WO2023165583A1 - Système et procédé d'administration ciblant une cellule oculaire - Google Patents

Système et procédé d'administration ciblant une cellule oculaire Download PDF

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WO2023165583A1
WO2023165583A1 PCT/CN2023/079439 CN2023079439W WO2023165583A1 WO 2023165583 A1 WO2023165583 A1 WO 2023165583A1 CN 2023079439 W CN2023079439 W CN 2023079439W WO 2023165583 A1 WO2023165583 A1 WO 2023165583A1
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lipid
lnp
lipids
delivery system
ionizable
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PCT/CN2023/079439
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Chinese (zh)
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周昌阳
孙怡迪
彭文博
汤竣杰
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益杰立科(上海)生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—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
    • A61K47/54—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 organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—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
    • A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • 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
    • 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

Definitions

  • This application relates to the field of biomedicine, in particular to a delivery system and method targeting eye cells.
  • CRISPR/Cas clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (Cas)
  • Cas CRISPR-associated protein
  • Topical administration is the optimal route due to the highest patient compliance and least invasiveness.
  • drug absorption occurs via corneal (cornea, aqueous humor, intraocular tissues) or non-corneal routes (conjunctiva, sclera, choroid/retinal pigment epithelium (RPE)).
  • corneal corneal
  • aqueous humor intraocular tissues
  • non-corneal routes conjunctiva, sclera, choroid/retinal pigment epithelium (RPE)
  • RPE choroid/retinal pigment epithelium
  • the viscosity of human blood is about 3-4mPa*s (cP), the viscosity is low, and the particles generally flow in the form of turbulent flow (turbulent flow), concentrated in the center of blood vessels; the viscosity of vitreous humor is much higher than that of human blood (viscosity see below table, about 100-300 times that of blood).
  • the way LNP moves in the high-viscosity liquid in the eye is mainly based on the stokes force, which presents a laminar flow and is affected by rotational viscous resistance ( ⁇ T and ⁇ R).
  • LNP tends to move at the eyeball endothelial cells (Donati, S., Caprani , S.M., Airaghi, G., Vinciguerra, R., Bartalena, L., Testa, F., Mariotti, C., Porta, G., Simonelli, F. and Azzolini, C., 2014. Vitreous substitutes: the present and the future. BioMed research international, 2014.).
  • the retinal and corneal endothelial cells in the eye are positively charged, and the vitreous solution is mainly hyaluronic acid hydrogel (negatively charged); there is a divergent micro-electric field from the injection site of the vitreous to the periphery of the eyeball (Zhao, Min, et al. "Electrical signaling in control of ocular cell behaviors.”Progress in retina and eye research 31.1(2012):65-88.).
  • the high-viscosity liquid in the vitreous has a different trajectory to the movement of LNP than blood, and because of its movement in the vitreous in the eye, the research experience in serum and other parts is difficult to apply.
  • the influence of the content of cationic lipids in the LNP formula and the ratio of pH-responsive lipids (C/P value) on sub-ocular tendency is mainly realized from two aspects of competition and synergy: 1
  • the ionization charge of LNP, with the increase of cationic lipid the overall charge of LNP will increase, which will tend to migrate to low-charge areas;
  • 2 The adsorption of corona by hyaluronic acid: As the content of cationic lipids increases, although the ionization efficiency will be improved (positive charge), but it will also Adsorbing more hyaluronic acid on its surface not only increases the particle size of LNP, but also shields positive charges. Competing bidirectional effects lead to its movement in the vitreous body, and the research experience
  • This application provides a method to achieve precise enrichment in different parts of the eyeball by regulating the ratio of cationic lipids content and pH-responsive lipids.
  • regulating the surface charge of LNP in the specific environment of the vitreous body and the interaction with hyaluronic acid By regulating the surface charge of LNP in the specific environment of the vitreous body and the interaction with hyaluronic acid, its enrichment to different eye regions is achieved.
  • the present application provides a method for delivering exogenous substances targeting specific cells in the eye, comprising administering lipid nanoparticles (LNP) to the vitreous, calculated by molar percentage, the lipid nanoparticles comprising the following components : Ionizable lipid 20%-70%, cholesterol-based lipid 30%-60%, structured lipid 25%-50%, pegylated lipid 1%-30%, wherein the ionizable lipid It includes pH-sensitive lipids and permanent cationic lipids, and the molar ratio (C/P value) of the permanent cationic lipids and pH-responsive lipids is 1:24 to 24:1.
  • LNP lipid nanoparticles
  • the eye-specific cells include corneal endothelial cells or choroidal cells.
  • the LNP is targeted to different cells of the eye by adjusting the C/P value in the LNP.
  • said LNP targets corneal endothelial cells when said C/P value is in the range of 1:24 to 2:1.
  • said LNP targets corneal endothelial cells when said C/P value is in the range of 8:42 to 32:18.
  • LNP targets choroidal cells when said C/P value is in the range of 12:1 to 24:1.
  • the content of the ionizable lipid is about 40%-60% by mole percentage.
  • the ionizable lipid is present in an amount of no more than about 50% by mole percent.
  • the content of the ionizable lipid is about 40%-50% by mole percentage.
  • the content of the ionizable lipid is about 45%-55% by mole percentage.
  • the content of the ionizable lipid is about 50% by mole percentage.
  • the content of the ionizable lipid is about 40-60%, and the C/P value is in the range of 8:42 to 32:18, the LNP Targets corneal endothelial cells.
  • said LNP targets choroidal cells.
  • the permanent cationic lipid is selected from the group consisting of: DOTAP, DDAB, DOTMA, DC-Chol, and combinations thereof.
  • pH-sensitive lipid is selected from MC-3, LP-01, and combinations thereof.
  • the structural lipid is selected from DPPC, DSPC, DOPE and combinations thereof.
  • the PEGylated lipid is selected from DAG-PEG, DAA-PEG, DMG-PEG, DSPE-PEG, C8-PEG, DOG-PEG, ceramide PEG, and combinations thereof.
  • the cholesterol-based lipid comprises cholesterol or PEGylated cholesterol.
  • the exogenous substances include compounds, nucleic acids, antibodies or active fragments thereof, peptides, lipids, protein drugs, protein conjugate drugs, enzymes, oligonucleotides or ribozymes.
  • the nucleic acid is selected from siRNA, miRNA, pri-miRNA, messenger RNA (mRNA), clustered regularly interspaced short palindromic repeat (CRISPR)-related nucleic acid, single guide RNA (sgRNA) ), CRISPR-RNA (crRNA), trans-activating crRNA (tracrRNA), plasmid DNA (pDNA), transfer RNA (tRNA), antisense oligonucleotide (ASO), guide RNA, double-stranded DNA (dsDNA), single One or more of stranded DNA (ssDNA), single stranded RNA (ssRNA) and double stranded RNA (dsRNA).
  • siRNA siRNA
  • miRNA messenger RNA
  • mRNA messenger RNA
  • CRISPR clustered regularly interspaced short palindromic repeat
  • sgRNA single guide RNA
  • crRNA CRISPR-RNA
  • tracrRNA trans-activating crRNA
  • pDNA plasmid DNA
  • nucleic acid comprises mRNA and/or sgRNA.
  • the mRNA comprises a nucleic acid sequence encoding an enzyme.
  • the mRNA comprises a nucleic acid sequence encoding a Cas protein.
  • the lipid nanoparticle is a nucleic acid lipoplex, wherein the molar ratio of element N to element P is 1:1 to 9:1.
  • the present application provides an LNP delivery system targeting specific cells in the eye, wherein the LNP comprises the following components: ionizable lipid 20%-70%, cholesterol-based lipid 30%-60%, Structured lipids 25%-50%, PEGylated lipids 1%-30%, wherein the ionizable lipids include pH-sensitive lipids and permanent cationic lipids, the permanent cationic lipids and pH-responsive lipids
  • the molar ratio of mass (C/P value) is between 1:24 and 24:1.
  • the eye-specific cells include corneal endothelial cells or choroidal cells.
  • the LNP is targeted to different cells of the eye by adjusting the C/P value in the LNP.
  • said LNP targets corneal endothelial cells when said C/P value is in the range of 1:24 to 2:1.
  • said LNP targets corneal endothelial cells when said C/P value is in the range of 8:42 to 32:18.
  • LNP targets choroidal cells when said C/P value is in the range of 12:1 to 24:1.
  • the content of the ionizable lipid is about 40%-60% by mole percentage.
  • the ionizable lipid is present in an amount of no more than about 50% by mole percent.
  • the content of the ionizable lipid is about 40%-50% by mole percentage.
  • the content of the ionizable lipid is about 45%-55% by mole percentage.
  • the content of the ionizable lipid is about 50% by mole percentage.
  • the content of the ionizable lipid is about 40-60%, and the C/P value is in the range of 8:42 to 32:18, the LNP Targets corneal endothelial cells.
  • the LNP targeting Corneal endothelial cells wherein the content of the ionizable lipid is about 50%, and the C/P value is in the range of 8:42 to 32:18, the LNP targeting Corneal endothelial cells.
  • said LNP targets choroidal cells.
  • the LNP targets choroidal cells.
  • the permanent cationic lipid is selected from the group consisting of: DOTAP, DDAB, DOTMA, DC-Chol, and combinations thereof.
  • pH-sensitive lipid is selected from MC-3, LP-01, and combinations thereof.
  • the structural lipid is selected from DPPC, DSPC, DOPE and combinations thereof.
  • the PEGylated lipid is selected from DAG-PEG, DAA-PEG, DMG-PEG, DSPE-PEG, C8-PEG, DOG-PEG, ceramide PEG, and combinations thereof.
  • the cholesterol-based lipid comprises cholesterol or PEGylated cholesterol.
  • the LNP when the LNP is selected from #2, #3, #4 and #5 in Table 1, the LNP targets corneal endothelial cells.
  • the LNP when the LNP is selected from #6 in Table 1, the LNP targets choroidal cells.
  • the LNP delivery system is configured as a liquid for intravitreal administration.
  • the administering comprises intravitreal injection.
  • the present application provides an LNP delivery system for targeted delivery of specific cells in the eye, wherein the LNP comprises the following components: ionizable lipid 20%-70%, cholesterol-based lipid 30%-60%, structured lipids 25%-50%, PEGylated lipids 1%-30%, wherein the ionizable lipids include pH-sensitive lipids and permanent cationic lipids, and the permanent cationic lipids
  • the molar ratio (C/P value) of lipids and pH-responsive lipids was between 1:24 and 24:1.
  • the present application provides the use of the LNP delivery system described in the present application in the preparation of a medicament for preventing and/or treating eye diseases or disorders.
  • the present application provides a pharmaceutical composition for treating ocular diseases or disorders, comprising lipid nanoparticles comprising a therapeutic agent, wherein the lipid nanoparticles comprise the following components: ionizable lipid 20%-70%, cholesterol-based lipids 30%-60%, structured lipids 25%-50%, pegylated lipids 1%-30%, wherein the ionizable lipids include pH-sensitive lipids and permanent cationic lipids, the molar ratio (C/P value) of the permanent cationic lipids and pH-responsive lipids is between 1:24 and 24:1.
  • the present application provides a pharmaceutical composition for treating corneal endothelial cell diseases or disorders, comprising lipid nanoparticles comprising a therapeutic agent, wherein the lipid nanoparticles comprise the following components: ionizable lipid 20%-70% lipids, 30%-60% cholesterol-based lipids, 25%-50% structured lipids, 1%-30% pegylated lipids, wherein the ionizable lipids include pH-sensitive lipids quality and permanent cationic lipids, the molar ratio (C/P value) of the permanent cationic lipids and pH-responsive lipids is between 1:24 and 2:1.
  • the present application provides a pharmaceutical composition for treating choroidal cell diseases or disorders, comprising lipid nanoparticles comprising a therapeutic agent, wherein the lipid nanoparticles comprise the following components: ionizable lipid 20%-70%, cholesterol-based lipids 30%-60%, structured lipids 25%-50%, pegylated lipids 1%-30%, wherein the ionizable lipids include pH-sensitive lipids and permanent cationic lipids, the molar ratio (C/P value) of the permanent cationic lipids and pH-responsive lipids is not less than 12:1.
  • the therapeutic agent is selected from the group consisting of:
  • the present application provides a method of treating an ocular disease or condition in a subject, the method comprising administering to the subject's eye a lipid nanoparticle comprising a therapeutic agent, the lipid nanoparticle comprising The following components: 20%-70% ionizable lipids, 30%-60% cholesterol-based lipids, 25%-50% structured lipids, 1%-30% pegylated lipids, wherein the The ionized lipids include pH-sensitive lipids and permanent cationic lipids, and the molar ratio (C/P value) of the permanent cationic lipids and pH-responsive lipids is between 1:24 and 24:1.
  • the therapeutic agent is selected from the group consisting of:
  • Figure 1 shows a TEM electron micrograph of the LNP described in this application.
  • Figure 2 shows the eye distribution of Ai9 mice.
  • Figure 3 shows that #2 is specifically enriched in eyeball corneal endothelial cells.
  • Figure 4 shows the transfection effect of LNP eyeball endothelial cells with different C/P values.
  • Figure 5 shows the transfection effect of LNP eyeball choroid with different C/P values of the present application.
  • LNP nanoparticles are prepared to achieve effective embedding of gene editing tools or other nucleic acid drugs.
  • the organic phase contains at least one ionizable lipid, at least one supporting lipid, at least one amphiphilic block copolymer and cholesterol, and is dissolved by an organic solvent that is miscible with water.
  • the organic solvent is preferably selected from ethanol, acetonitrile, acetone and the like.
  • Aqueous phase an aqueous solution of gene editing tools, wherein the content of nucleic acid substances (such as mRNA) is 0.5-50% (w/v), and the pH is 3.0-7.0.
  • the aqueous salt solution is selected from: citrate buffer, phosphate buffer, Tris-HCl buffer system.
  • the mixing of organic phase and aqueous phase can be achieved by microfluidic and impinging flow reactors.
  • the embedding efficiency of gene editing tool RNA can be optimized by adjusting the N/P ratio (molar ratio) of the system, and the N/P ratio is 1:1 to 9:1.
  • the N/P ratio here specifically refers to the molar ratio of element N to element P in the LNP/mRNA system.
  • LNP was prepared by the method of Example 1.1, and LNP was prepared by regulating the molar ratio of ionizable lipid and cationic lipid, and its embedding rate for more than 2000bp mRNA was characterized.
  • RNA is derived from RNA extracted from yeast, purchased from McLean, Cat. No. R822593
  • the embedding rate of prepared LNP is determined by Quant-iTTM RNA Reagent and Kit assay.
  • Solution configuration Dilute an appropriate amount of 20 ⁇ TE buffer solution to 1 ⁇ with ultrapure water, which is enough for the day’s experiment. Dilute the concentrated dye solution with 1 ⁇ TE (large range 25-1000ng/ml RNA) at a ratio of 1:200, (small range 1-50ng/ml RNA) at a ratio of 1:2000. Wrap it in gold foil or store it in a dark place away from light. Dilute TritonX-100 to 5% concentration with 1 ⁇ TE buffer for use.
  • Sample processing set ultrapure water with RNA concentration of 0 as the blank background, set TE buffer instead of LNP plus 5% TritonX-100 as the free RNA test sample, and set LNP plus 5% TritonX-100 as the total RNA test sample . Take the LNP sample to be determined and add an equal volume of 5% TritonX-100, 1 ⁇ TE solution to the blank, and incubate at 50-60°C for 5-10 minutes.
  • the incubated LNP samples were diluted to 10-400 times with 1 ⁇ TE buffer solution (appropriately adjusted according to the RNA concentration of the sample group). After dilution, 100 ⁇ l was added to a 96-well plate, and then 100 ⁇ l of the diluted concentrated dye solution was added in the dark, and the fluorescence absorbance was measured within 5 minutes.
  • the measurement conditions are an excitation wavelength of 480 nm and an emission wavelength of 520 nm.
  • the SORT formula (#15&#16) is based on pH-responsive lipids, adding a certain proportion of cationic lipids so that the overall ionizable lipids content reaches more than 60% (higher charge). It affects the embedding rate of large fragments of mRNA.
  • the formulas of the present invention (#1-#14) control the molar ratio of total ionizable lipids within 60%, ensuring a higher embedding rate of large fragment mRNA (above 90%).
  • Table 3 The delivery system of the present invention presents different potentials and particle sizes in serum and vitreous simulated fluid
  • mice Eight-week-old mice were injected intraperitoneally with a mixture of tetamine, zolazepam (1:1, 2.25 mg/kg body weight) and xylazine hydrochloride (0.7 mg/kg body weight) through anesthesia. Under an operating microscope, inject 2ul LNP (200ng/ul Cre mRNA-encapsulated lipid nanoparticles) (Leica Microsystems Ltd.) (Cre mRNA sequence is GenBank: AAL31698.1) into the vitreous using a Nanofil syringe with a 33G blunt needle. .
  • mice were dissected, fresh eyeball tissues were washed with PBS, fixed in 4% paraformaldehyde for 48 hours, dehydrated in 30% sucrose overnight, OCT (Sakura Finetek ) embedded tissue, cut into about 8 ⁇ m thickness for immunofluorescent staining.
  • Immunofluorescence antibody soak slices in PBS for 5 minutes, repeat three times, use 3% BSA to block non-specific antigens, incubate at room temperature for 30 minutes, and then use ZO-1 antibody (Proteintech, 21773-1-AP, 1:1000) for 4 overnight incubations , wash the primary antibody three times with TBST, 5 min each time, incubate with FITC-labeled secondary antibody for 2 hours at room temperature, stain the nuclei with DAPI for 10 min, mount the slide, observe and take pictures with a fluorescent microscope (Olympus VS120 Automated Slide Scanner).
  • ZO-1 antibody Proteintech, 21773-1-AP, 1:1000
  • LNP can be enriched in corneal endothelial cells at C/P values between 1/24 and 2/1, while beyond this range as C/P If the P value is 24/1 (#6), it cannot be effectively enriched in the corneal endothelium, and if it is lower than this range (#1), it cannot be effectively transfected.
  • #6 cannot be enriched into the corneal endothelial cells, but due to its high concentration of positively charged molecules cationic lipids, it can wrap hyaluronic acid, resulting in a larger particle size, and then hitchhike on the automatic clearance mechanism in the eye, From the retina into the choroid, and then achieve the enrichment of the choroid.
  • the part indicated by the arrow is the choroid.
  • the C/P value is greater than or equal to 12
  • the choroid is obviously transfected, but the retina is not.

Abstract

L'invention concerne un procédé d'administration de substance exogène ciblant une cellule oculaire spécifique, comprenant l'application d'une nanoparticule lipidique (NPL) à un corps vitreux. Sur la base d'un pourcentage molaire, la nanoparticule lipidique comprend les composants suivants : 20 % à 70 % de lipide ionisable, 30 % à 60 % de lipide à base de cholestérol, 25 % à 50 % de lipide structural et 1 % à 30 % de lipide pégylé, le lipide ionisable comprenant un lipide sensible au pH et un lipide cationique permanent, et le lipide cationique permanent et le lipide sensible au pH étant dans un rapport molaire (valeur C/P) de 1:24 à 24:1. En ajustant la valeur C/P, la NPL est autorisée à cibler différentes cellules intraoculaires, et une administration précise ciblant les cellules intraoculaires est obtenue.
PCT/CN2023/079439 2022-03-04 2023-03-03 Système et procédé d'administration ciblant une cellule oculaire WO2023165583A1 (fr)

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