WO2011072240A1 - Administration d'un médicament, le témozolomide, dans le cadre d'un traitement systémique du cancer - Google Patents

Administration d'un médicament, le témozolomide, dans le cadre d'un traitement systémique du cancer Download PDF

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Publication number
WO2011072240A1
WO2011072240A1 PCT/US2010/059919 US2010059919W WO2011072240A1 WO 2011072240 A1 WO2011072240 A1 WO 2011072240A1 US 2010059919 W US2010059919 W US 2010059919W WO 2011072240 A1 WO2011072240 A1 WO 2011072240A1
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WIPO (PCT)
Prior art keywords
formula
drug delivery
tmz
delivery system
lll
Prior art date
Application number
PCT/US2010/059919
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English (en)
Inventor
Rameshwar Patil
Eggehard Holler
Keith L. Black
Julia Y. Ljubimova
Original Assignee
Cedars-Sinai Medical Center
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Publication date
Application filed by Cedars-Sinai Medical Center filed Critical Cedars-Sinai Medical Center
Priority to US13/513,145 priority Critical patent/US8785371B2/en
Priority to EP10836765.7A priority patent/EP2509421B1/fr
Publication of WO2011072240A1 publication Critical patent/WO2011072240A1/fr
Priority to US14/179,195 priority patent/US9320807B2/en
Priority to US15/054,266 priority patent/US9629919B2/en
Priority to US15/450,519 priority patent/US9827325B2/en

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    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A61K47/6897—Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies
    • A61K47/6898—Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies using avidin- or biotin-conjugated antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2881—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD71
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3015—Breast
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3053—Skin, nerves, brain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell

Definitions

  • TMZ Temozolomide
  • a drug delivery system comprising a polymalic acid platform conjugated to a pro-drug, and one or more targeting antibodies, a trileucine (LLL) moiety, and/or a polyethylene glycol (PEG) moiety.
  • the pro-drug comprises a therapeutically effective amount of a compound of the formula:
  • the one or more targeting antibodies is a monoclonal antibody to transferrin receptor (TfR).
  • the polymalic acid platform comprises a compound of the formula:
  • the one or more targeting antibodies is a anti-TfR humanized antibody.
  • the anti-TfR humanized antibody is used for active transport to a tumor.
  • one or more targeting antibodies is an anti-TfR mouse monoclonal antibody and/or an anti-TfR human monoclonal antibody .
  • compositions comprising a therapeutically effective amount of a multifunctional nanoconjugate of temozolmide (TMZ), and a
  • the multifunctional nanoconjugate of TMZ is a compound of the formula:
  • the multifunctional nanoconjugate of TMZ is a compound of the formula:
  • inventions include a method of treating a disease and/or condition in an individual, comprising administering a therapeutically effective dosage of a drug delivery system comprising a polymalic acid platform conjugated to a pro-drug, and one or more targeting antibodies, a trileucine (LLL) moiety, and/or a polyethylene glycol (PEG) moiety to the individual, and treating the individual.
  • the pro-drug comprises a therapeutically effective amount of a compound of the formula: (Formula 1), or a pharmaceutical equivalent, analog, derivative and/or salt thereof.
  • the targeting antibody is a monoclonal antibody to transferrin receptor (TfR).
  • the polymalic acid platform comprises a compound of the formula:
  • the drug delivery system comprises a compound of the formula:
  • the drug delivery system comprises a compound of the formula:
  • the drug delivery system is administered to the individual intravenously. In another embodiment, the drug delivery system is administered to the individual at a concentration of about 4 mg/kg. In another embodiment, the drug delivery system is administered to the individual by direct injection and/or orally. In another embodiment, the drug delivery system is administered to the individual at a concentration of 75 mg/m 2 . In another embodiment, the individual is a human. In another embodiment, the individual is a mouse and/or rat. In antoher embodiment, the drug delivery system comprises an anti-TfR mouse monoclonal antiboday and/or an anti-TfR human monoclonal antibody. In another embodiment, the drug delivery system comprises an anti-TfR humanized antibody.
  • Various embodiments include a method of preparing a drug delivery system, comprising: conjugating a compound of the formula:
  • the ionic polymalic acid comprises one or more targeting antibodies, a trileucine (LLL) moiety, and/or a polyethylene glycol (PEG) moiety.
  • the ionic polymalic acid comprises an anti-TfR humanized antibody for transporting to a tumor.
  • Figure 1 depicts, in accordance with an embodiment herein, schematic presentation of the drug delivery system.
  • Figure 2 depicts, in accordance with an embodiment herein, liposomal leakage assay: a) Liposome leakage of P/LOEt and P/LLL conjugates, b) Liposome leakage of P/LLL/TMZH and P/PEG/LLL/TMZH conjugates. Percentage refers to ratio of pendant -COOH conjugated (total PMLA pendant -COOH is 100%). % Leakage compared to complete leakage in the presence of 0.25% (v/v) Triton X-100.
  • Figure 3 depicts, in accordance with an embodiment herein, nanoconjugate degradation in PBS and human plasma. Degradation of conjugate P/LLL(40%)TMZH( 17%) in PBS and human plasma at 4°C and 37°C studied by relative changes in molecular size indicated by column retention times (% molecular weights) of SEC-HPLC and hydrodynamic diameter measured by Zetasizer. 100% refers to the size at time zero.
  • Figure 4 depicts, in accordance with an embodiment herein, cell viability of nanoconjugate with LLL: Effects on cell viability of TMZ, P/LLL(40%),
  • P/LLL(40%)/TMZH(17%) was the most effective nanoconjugate.
  • Figure 5 depicts, in accordance with an embodiment herein, cell viability of
  • Nanoconjugate with LOEt Effects on cell viability of TMZ, P/PEG(2%)/LOEt(40%) and P/PEG(2%)/LOEt(40%)/TMZH(17%) on a) U87MG and b) T98G cells.
  • Figure 6 depicts, in accordance with an embodiment herein, cell viability of LLL nanoconjugates with antibody: Effects on cell viability of TMZ,
  • Figure 7 depicts, in accordance with an embodiment herein, drug internalization into cultured human glioma U87MG cells by confocal microscopy: a) 1 h incubation with
  • FIG. 8 depicts, in accordance with an embodiment herein, pH-dependent conversion of TMZ to metabolites, 5-(3-methyltriazen-l-yl)imidazole-4-carboxamide (MTIC), 4-amino-5- imidazole-carboxamide (AIC), methyldiazonium ion and DNA methylation (6)
  • FIG. 9 depicts, in accordance with an embodiment herein, (a) temozolomide (TMZ) and
  • FIG. 10 depicts, in accordance with an embodiment herein, synthetic strategy for LOEt conjugates containing TMZH.
  • Figure 11 depicts, in accordance with an embodiment herein, synthetic strategy for LLL conjugates containing TMZH.
  • Figure 12 depicts, in accordance with an embodiment herein, comparison of tumor growth rate between treated and untreated animals.
  • Figure 13 depicts, in accordance with an embodiment herein, comparison of tumor volume between treated and untreated animals.
  • TTZ also refers to temozolomide, and is a compound of the formula:
  • TTZH temozolomide hydrazide
  • PMLA poly( -L-malic acid)
  • Human TfR mAb means anti-human transferrin receptor monoclonal antibody.
  • LOEt means L-leucine ethyl ester
  • LDL is an abbreviation of L-Leu-(L-Leu)-(L-Leu).
  • Alex680 means Alexa Fluor 680 C2 maleimide.
  • PMLA-LLL includes PMLA containing LLL, which is conjugated by amide bond involving the N- terminal -NH 2 .
  • the term "PMLA-LLL40%” includes PMLA containing 40% of pendant carboxylates (100%) conjugated by amide bond involving the N-terminal -NH 2 of oligopeptide trileucine LLL.
  • the term “Polycefin” is a general name for therapeutic nanoconjugates based on polymalic acid for drug delivery. It may contain multifunctional components, such as a drug, a targeting moiety, and an endosome escaping unit.
  • temozolomide is a pro-drug releasing a DNA alkylating agent that may treat glial tumors when combined with radiation.
  • TMZ is toxic and therapeutic dosages are limited by severe side effects. Targeted delivery is thus needed to improve efficiency and reduce non-tumor tissue toxicity.
  • the inventors synthesized multifunctional targetable nanoconjugates of TMZ hydrazide using a poly( -L-malic acid) platform, which contained a targeting monoclonal antibody to transferrin receptor (TfR), trileucine (LLL) for pH- dependent endosomal membrane disruption, and PEG for protection.
  • TfR transferrin receptor
  • LDL trileucine
  • the present invention provides a composition comprising a multifunctional nanoconjugate of temozolomide (TMZ), or a pharmaceutical equivalent, analog, derivative, or salt thereof.
  • the multifunctional nanoconjugate of TMZ, or a pharmaceutical equivalent, analog, derivative, or salt thereof comprises TMZ conjugated to an ionic polymalic acid.
  • the TMZ, or pharmaceutical equivalent, analog, derivative, or salt thereof comprises TMZ hydrazide.
  • the ionic polymalic acid comprises poly( -L-malic acid).
  • the poly( -L-malic acid) contains a targeting moiety, a pH-dependent endosome membrane disruption moiety, and/or a PEG moiety.
  • the targeting moiety comprises a targeting monoclonal antibody to transferrin receptor.
  • the endosome membrane disruption moiety comprises trileucine (LLL) and/or L-leucine ethyl ester (LoEt).
  • the water-soluble TMZ nanoconjugates had hydrodynamic diameters in the range of 6.5 to 14.8 nm and potentials in the range of -6.3 to -17.7 mV. 50% degradation in human plasma was observed in 40 h at 37°C.
  • TMZ conjugated with polymer had a half-life of 5-7 h, compared with 1.8 h for free TMZ.
  • the strongest reduction of human brain and breast cancer cell viability was obtained by versions of TMZ nanoconjugates containing LLL and anti-TfR antibody.
  • TMZ-resistant cancer cell lines were sensitive to TMZ
  • the present invention provides a method of treating a cancer by administering a therapeutically effective dosage of a composition comprising a multifunctional nanoconjugate of temozolomide (TMZ), or a pharmaceutical equivalent, analog, derivative, or salt thereof, to an individual.
  • TMZ multifunctional nanoconjugate of temozolomide
  • the multifunctional nanoconjugate of temozolomide (TMZ), or a pharmaceutical equivalent, analog, derivative, or salt thereof is administered to the individual systemically.
  • the multifunctional nanoconjugate of temozolomide (TMZ), or a pharmaceutical equivalent, analog, derivative, or salt thereof is administered to the individual systemically via intravenous administration.
  • the multifunctional nanoconjugate of temozolomide (TMZ), or a pharmaceutical equivalent, analog, derivative, or salt thereof is administered to the individual orally and/or via direct injection.
  • the cancer is brain cancer.
  • side effects to the individual are minimized due to less free diffusion of the TMZ, wherein the TMZ is conjugated to a polycefin platform.
  • side effects to the individual are minimized to the individual due to specific tumor treatment and targeting resulting a homing device moiety of the multifunctional nanoconjugate of TMZ.
  • the inventors have successfully conjugated TMZ via the hydrazide bond to the highly negatively charged PMLA that renders the prodrug no longer diffusible through membranes. This allows a highly more potent and effective delivery of TMZ (or other drugs). Unlike the conjugated TMZ form, the more traditional orally applied TMZ for treating human gliomas has the potency to be distributed all over the entire organism. After penetration of the lipophilic prodrug through membranes into the cytoplasm of recipient cells it will be activated by the hydrolytic mechanism described herein.
  • the active drug is then ready to methylate proteins and especially DNA, guanine at N7 position, followed by methylation of adenine at the 03 position and of guanine at the 06 position (33). Failure of repair will drive these cells into apoptosis. Hydrolytic activation of the prodrug at sites other than the cytoplasm is inefficient due to the fact that the cationic methyl diazonium like any other charged molecule cannot passively penetrate membranes. However, in contrast, by conjugating TMZ and rendering the prodrug no longer diffusible through the membranes, the active methyl diazonium cation can only be generated from the nanodrug.
  • the nanodrug can only give rise to nucleic acid methylation if it is internalized into the cytoplasm of recipient cells.
  • a multifunctional nanoconjugate, or a pharmaceutical equivalent, analog, derivative, or salt thereof was synthesized with PMLA as the platform and prodrug TMZ in its hydrazide form, H 2 N-Leu-Leu-LeuOH (LLL) or NH 2 -LeuOEt (LOEt) for disruption of endosomal membrane, antibodies for targeting, and PEG against resorption and enzyme degradation.
  • PMLA as the platform and prodrug TMZ in its hydrazide form
  • LLL H 2 N-Leu-Leu-LeuOH
  • LOEt NH 2 -LeuOEt
  • the present invention provides a method of preparing a
  • the multifunctional nanoconjugate of TMZ is prepared by the following steps, or a combination thereof: (1) chemical activation of the PMLA pendant carboxyl groups forming the NHS-ester and subsequently the nucleophilic replacement by forming stable amide bonds; (2) conjugation of antibodies via thioether bond formation, where because of the PMLA chain length inhomogeneity, an excess of mAb is chosen in order to increase the likelihood that at least one molecule was conjugated with each polymer chain; (3) conjugation with LLL, where because the amount of 40% of carboxyl groups conjugated with LLL for most efficient membrane disruption activity limits the amount of TMZH conjugation to 17%, in order to increase the amount of TMZH loading, (4) carboxyl activation is repeated after conjugation with LLL, (5) before conjugation with TMZH
  • the present invention is also directed to a kit for materials for preparing a multifunctional nanoconjugate of temozolomide (TMZ), as well as the administration of the multifunctional nanoconjugate of TMZ to the individual, and may include a polymalic acid platform, PEG for protection, antibodies for targeting, TMZ molecules in hydrazide form, COOH for solubility in aqueous solvent, and tracking molecules such as Alexa Fluor 680, and combinations thereof.
  • the kit is an assemblage of materials or components, including at least one of the inventive compositions.
  • kits The exact nature of the components configured in the inventive kit depends on its intended purpose. For example, some embodiments are configured for the purpose of treating brain cancer or drug delivery in mammalian subjects, such as, but not limited to, human subjects, farm animals, domestic animals, and laboratory animals. Instructions for use may be included in the kit. "Instructions for use” typically include a tangible expression describing the technique to be employed in using the components of the kit to effect a desired outcome, such as to prepare a multifunctional nanoconjugate of TMZ and to deliver a therapeutically effective dosage of TMZ to an individual.
  • the kit also contains other useful components, such as, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia as will be readily recognized by those of skill in the art.
  • useful components such as, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia as will be readily recognized by those of skill in the art.
  • the materials or components assembled in the kit can be provided to the practitioner stored in any convenient and suitable ways that preserve their operability and utility.
  • the components can be in dissolved, dehydrated, or lyophilized form; they can be provided at room, refrigerated or frozen temperatures.
  • the components are typically contained in suitable packaging material(s).
  • packaging material refers to one or more physical structures used to house the contents of the kit, such as inventive compositions and the like.
  • the packaging material is constructed by well known methods, preferably to provide a sterile, contaminant-free environment.
  • the packaging materials employed in the kit are those customarily utilized in preparing a nanoconjugate.
  • a package refers to a suitable solid matrix or material such as glass, plastic, paper, foil, and the like, capable of holding the individual kit components.
  • a package can be a glass vial used to contain suitable quantities of an inventive composition containing a solution of multifunctional nanoconjugate of TMZ or components thereof.
  • the packaging material generally has an external label which indicates the contents and/or purpose of the kit and/or its components.
  • the present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient along with a therapeutically effective amount of Polycefin-LLL.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.
  • compositions according to the invention may be formulated for delivery via any route of administration.
  • Route of administration may refer to any administration pathway known in the art, including but not limited to an intravenous injection, aerosol, nasal, oral, transmucosal, transdermal or parenteral.
  • Parenteral refers to a route of administration that is generally associated with injection, including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal,
  • compositions may be in the form of solutions or suspensions for infusion or for injection, or as lyophilized powders.
  • compositions according to the invention can also contain any pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body.
  • the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof.
  • Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.
  • compositions according to the invention can also be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water.
  • Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non- aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • the pharmaceutical compositions according to the invention may be delivered in a therapeutically effective amount.
  • the precise therapeutically effective amount is that amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration.
  • Typical dosages of an effective delivery of a multifunctional nanoconjugate of TMZ, or a pharmaceutical equivalent, analog, derivative, or salt thereof can be in the ranges recommended by the manufacturer where known therapeutic compounds are used, and also as indicated to the skilled artisan by the in vitro responses or responses in animal models. Such dosages typically can be reduced by up to about one order of magnitude in concentration or amount without losing the relevant biological activity.
  • the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based, for example, on the in vitro responsiveness of the relevant primary cultured cells or histocultured tissue sample, such as biopsied malignant tumors, or the responses observed in the appropriate animal models, as previously described.
  • various embodiments of the invention include the therapeutically effective delivery of a multifunctional nanoconjugate of TMZ, or a pharmaceutical equivalent, analog, derivative, or salt thereof, to an individual in treatment of brain cancer.
  • the invention may be applied to any number of targets where it would be beneficial to deliver a drug or molecule to an individual while decreasing side effects due to less free diffusion and/or targeted delivery.
  • any number of conditions and/or diseases may be beneficially treated and the invention is in no way limited to treatment of brain cancer and/or tumor suppression.
  • various embodiments described herein may include the treatment of HIV and/or AIDS, and any other number of conditions where it is advantageous to deliver a therapeutically effective dosage of a drug.
  • Various embodiments of the invention may also be practiced in conjunction with an overall treatment regimen.
  • various embodiments include the delivery of TMZ by way of disruption of the endosome.
  • additional drugs or substances that were previously inactive in the endosome will then become active upon the disruption of the endosome.
  • various embodiments of the invention may include additional drugs or substances administered to the subject being treated and the invention is not only limited to drugs and/or molecules covalently linked to the scaffold as described herein.
  • various embodiments of the invention may be used in conjunction with or in combination with additional therapeutics.
  • Example 1 is provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention.
  • Example 1 is provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention.
  • Example 1 is provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention.
  • Example 1 is provided to
  • TMZ General Temozolomide
  • TfR targeting monoclonal antibody to transferrin receptor
  • LDL trileucine
  • the water-soluble TMZ nanoconjugates had hydrodynamic diameters in the range of 6.5 to 14.8 nm and potentials in the range of -6.3 to -17.7 mV. 50% degradation in human plasma was observed in 40 h at 37°C.
  • TMZ conjugated with polymer had a half-life of 5-7 h, compared with 1.8 h for free TMZ.
  • the strongest reduction of human brain and breast cancer cell viability was obtained by versions of TMZ nanoconjugates containing LLL and anti-TfR antibody.
  • TMZ-resistant cancer cell lines were sensitive to TMZ
  • TMZ-polymer nanoconjugates entered the tumor cells by receptor- mediated endocytosis, effectively reduced cancer cell viability, and can be used for targeted tumor treatment.
  • TMZ was purchased from AK Scientific, Inc. (Mountain View, CA, USA).
  • TMZH TMZ hydrazide
  • RVS10 was purchased from Southern Biotech (Birmingham, AL, USA).
  • PMLA 100 kDa;
  • Leu-OEt Leu-OEt
  • LLL NH 2 -Leu-Leu-Leu-OH
  • PDP 3-(2- Pyridyldithio)-propionate
  • N-Hydroxysuccinimide (NHS) (1 mmol) and ,N'-dicyclohexylcarbodiimide DCC (1 mmol) dissolved in 2 ml of DMF were added consecutively to the solution of 116 mg of PMLA (1 mmol with regard to malyl units) dissolved in 1 ml of anhydrous acetone under vigorous stirring at room temperature (RT).
  • the reaction mixture became turbid almost immediately upon addition of the NHS/DCC mixture indicating the formation of dicyclohexylurea.
  • P/PEG(2%)/TMZH(30%) was obtained after freeze drying.
  • Conjugate P/LLL(40%) was dissolved in phosphate buffer and isolated as described for conjugate P/PEG(2%)/TMZH(30%).
  • TMZH conjugate P/PEG(2%)/TMZH(30%).
  • a second round of carboxyl activation was performed: A solution of NHS (0.217 mmol) and of DCC (0.217 mmol) in 1 ml of DMF were added consecutively to the solution of 56 mg of P/LLL(40%) (0.217 mmol of free acid groups) dissolved in 1 ml of anhydrous DMF under vigorous stirring at RT.
  • TMZH 15 mg/ml in DMF, 17 mol% with regard to malyl units
  • TEA 0.037 mmol
  • MEA was synthesized in the absence of this reagent.
  • PMLA activated at carboxyl groups was prepared as described for conjugate P/PEG(2%)/TMZH(30%).
  • a solution of LLL, 0.4 mmol, in DMF 50 mg/ml (40 Mol-% with regard to malyl units) and TFA (125 Mol-% with regard to LLL) was added drop-wise to dissolve the tripeptide at RT.
  • TEA 0.4 mmol in DMF (1 :25 v/v) was then added slowly over 30 min.
  • Alex680 dissolved in DMF at 1 mg/ml was added to the solution of desired conjugates (2 mg/ml) in 100 mM sodium phosphate buffer with 150 mM NaCl, pH 5.5.
  • the reaction mixture was stirred at RT for 1 h and passed over Sephadex G-75 pre equilibrated with 100 mM sodium phosphate buffer, 150 mM NaCl, pH 6.8.
  • the product was concentrated via membrane filtration.
  • Alex680 labeling was performed before blocking of excess free thiol groups by PDP.
  • the diameter that is measured in DLS refers to the particle diffusion within a fluid and is referred to as the hydrodynamic diameter corresponding to the diameter of a sphere that has the same translational diffusion coefficient as the particle.
  • the potential was calculated from the electrophoretic mobility based on the Helmholtz-Smoluchowski formula, using electrophoresis M3-PALS (29, 30). All calculations were carried out by the Zetasizer 6.0 software. For the particle size measurements at 25°C, the solutions were prepared in PBS at a concentration of 2 mg/ml, filtered through a 0.2 ⁇ pore membrane.
  • the concentration of the sample dissolved in water containing 10 mM NaCl was 2 mg/ml, and the voltage applied was 150 V. All the conjugate solutions were prepared immediately before analysis at 25 °C. Data represent the mean ⁇ standard deviation obtained for three measurements.
  • Fluorescent assay for calcein release from loaded phosphatidylcholine/cholesterol liposomes (31) purified over Sephadex G-50 was used to determine leakage activity of synthesized polymer conjugates.
  • nanoconjugates were serially diluted in 50 ⁇ buffer containing appropriate mixtures of 137 mM HEPES, pH 7.4 and 137 mM citrate, pH 5.0.
  • Triplicate samples were mixed with 50 ⁇ liposome suspensions in 5 mM HEPES buffer, 150 mM NaCl, pH 7.4 (final lipid concentration 160 ⁇ ). After 1 h at RT, fluorescence was read by an ELISA reader at 485 nm excitation and 535 nm emission wavelengths.
  • Triton X-100, 0.25% (v/v) was used as a reference for 100% leakage.
  • the degradation of nanoconjugates in human plasma was carried out at 37°C with a polymer concentration of 1 mg/ml.
  • the sample vials were sealed to avoid evaporation and stored at 37°C in an incubator.
  • For the isolation from the plasma aliquots of 1 ml were extracted with 5 ml of chloroform/ethyl acetate (1 : 1 v/v).
  • the copolyester contained in the organic phase was dried and re-dissolved in PBS buffer. Size reduction due to degradation was followed by measurement of the hydrodynamic diameter in Zetasizer or of the molecular weight by SEC- HPLC. Sample preparation with the polymers of known M w was used to verify that the isolation method had no effect on molecular weights.
  • MDA-MB-231 and MDA-MB-468 Leibovitz's L-15 medium with 10% fetal bovine serum was used. Cells were seeded at 10 3 per well (0.1 ml) in 96-well flat-bottomed plates and incubated overnight at 37°C in humid atmosphere with 5% CO2 (MDA-MB-231 and
  • MDA-MB-468 were incubated without CO2). After exposure to synthesized conjugates for 24 h, medium was replaced every 48 h. Cell viability was measured on day 5 for T98G and day 7 for the rest of the cell lines using the CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit (Cat. No.PR-G3580; Promega, Madison, WI, USA). Yellow [3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] (MTS) is bioreduced by cells into formazan that is soluble in the tissue culture medium.
  • the absorbance reading at 490 nm from the 96-well plates is directly proportional to the number of living cells (32).
  • the viability of the untreated cells was taken as 100%.
  • the results shown are the means ⁇ standard deviation of three independent measurements. Data were analyzed by statistical software GraphPad Prism 3.0.
  • Alex680 excitation 670 nm and emission 685-750 nm.
  • the images were processed by ImageJ 1.41 ⁇ software from IH.
  • the multi component drug delivery system schematically presented in Figure 1 was synthesized with PMLA as the platform and prodrug TMZ in its hydrazide form, H 2 N-Leu-Leu- LeuOH (LLL) or NH 2 -LeuOEt (LOEt) for disruption of endosomal membrane, antibodies for targeting, and PEG against resorption and enzyme degradation.
  • the first part of the conjugation included the chemical activation of the PMLA pendant carboxyl groups forming the NHS-ester and subsequently the nucleophilic replacement by forming stable amide bonds. Conjugation of antibodies via thioether bond formation followed in the second part.
  • TMZ contents by NMR and UV measurement were the same within 3% deviation measured for conjugate P/PEG(2%)/TMZH(30%).
  • Conjugates had characteristic values of hydrodynamic diameters and zeta potentials (Table I). Free PMLA and P/LLL(40%)/TMZH(17%) had the smallest hydrodynamic diameter, whereas additionally conjugated PEG5000 increased the diameter by about 2 nm and mAb, by about 8 nm.
  • the value of potential can be used to differentiate between PMLA, -22.9 mV, and nanoconjugates with neutral ligands like TMZH, LOEt, for example -7mV for P/PEG(2%)/LOEt(40%)/TMZH(17%), and conjugates with charged ligands like LLL (instead of LOEt), for example -11.5 mV for P/PEG(2%)/LLL(40%)/TMZH(17%) (Table 1).
  • Conjugates were also distinguished by other properties, e.g., by their capability for liposome leakage. As shown in Figure 2, the conjugate P/PEG(2%)LLL(40%)/TMZH(17%) was pH-sensitive, whereas the conjugate
  • P/LLL(40%)/TMZH(17%) was not. Another property was the effect on U87MG and MDA-MB- 468 cell viability. It was more affected by the conjugate P/LLL(40%)/TMZH(17%) ( Figure 4) than by P/PEG(2%)LLL(40%)/TMZH(17%) ( Figure 6).
  • TMZ is a prodrug and undergoes spontaneous conversion to the active alkylating agent at neutral or alkaline pH.
  • Half-lives were measured at physiological pH 7.4 in PBS and summarized in Table I.
  • the decomposition of free and conjugated TMZH by hydro lytic ring opening (Chart 1) was a first order reaction for free TMZ or TMZH and conjugated TMZH (data not shown).
  • the half-life was 1.80 ⁇ 0.1 h and for TMZH, 1.98 ⁇ 0.1 h.
  • Half- life was significantly enhanced, about 3-4 times, after conjugation with the polymer.
  • TMZ had a half life of 7.34 ⁇ 0.2 h for conjugate P/LLL(40%)/TMZH(17%) and 7.10 ⁇ 0.2 h for
  • TMZ can passively permeate the cells, where it is ultimately activated to the nucleic acid methylating methyldiazonium cation (33).
  • Targeting of glioma cells by conjugated mAb would involve binding of the nanoconjugate delivery vehicle to
  • P/LLL(40%)/TMZH(17%) significantly decreased cell viability of all four cell cultures, gliomas U87MG and T98G, and breast cancer cell lines MD A-MB-231 and MDA-MB-468.
  • free TMZ was inactive in all lines except U87MG.
  • Conjugate P/LLL(40%) as a control had little or no effect on cell viability due to the absence of the prodrug ( Figure 4) and this was not changed by the addition of PEG5000.
  • Orally applied TMZ to treat human gliomas has the potency to be distributed all over the entire organism.
  • the active drug is then ready to methylate proteins and especially DNA, guanine at N7 position, followed by methylation of adenine at the 03 position and of guanine at the 06 position (33). Failure of repair will drive these cells into apoptosis.
  • Hydrolytic activation of the prodrug at sites other than the cytoplasm is inefficient due to the fact that the cationic methyl diazonium like any other charged molecule cannot passively penetrate membranes.
  • the inventors have succeeded to conjugate TMZ via the hydrazide bond to the highly negatively charged PMLA that renders the prodrug no longer diffusible through membranes.
  • the active methyl diazonium cation can only be generated from the nanodrug. Free passive diffusion of the PMLA conjugate into recipient cells is highly unlikely because of its high negative charge, and generation of active drug outside the cytoplasm would not be effective due to its own intrinsic charge. Therefore, the nanodrug can only give rise to nucleic acid methylation if it is internalized into the cytoplasm of recipient cells.
  • the results in Figure 7 show that drug uptake follows most likely receptor-mediated endocytosis and possibly pinocytotic pathways of the conjugates P/PEG(2%)/LLL(40%)/TMZH(17%)/HuTfR
  • the inventors synthesized the nanodrug carrying targeting TfR antibodies, endosome escape unit, and the prodrug.
  • the results in Figures 4 and 6 show the delivery and prodrug activation to follow the anticipated mechanism.
  • the effect of the targeting HuTfR mAb was observed in the case of human glioma U87MG cells.
  • a significant reduction of viability is seen in the presence of the endosome escape unit LLL for all cell lines shown in Figure 4 and 6. This in agreement with the stringent requirement for endosome escape in the prodrug delivery mechanism.
  • glioma U87MG cells responded to treatment with free TMZ
  • cell viability of glioma T98G and breast cancer MDA-MB-231 and MDA-MB-468 cells did not change.
  • These cell lines are known to be TMZ resistant (32-34).
  • TMZ resistant 32-34
  • T98G cells resistance has been referred to overproduction of 06-methyl guanine methyltransferase (MGMT) (32)
  • MGMT 06-methyl guanine methyltransferase
  • MDA- MB-231 cells has been associated with unbalanced expression of DNA glycosylase and DNA polymerase expression (34), and the mechanism of resistance is not known for MDA-MB-468 cells.
  • P/PEG(2%)/LLL(40%)/TMZH(17%) and P/LLL(40%)/TMZH(17%)/HuTfR mAb(0.25%) were designed as lead compounds with potential for treatment of glial tumors in vivo.
  • the drug delivery system offers a biodegradable, non-toxic, and non-immunogenic scaffold obtained from a biological source, thus opening an avenue for drug delivery without the danger of liver storage disease.
  • Conjugation of TMZH to this platform has been challenging because of the sensitivity of the prodrug to neutral and alkaline pH. Nonetheless, syntheses of TMZ nanodrugs have been worked out to be readily achievable and highly reproducible.
  • the solution properties such as solubility and absence of aggregation, size in the nanometer range, and slightly negative zeta potential are favorable for drug delivery (35, 36).
  • One of the lead conjugates contains PEG5000, which minimizes enzymatic nanodrug degradation and clearance by the reticulo-endothelial system (37).
  • the nanodrugs are stable in human plasma over several hours, and the range of half-life for active drug formation has increased several-fold over that of free TMZ by conjugation to the PMLA platform.
  • the increased half-life of conjugated TMZ favors an efficient delivery of functional prodrug in vivo.
  • the nanodrug will be accumulated in the interstitial space of malignant glioma by EPR effect (19) and/or active mAb targeting of overexpressed TfR on vascular endothelium next to the tumor (21). From the interstitium, the nanodrug will enter the endosomal system of tumor cells and become activated in the cytoplasm after endosomal escape. Accumulation in the tumor by EPR effect and especially, active mAb targeting provides efficiency of tumor treatment with minimal side effects for healthy tissue.
  • TMZH was conjugated to PMLA platform, which was equipped with anti-human TfR antibodies for tumor cell targeting by receptor mediated endocytosis; and pH-dependent LLL for endosome escape.
  • the lead compounds P/PEG(2%)/LLL(40%)/TMZH(17%)/HuTfR mAb(0.25%) and
  • P/LLL(40%)/TMZH(17%) showed significant reduction in tumor cell viability of both human glioma and human breast cancer cell lines. Cell viability was significantly reduced in cases of TMZ-resistant cell lines where free TMZ had no effect.
  • Nanoconjugates are highly soluble in aqueous solutions and were dissolved in PBS prior to the administration. Drug was administered intravenously (I.V.) for five consecutive days at a temozolomide concentration of 4 mg/kg. Tumor volume was measured 3 times a week and all the animals were euthanatized on day 37.
  • TTZ Temozolomide
  • Cycle 1 150 mg/m 2 ⁇ corresponds to 4.6 mg/kg) p.o. daily followed by 23 days without treatment.
  • Cycle 2 to 6 200 mg/m 2 ⁇ corresponds to 6.15 mg/kg) p.o. daily followed by 23 days without treatment if toxicity does not occur.
  • TMZ can be administered via I.V. injection.
  • the inventors used mouse xenograft (U87MG, human glioma): 4 mg/kg intravenous injections for 5 consecutive days.
  • the drug is less toxic because the direct tumor delivery and drug concentration in the tumor site is higher than after oral drug is administrated.
  • TMZ covalently attached on polymer overcomes drug resistance.

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Abstract

La présente invention concerne des procédés d'administration de médicaments en vue du traitement d'une maladie ou d'une affection telle que le cancer. Dans un mode de réalisation, l'invention concerne un procédé de préparation d'un nanoconjugué multifonctionnel de témozolomide (TMZ) par association du TMZ sous sa forme d'hydrazide avec une plateforme à base d'acide polymalique. Dans un autre mode de réalisation, la plateforme à base d'acide polymalique est associée à un anticorps monoclonal dirigé contre le récepteur de la transferrine, à une fraction trileucine (LLL) et/ou à une fraction polyéthylène glycol (PEG). La présente invention concerne des procédés d'administration de médicaments en vue du traitement d'une maladie ou d'une affection telle que le cancer. Dans un mode de réalisation, l'invention concerne un procédé de préparation d'un nanoconjugué multifonctionnel de témozolomide (TMZ) par association du TMZ sous sa forme d'hydrazide avec une plateforme à base d'acide polymalique. Dans un autre mode de réalisation, la plateforme à base d'acide polymalique est associée à un anticorps monoclonal dirigé contre le récepteur de la transferrine, à une fraction trileucine (LLL) et/ou à une fraction polyéthylène glycol (PEG).
PCT/US2010/059919 2009-12-10 2010-12-10 Administration d'un médicament, le témozolomide, dans le cadre d'un traitement systémique du cancer WO2011072240A1 (fr)

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US14/179,195 US9320807B2 (en) 2009-12-10 2014-02-12 Drug delivery of temozolomide for systemic based treatment of cancer
US15/054,266 US9629919B2 (en) 2009-12-10 2016-02-26 Drug delivery of temozolomide for systemic based treatment of cancer
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EP2271368A1 (fr) * 2008-04-11 2011-01-12 Cedars-Sinai Medical Center Poly(acide béta-malique) avec tripeptide leu-leu-leu pendant pour une administration efficace de médicament cytoplasmique
EP2271368A4 (fr) * 2008-04-11 2013-01-23 Cedars Sinai Medical Center Poly(acide béta-malique) avec tripeptide leu-leu-leu pendant pour une administration efficace de médicament cytoplasmique
US9827325B2 (en) 2009-12-10 2017-11-28 Cedars-Sinai Medical Center Drug delivery of temozolomide for systemic based treatment of cancer
US10583151B2 (en) 2010-12-30 2020-03-10 Cedars-Sinai Medical Center Polymalic acid-based nanobiopolymer compositions
US10383958B2 (en) 2011-04-06 2019-08-20 Cedars-Sinai Medical Center Polymalic acid based nanoconjugates for imaging
JP2018505195A (ja) * 2015-02-12 2018-02-22 ネオンク テクノロジーズ インク． ペリリルアルコール誘導体を含む医薬組成物
WO2020121304A1 (fr) * 2018-12-10 2020-06-18 Ariel Scientific Innovations Ltd. Conjugués thérapeutiques
EP3894397A4 (fr) * 2018-12-10 2022-09-28 Ariel Scientific Innovations Ltd. Conjugués thérapeutiques

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US20120328555A1 (en) 2012-12-27
US20170274085A1 (en) 2017-09-28
EP2509421A1 (fr) 2012-10-17
EP2509421A4 (fr) 2013-11-06
US9827325B2 (en) 2017-11-28
US9629919B2 (en) 2017-04-25
US8785371B2 (en) 2014-07-22
EP2509421B1 (fr) 2020-02-05
US9320807B2 (en) 2016-04-26
US20160175450A1 (en) 2016-06-23

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