the same extent regardless of the presence of NBMPR. Table 5. Drug sensitivities of daunorubicin (DNR) in the presence of or in the absence of a nucleoside transporter inhibitor NBMPR.
  • CPX-351 a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1 :5 molar ratio, is approved for newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in the United States and Europe. Whilst CPX-351 demonstrated improved overall survival and a similar safety profile vs 7+3 in the phase 3 clinical trial (NCT01696084). the safety of CXP-351 related to cardiac function has not been fully described, an important consideration, due to the known cardiot oxi city risk from anthracyclines.
  • Cardiac impairment was determined by cardiac adverse events (AEs) as well as echocardiogram (ECHO) measures including left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). which were assessed at baseline and two follow-up visits (follow-up 1: 30-45 days from last induction or prior to consolidation or salvage therapy; follow-up 2: Day 150 or 45 days ( ⁇ 10 days) from last treatment).
  • AEs cardiac adverse events
  • ECHO echocardiogram
  • LVEF left ventricular ejection fraction
  • GLS global longitudinal strain
  • a clinically significant change in LVEF (>10% absolute change from baseline and LVEF ⁇ 53%) or GLS (>12% relative change from baseline and GLS ⁇ 18%) was less common in patients treated with CPX-351 vs 7+3 (8% vs 16% and 21% vs 44%, respectively) at follow-up 1 or 2.
  • the frequency of any cardiac disorder was similar in both CPX-351 and 7+3-treated patients (38% vs 40%).
  • Tachycardia was most frequent in CPX-351 -treated patients than in 7+3-treated patients (19% vs 9%), while atrial fibrillation was most frequent in 7+3-treated patients than in CPX-351 -treated patients (13% vs 3%).

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Abstract

L'invention concerne diverses formulations pour une polythérapie avec un liposome et un inhibiteur de SRBI, conduisant à une absorption améliorée du liposome par une cellule cible sont fournies et exemplifiées par une polythérapie avec CPX-351 et BLT-1. L'invention concerne également diverses formulations pour une polythérapie avec un liposome et un inhibiteur d'ENT conduisant à une absorption améliorée de cytarabine encapsulée dans des liposomes par une cellule cible. L'invention concerne également des procédés d'utilisation des formulations en polythérapie. L'invention concerne également un procédé de réduction de la cardiotoxicité dans une population de patients stratifiés dans l'âge subissant une thérapie avec de la cytarabine et de la daunorubicine, CPX-351.
PCT/IB2024/000175 2023-04-03 2024-04-03 Modulateurs de l'absorption de nanoparticules WO2024209267A2 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993754A (en) 1974-10-09 1976-11-23 The United States Of America As Represented By The United States Energy Research And Development Administration Liposome-encapsulated actinomycin for cancer chemotherapy
US4145410A (en) 1976-10-12 1979-03-20 Sears Barry D Method of preparing a controlled-release pharmaceutical preparation, and resulting composition
US4224179A (en) 1977-08-05 1980-09-23 Battelle Memorial Institute Process for the preparation of liposomes in aqueous solution
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4522803A (en) 1983-02-04 1985-06-11 The Liposome Company, Inc. Stable plurilamellar vesicles, their preparation and use
US4588578A (en) 1983-08-08 1986-05-13 The Liposome Company, Inc. Lipid vesicles prepared in a monophase
US8518437B2 (en) 2001-11-13 2013-08-27 Celator Pharmaceuticals, Inc. Lipid carrier compositions with enhanced blood stability
US9884851B2 (en) 2012-10-19 2018-02-06 Massachusetts Institute Of Technology Heterocycle-bisamide inhibitors of scavenger receptor BI
US9994851B2 (en) 2004-06-28 2018-06-12 The University Of Western Australia Antisense oligonucleotides for inducing exon skipping and methods of use thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993754A (en) 1974-10-09 1976-11-23 The United States Of America As Represented By The United States Energy Research And Development Administration Liposome-encapsulated actinomycin for cancer chemotherapy
US4145410A (en) 1976-10-12 1979-03-20 Sears Barry D Method of preparing a controlled-release pharmaceutical preparation, and resulting composition
US4224179A (en) 1977-08-05 1980-09-23 Battelle Memorial Institute Process for the preparation of liposomes in aqueous solution
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4522803A (en) 1983-02-04 1985-06-11 The Liposome Company, Inc. Stable plurilamellar vesicles, their preparation and use
US4588578A (en) 1983-08-08 1986-05-13 The Liposome Company, Inc. Lipid vesicles prepared in a monophase
US8518437B2 (en) 2001-11-13 2013-08-27 Celator Pharmaceuticals, Inc. Lipid carrier compositions with enhanced blood stability
US9994851B2 (en) 2004-06-28 2018-06-12 The University Of Western Australia Antisense oligonucleotides for inducing exon skipping and methods of use thereof
US9884851B2 (en) 2012-10-19 2018-02-06 Massachusetts Institute Of Technology Heterocycle-bisamide inhibitors of scavenger receptor BI

Non-Patent Citations (73)

* Cited by examiner, † Cited by third party
Title
ANDERSON ET AL., LEUKEMIA RESEARCH, vol. 74, 2018, pages 121 - 129
ARBER DAORAZI AHASSERJIAN R ET AL.: "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia", BLOOD, vol. 127, no. 20, 2016, pages 2391 - 2405
BINNEMARS-POSTMA KATEN HOOPEN HWSTORM GPRAKASH J: "Differential uptake of nanoparticles by human M1 and M2 polarized macrophages: protein corona as a critical determinant", NANOMEDICINE (LOND)., vol. 11, no. 22, 2016, pages 2889 - 2902
BORÉN JPACKARD CJTASKINEN MR: "The Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans", FRONT ENDOCRINOL (LAUSANNE, vol. 11, 2020, pages 474
BOSWELL-CASTEELHAYS, NUCLEOSIDES NUCLEOTIDES NUCLEIC ACIDS, vol. 36, no. 1, 2017, pages 7 - 30
CARACCIOLO GCARDARELLI FPOZZI D ET AL.: "Selective targeting capability acquired with a protein corona adsorbed on the surface of 1,2-dioleoyl-3-trimethylammonium propane/DNA nanoparticles", ACS APPL MATER INTERFACES, vol. 5, no. 24, 2013, pages 13171 - 13179
COMMISSO CDAVIDSON SMSOYDANER-AZELOGLU RG ET AL.: "Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells", NATURE, vol. 497, no. 7451, 2013, pages 633 - 637, XP055322083, DOI: 10.1038/nature12138
CONG VTHOUNG JLKAVALLARIS MCHEN XTILLEY RDGOODING JJ: "How can we use the endocytosis pathways to design nanoparticle drug-delivery vehicles to target cancer cells over healthy cells?", CHEM SOC REV., vol. 51, no. 17, 2022, pages 7531 - 7559
CORTES ET AL., CANCER, vol. 121, no. 2, 2015, pages 234 - 42
DAMKE HBABA TVAN DER BLIEK AMSCHMID SL: "Clathrin-independent pinocytosis is induced in cells overexpressing a temperature-sensitive mutant of dynamin", J CELL BIOL., vol. 131, no. 1, 1995, pages 69 - 80
DEN BOER MLPIETERS RKAZEMIER KM: "Janka-Schaub GE, Henze G. Veerman AJ. Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia", LEUKEMIA, vol. 13, no. 12, 1999, pages 2023 - 2030
DI ET AL., DRUG DEV. IND. PHARM., vol. 45, no. 1, 2019, pages 21 - 26
DI YWASAN EKCAWTHRAY JWASAN KM: "Scavenger receptor class BI (SR-BI) mediates uptake of CPX-351 into K562 leukemia cells", DRUG DEV IND PHARM., vol. 45, no. 1, 2019, pages 21 - 26
DIGIACOMO LCARDARELLI FPOZZI D ET AL.: "An apolipoprotein-enriched biomolecular corona switches the cellular uptake mechanism and trafficking pathway of lipid nanoparticles", NANOSCALE, vol. 9, no. 44, 2017, pages 17254 - 17262
DINARDO ET AL., EXPERT OPIN PHARMACOTHER, vol. 6, no. 1, 2015, pages 95 - 106
DING YWANG YZHOU J ET AL.: "Direct cytosolic siRNA delivery by reconstituted high density lipoprotein for target-specific therapy of tumor angiogenesis", BIOMATERIALS, vol. 35, no. 25, 2014, pages 7214 - 7227, XP028868106, DOI: 10.1016/j.biomaterials.2014.05.009
DOS SANTOS TVARELA JLYNCH 1SALVATI ADAWSON KA: "Effects of transport inhibitors on the cellular uptake of carboxylated polystyrene nanoparticles in different cell lines", PLOS ONE, vol. 6, no. 9, 2011, pages e24438
EHRLICH MBOLL WVAN OIJEN A ET AL.: "Endocytosis by random initiation and stabilization of clathrin-coated pits", CELL, vol. 118, no. 5, 2004, pages 591 - 605
FELDMAN EJKOLITZ JETRANG JM ET AL.: "Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia", LEUK RES., vol. 36, no. 10, 2012, pages 1283 - 1289, XP055586667, DOI: 10.1016/j.leukres.2012.07.006
FENG HWANG MWU C ET AL.: "High scavenger receptor class B type I expression is related to tumor aggressiveness and poor prognosis in lung adenocarcinoma: A STROBE compliant article", MEDICINE (BALTIMORE, vol. 97, no. 13, 2018, pages e0203
GABIZON ASHMEEDA HBARENHOLZ Y: "Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies", CLIN PHARMACOKINET., vol. 42, no. 5, 2003, pages 419 - 436, XP009094909, DOI: 10.2165/00003088-200342050-00002
GRADISHAR WJTJULANDIN SDAVIDSON N ET AL.: "Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer", J CLIN ONCOL., vol. 23, no. 31, 2005, pages 7794 - 7803, XP055089298, DOI: 10.1200/JCO.2005.04.937
GREF RMINAMITAKE YPERACCHIA MTTRUBETSKOY VTORCHILIN VLANGER R: "Biodegradable long-circulating polymeric nanospheres", SCIENCE., vol. 263, no. 5153, 1994, pages 1600 - 1603, XP002503997, DOI: 10.1126/science.8128245
GUTIERREZ-PAJARES JLBEN HASSEN CCHEVALIER SFRANK PG: "SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer", FRONT PHARMACOL, vol. 7, 2016, pages 338
HUANG JLJIANG GSONG QX ET AL.: "Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis", NAT COMMUN, vol. 8, 2017, pages 15144
KAKSONEN MROUX A: "Mechanisms of clathrin-mediated endocytosis", NAT REV MOL CELL BIOL., vol. 19, no. 5, 2018, pages 313 - 326
KALEPU SNEKKANTI V: "Improved delivery of poorly soluble compounds using nanoparticle technology: a review", DRUG DELIV TRANSL RES., vol. 6, no. 3, 2016, pages 319 - 332, XP035968826, DOI: 10.1007/s13346-016-0283-1
KUHN DAVANHECKE DMICHEN B ET AL.: "Different endocytotic uptake mechanisms for nanoparticles in epithelial cells and macrophages", BEILSTEIN J NANOTECHNOL., vol. 5, 2014, pages 1625 - 1636
LANCET ET AL., AMERICAN SOCIETY OF CLINICAL ONCOLOGY, 2016
LANCET ET AL., BLOOD, vol. 123, no. 21, 2014, pages 3239 - 46
LANCET JEUY GLNEWELL LF ET AL.: "CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial", LANCET HAEMATOL., vol. 8, no. 7, 2021, pages e481 - e491
LI JWANG JLI MYIN LLI XAZHANG TG: "Up-regulated expression of scavenger receptor class B type 1 (SR-B1) is associated with malignant behaviors and poor prognosis of breast cancer", PATHOL RES PRACT., vol. 212, no. 6, 2016, pages 555 - 559, XP029544348, DOI: 10.1016/j.prp.2016.03.011
LIM ET AL., LEUK RES., vol. 34, no. 9, 2010, pages 1214 - 23
LIN HPSINGLA BGHOSHAL P ET AL.: "Identification of novel macropinocytosis inhibitors using a rational screen of Food and Drug Administration-approved drugs", BR J PHARMACOL, vol. 175, no. 18, 2018, pages 3640 - 3655
MAEDA H.: "Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity", ADV DRUG DELIV REV., vol. 91, 2015, pages 3 - 6, XP029265305, DOI: 10.1016/j.addr.2015.01.002
Marcel Dekker, Inc.; "UniProtKB", Database accession no. 2022_01
MATSUDA YYAMAUCHI THOSONO N ET AL.: "Combination of panobinostat with ponatinib synergistically overcomes imatinib-resistant CML cells", CANCER SCI., vol. 107, no. 7, 2016, pages 1029 - 1038
MATSUMURA YMAEDA H: "A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs", CANCER RES., vol. 46, 1986, pages 6387 - 6392, XP002084436
MEANS NELECHALAWAR CKCHEN WRBHATTACHARYA RMUKHERJEE P: "Revealing macropinocytosis using nanoparticles", MOL ASPECTS MED., vol. 83, 2022, pages 100993
MOL CELL PROTEOMICS, vol. 5, no. 1, 2006, pages 144 - 156
NG KKLOVELL JFZHENG G: "Lipoprotein-inspired nanoparticles for cancer theranostics", ACC CHEM RES., vol. 44, no. 10, 2011, pages 1105 - 1113, XP055247826, DOI: 10.1021/ar200017e
NIELAND TJEHRLICH MKRIEGER MKIRCHHAUSEN T: "Endocytosis is not required for the selective lipid uptake mediated by murine SR-BI", BIOCHIM BIOPHYS ACTA, vol. 1734, no. 1, 2005, pages 44 - 51, XP004873140, DOI: 10.1016/j.bbalip.2005.02.007
NIELAND TJPENMAN MDORI LKRIEGER MKIRCHHAUSEN T: "Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI.", PROC NATL ACAD SCI, vol. 99, no. 24, 2002, pages 15422 - 15427, XP002381179, DOI: 10.1073/pnas.222421399
NIELAND TJSHAW JTJAIPURI FA ET AL.: "Identification of the molecular target of small molecule inhibitors of HDL receptor SR-BI activity", BIOCHEMISTRY, vol. 47, no. 1, 2008, pages 460 - 472
NIKANJAM ET AL., CANCER CHEMOTHER PHARMACOL, vol. 81, no. 1, 2018, pages 171 - 8
OFRAN ET AL., LEUKEMIA, vol. 30, no. 8, 2016, pages 1796
ONISHCHENKO NTRETIAKOVA DVODOVOZOVA E: "Spotlight on the protein corona of liposomes", ACTA BIOMATER., vol. 134, 2021, pages 57 - 78, XP086833969, DOI: 10.1016/j.actbio.2021.07.074
PALCHETTI SCOLAPICCHIONI VDIGIACOMO L ET AL.: "The protein corona of circulating PEGylated liposomes", BIOCHIM BIOPHYS ACTA, vol. 1858, no. 2, 2016, pages 189 - 196, XP029374417, DOI: 10.1016/j.bbamem.2015.11.012
PANCHOO MLACKO A: "Scavenger receptor class B type 1 regulates neuroblastoma cell proliferation, migration and invasion", BIOCHEM BIOPHYS RES COMMUN., vol. 495, no. 1, 2018, pages 614 - 620
PILON ABRIAND OLESTAVEL S ET AL.: "Apolipoprotein All enrichment of HDL enhances their affinity for class B type I scavenger receptor but inhibits specific cholesteryl ester uptake", ARTERIOSCLER THROMB VASE BIOL., vol. 20, no. 4, 2000, pages 1074 - 1081
POZZI DCARACCIOLO GDIGIACOMO L ET AL.: "The biomolecular corona of nanoparticles in circulating biological media", NANOSCALE., vol. 7, no. 33, 2015, pages 13958 - 13966
QUAGLIARINI EDIGIACOMO LRENZI SPOZZI DCARACCIOLO G: "A decade of the liposome-protein corona: Lessons learned and future breakthroughs in theranostics", NANO TODAY, vol. 47, 2022, pages 101657
RALDUE ET AL., TOX. LETTERS, vol. 175, no. 1-3, 2007, pages 1 - 7
REHAN ET AL., SLAS DISCOVERY, vol. 24, no. 10, 2019, pages 953 - 968
RENNICK JJJOHNSTON APR: "Parton RG. Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics", NAT NANOTECHNOL., vol. 16, no. 3, 2021, pages 266 - 276, XP037409683, DOI: 10.1038/s41565-021-00858-8
ROBOZ, HEMATOLOGY, AM SOC HEMATOL EDUC PROGRAM, vol. 2011, 2011, pages 43 - 50
SAKAI-KATO KSAKURAI MTAKECHI-HARAYA YNANJO KGODA Y: "Involvement of scavenger receptor class B type 1 and low-density lipoprotein receptor in the internalization of liposomes into HepG2 cells", BIOCHIM BIOPHYS ACTA BIOMEMBR., vol. 1859, no. 11, 2017, pages 2253 - 2258
SHEN WJASTHANA SKRAEMER FBAZHAR S: "Scavenger receptor B type 1: expression, molecular regulation, and cholesterol transport function", J LIPID RES., vol. 59, no. 7, 2018, pages 1114 - 1131
SHEN WJAZHAR SKRAEMER FB: "SR-B1: A Unique Multifunctional Receptor for Cholesterol Influx and Efflux", ANNU REV PHYSIOL., vol. 80, 2018, pages 95 - 116
SHI JKANTOFF PWWOOSTER RFAROKHZAD OC: "Cancer nanomedicine: progress, challenges and opportunities", NAT REV CANCER., vol. 17, no. 1, 2017, pages 20 - 37, XP037114948, DOI: 10.1038/nrc.2016.108
SIEGEL ET AL., CA CANCER J CLIN, vol. 68, no. 1, 2018, pages 7 - 30
SOUSA DE ALMEIDA MSUSNIK EDRASLER BTALADRIZ-BLANCO PPETRI-FINK AROTHEN-RUTISHAUSER B: "Understanding nanoparticle endocytosis to improve targeting strategies in nanomedicine", CHEM SOC REV, vol. 50, no. 9, 2021, pages 5397 - 5434
TAKEMURA HURASAKI YYOSHIDA AFUKUSHIMA TUEDA T: "Simultaneous treatment with 1-beta-D-arabinofuranosylcytosine and daunorubicin induces cross-resistance to both drugs due to a combination-specific mechanism in HL60 cells", CANCER RES., vol. 61, no. 1, 2001, pages 172 - 177
TARDI ET AL., LEUK RES., vol. 33, no. 1, 2009, pages 129 - 39
TARDI PJOHNSTONE SHARASYM N ET AL.: "In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy", LEUK RES, vol. 33, no. 1, 2009, pages 129 - 139, XP002652274, DOI: 10.1016/j.leukres.2008.06.028
TENZER SDOCTER DKUHAREV J ET AL.: "Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology", NAT NANOTECHNOL., vol. 8, no. 10, 2013, pages 772 - 781
TEODORI E, DEI S, CORONNELLO M: "N-alkanol-N-cyclohexanol amine aryl esters: Multidrug resistance (MDR) reversing agents with high potency and efficacy", EUR J MED CHEM., vol. 127, 2017, pages 586 - 598, XP029907448, DOI: 10.1016/j.ejmech.2017.01.019
VAN DER KOLK DMDE VRIES EGKONING JAVAN DEN BERG EMILLER MVELLENGA E: "Activity and expression of the multidrug resistance proteins MRP 1 and MRP2 in acute myeloid leukemia cells, tumor cell lines, and normal hematopoietic CD34+ peripheral blood cells", CLIN CANCER RES., vol. 4, no. 7, 1998, pages 1727 - 1736
WANG-GILLAM AHUBNER RASIVEKE JT ET AL.: "NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors", EUR J CANCER., vol. 108, 2019, pages 78 - 87, XP085591196, DOI: 10.1016/j.ejca.2018.12.007
WU LZHANG JWATANABE W: "Physical and chemical stability of drug nanoparticles", ADV DRUG DELIV REV., vol. 63, no. 6, 2011, pages 456 - 469, XP028374104, DOI: 10.1016/j.addr.2011.02.001
XU GLOU NXU Y ET AL.: "Diagnostic and prognostic value of scavenger receptor class B type 1 in clear cell renal cell carcinoma", TUMOUR BIOL, vol. 39, no. 5, 2017, pages 1010428317699110
YANG SDAMIANO MGZHANG H ET AL.: "Biomimetic, synthetic HDL nanostructures for lymphoma", PROC NATL ACAD SCI, vol. 110, no. 7, 2013, pages 2511 - 2516, XP055061406, DOI: 10.1073/pnas.1213657110
YU XGUO CFISHER PBSUBJECK JRWANG XY: "Scavenger Receptors: Emerging Roles in Cancer Biology and Immunology", ADV CANCER RES., vol. 128, 2015, pages 309 - 364

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