WO2022156419A1 - Préparation d'un support de carbonate de calcium enrobé d'un lipide chargé en ce6, son procédé de préparation et son application - Google Patents

Préparation d'un support de carbonate de calcium enrobé d'un lipide chargé en ce6, son procédé de préparation et son application Download PDF

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WO2022156419A1
WO2022156419A1 PCT/CN2021/137048 CN2021137048W WO2022156419A1 WO 2022156419 A1 WO2022156419 A1 WO 2022156419A1 CN 2021137048 W CN2021137048 W CN 2021137048W WO 2022156419 A1 WO2022156419 A1 WO 2022156419A1
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preparation
aqueous solution
dopa
inverse microemulsion
hexane
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戴文鑫
徐朗
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海南回元堂药业有限公司
戴文鑫
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention relates to the technical field of pharmaceutical preparations, in particular to a preparation of lipid-coated calcium carbonate carrier-loaded Ce6 and a preparation method and application thereof.
  • Immunotherapy for cancer is a novel class of therapies that includes cancer vaccines, immune checkpoint therapy, and other T-cell therapies.
  • cancer vaccines with irreplaceable advantages (such as simple preparation and low cost) are widely regarded as potential cancer treatments.
  • DCs dendritic cells
  • Recent studies have gradually revealed the critical function of dendritic cells (DCs) in activating T cells and triggering immune responses, which are essential for immunotherapy.
  • Multiple previous studies have focused on finding vaccines for cancer immunotherapy.
  • currently available cancer vaccines often require complex processing of blood products to provide antigens/adjuvants to meet subject vaccination requirements. Therefore, an intelligent artificial vaccine that minimizes the processing procedures required to provide a robust immune response and excellent anti-cancer effects is very difficult, but also very promising.
  • CC calcium carbonate
  • EPR enhanced permeability and retention
  • the technical problem to be solved by the present invention is to provide a lipid-coated calcium carbonate carrier-loaded Ce6 preparation (Li/CC-Ce6) and its preparation method and application, which can be used as a potential for effective colon cancer immunotherapy. In situ vaccine.
  • the invention provides a preparation method of Li/CC-Ce6, which comprises:
  • the calcium chloride aqueous solution, the Ce6 aqueous solution and the n-hexane emulsion are mixed to make inverse microemulsion A;
  • the sodium carbonate aqueous solution, the DOPA aqueous solution and the n-hexane emulsion are mixed to make inverse microemulsion B;
  • the organic solvent is a mixture of ethanol and chloroform.
  • the solution containing Li/CC-Ce6 is centrifuged, washed with straight-chain alcohol, and dried to obtain a white powder product, which is Li/CC-Ce6.
  • the straight chain alcohol is n-butanol.
  • the mass ratio of CTAB, n-butanol and n-hexane is (4-5):(8-10):(18-36).
  • the mass ratio of CTAB, n-butanol and n-hexane is 3:1:25.
  • the ratio of the calcium chloride aqueous solution, the Ce6 aqueous solution and the n-hexane emulsion is (2.5mL-12.5mL): (2.5mL-12.5mL): (90g-110g);
  • the ratio of the calcium chloride aqueous solution, the Ce6 aqueous solution and the n-hexane emulsion is (2.5mL-12.5mL): (2.5mL-12.5mL): (108g-109g);
  • the ratio of the calcium chloride aqueous solution, the Ce6 aqueous solution and the n-hexane emulsion is 12.5mL: 12.5mL: 108.5g;
  • the invention has carried out experimental verification on the dosage of calcium chloride aqueous solution of 2.5mL, 7.5mL and 12.5mL, and carried out experimental verification on the dosage of DOPA solution of 2.5mL, 7.5mL and 12.5mL.
  • the results show that the prepared nanometer Neither the particle size nor the encapsulation efficiency of the particles is as good as the effect when the ratio of the calcium chloride aqueous solution, the Ce6 aqueous solution and the n-hexane emulsion is 12.5 mL: 12.5 mL: 108.5 g.
  • the ratio of the sodium carbonate aqueous solution, the DOPA aqueous solution and the n-hexane emulsion is (2.5 mL-12.5 mL): (2.5 mL-12.5 mL): (90 g-110 g).
  • the ratio of the sodium carbonate aqueous solution, the DOPA aqueous solution and the n-hexane emulsion is (2.5 mL-12.5 mL): (2.5 mL-12.5 mL): (108 g-109 g).
  • the ratio of the sodium carbonate aqueous solution, the DOPA aqueous solution and the n-hexane emulsion is 12.5 mL: 12.5 mL: 108.5 g.
  • the invention has carried out experimental verification on the dosage of sodium carbonate aqueous solution of 2.5mL, 7.5mL and 12.5mL, and carried out experimental verification on the dosage of DOPA solution of 2.5mL, 7.5mL and 12.5mL.
  • the results show that the prepared nanoparticles Neither the particle size nor the encapsulation efficiency of the sodium carbonate solution is as good as the effect when the ratio of sodium carbonate aqueous solution, DOPA solution and the n-hexane emulsion is 12.5mL:12.5mL:108.5g.
  • the concentration of calcium chloride is 2mol/L
  • the concentration of Ce6 is 2mol/L
  • the concentration of sodium carbonate is 2mol/L
  • the concentration of DOPA is 2 mol/L.
  • the preparation of the inverse microemulsion A includes mixing the calcium chloride aqueous solution, the Ce6 aqueous solution and the n-hexane emulsion, and then aging for 1 hour to 24 hours;
  • the preparation of the inverse microemulsion B includes mixing the sodium carbonate aqueous solution, the DOPA aqueous solution and the n-hexane emulsion, and then aging for 1 h to 24 h.
  • the volume ratio of the inverse microemulsion A and the inverse microemulsion B is 1:1; the conditions for mixing the inverse microemulsion A and the inverse microemulsion B include stirring at room temperature for 20 minutes.
  • the volume of absolute ethanol is 1/2 of the sum of the volumes of inverse microemulsion A and inverse microemulsion B.
  • the added amount of CC-Ce6, DOPC, FA-DSPE-PEG and cholesterol will affect the particle size of the obtained nanoparticles. It has been repeatedly verified in the present invention that under the conditions described in the examples, the obtained particle size is most suitable for entering the organism as a drug for treating tumors.
  • the mass ratio of the DOPA-modified CC-Ce6, DOPC, FA-DSPE-PEG and cholesterol was 9.79:7.86:50.01:3.87.
  • Li/CC-Ce6 prepared by the preparation method of the present invention.
  • Li/CC-Ce6 prepared by the preparation method of the present invention in preparing a medicine for treating colorectal cancer.
  • the present invention provides a Li-coated CC nanoparticle (Li/CC) as a carrier for loading Ce6 (Li/CC-Ce6), and ultimately as a potential in situ vaccine for effective colorectal cancer immunotherapy. It has been verified many times that compared with other preparation steps or parameters, the Li/CC-Ce6 prepared under the parameters provided by the present invention has higher stability, biocompatibility and tumor targeting, and can be effectively produced under laser stimulation.
  • ROS ROS can trigger apoptosis to expose TAA and are expected to recruit DCs into tumor tissues through an inflammation-mimicking mechanism. DCs are activated in situ to release corresponding inflammation (including IL-6 and TNF- ⁇ ) and trigger subsequent immune response cascades. Both in vitro and in vivo experiments demonstrate the powerful ability of this platform to enhance DC vaccination, which can effectively inhibit the growth of primary and distantly growing tumors, which may be a new approach to effectively treat cancer.
  • Figure 3 shows the ROS generation capacity of Li/CC-Ce6,
  • A the absorbance changes of DPBF at 418 nm after Li/CC-Ce6 (Ce6 concentration of 0.1 mg/mL) irradiation (1W/cm 2 ) at different time intervals
  • Figure 4 shows in vitro ROS generation analysis of Li/CC-Ce6,
  • A representative CLSM images of cells treated with different formulations with/without laser irradiation, scale bar: 20 ⁇ m
  • Figure 9 shows the in vivo anticancer efficacy of different nanoformulations in CT-26 tumor-bearing C57BL/6 mice,
  • A PDT-based Li/CC-Ce6 inhibits CT-26 tumors by dead tumor cells and orthotopic DC vaccination
  • the invention provides a preparation of lipid-coated calcium carbonate carrier-loaded Ce6, a preparation method and application thereof, and those skilled in the art can learn from the content of this article and appropriately improve process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention.
  • the method and application of the present invention have been described through the preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the methods and applications herein without departing from the content, spirit and scope of the present invention, so as to realize and apply the present invention. Invention technology.
  • test materials used in the present invention are all common commercial products and can be purchased in the market.
  • calcium chloride (calcium chloride), sodium carbonate (sodium carbonate), 1,3-diphenylisobenzofuran (1,3-diphenylisobenzofuran, DPBF), methylthiazolyl tetrazolium (MTT), 2 ',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA), chlorin e6 (Ce6), folic acid (FA), TritonX-100, paraformaldehyde and paraformaldehyde cholesterol, by Sigma -Courtesy of Aldrich (St. Louis, MO, USA).
  • the inner leaflet lipid (the inner leaflet, DOPA), dioleoylphosphatidylcholine (dioleoylphosphatidylcholine, DOPC), folic acid-modified distearoylphosphatidylethanolamine-polyethylene glycol (The folate modified distearoylphosphatidyl ethanolamine-polyethylene glycol, FA-DSPE-PEG), purchased from Ponsure Biotechnology (Shanghai, China).
  • CT-26 mouse colorectal cancer cell line
  • NIH3T3 mouse embryonic fibroblast
  • All cell lines were cultured using the protocol in the previous report.
  • Multicellular tumor spheroids (MCTS) were established based on previous studies. Sixty male C57BL/6J mice (6-8 weeks old) were purchased from Wuhan Institute of Model Animals (Wuhan, China) and housed under standard conditions. The establishment of the CT26 tumor xenograft model followed a previously reported protocol. All animal procedures used were approved by the IEC (Institutional Ethics Committee) of Jeonbuk National University.
  • CaCl2 and Ce6 were dispersed in a water-in-oil microemulsion.
  • the same microemulsion containing Na2CO3 and DOPA was also prepared.
  • the two solutions were mixed for 20 minutes to prepare hydrophobic DOPA-modified CC-Ce6, and the product was precipitated with absolute ethanol and centrifuged (CR22, Hitachi, Japan).
  • DOPA-modified CC-Ce6 was mixed with appropriate amount of DOPC, FA-DSPE-PEG and cholesterol in a mixed solution of chloroform and ethanol (1:1, v/v).
  • the formed film was dispersed in medium PBS to obtain Li/CC-Ce6 solution. Specific steps include:
  • CTAB cetyltrimethylammonium bromide, also known as cetyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, cetyltrimethylammonium bromide,
  • 40.68g n-butanol, 180.00g n-hexane was added to the conical flask in turn, heated to 50°C, magnetically stirred for 15min, 3000rpm, and prepared into n-hexane emulsion;
  • the DOPA-modified CC-Ce6 was mixed with an appropriate amount of DOPC, FA-DSPE-PEG and cholesterol in a mixed solution of chloroform and ethanol (1:1, v/v). After evaporating the solvent by steam, the formed film was dispersed in medium PBS to obtain Li/CC-Ce6 solution.
  • CC-Ce6 alone was used as a control and prepared using a method similar to Example 1, but without the addition of DOPA and lipids.
  • the encapsulation efficiency of Ce6 in the formulation was determined to be 8.1%.
  • Preparation of sodium salt-containing inverse microemulsion take 12.5 ml of the sodium carbonate aqueous solution obtained in step 3) and 108.5 g of n-hexane emulsion obtained in step 4) to prepare a sodium carbonate inverse microemulsion;
  • CC-Ce6 The two solutions of 5) and 6) were mixed for 20 minutes to prepare CC-Ce6.
  • the product was precipitated with absolute ethanol and centrifuged. Centrifugation speed 3000rpm, 40min. After thorough washing with ethanol, CC-Ce6 was mixed with an appropriate amount of DOPC, FA-DSPE-PEG and cholesterol in a mixed solution of chloroform and ethanol (1:1, v/v). After evaporating the solvent by steam, the formed film was dispersed in medium PBS to obtain a CC-Ce6 solution.
  • Li/CC-Ce6 was measured using ZS90 (Malvern, UK) and its morphology was observed by transmission electron microscopy (TEM, JEM-2100, JEOL, Japan). The size change of Li/CC-Ce6 in PBS/mouse plasma was observed for 48 hours to assess colloidal stability. Hemolysis assays were performed according to previous reports. The adsorption capacity of BSA was determined as reported previously. Western blot analysis was performed using standard protocols with the corresponding antibodies from Abcam (UK). IL-6 and TNF- ⁇ levels in serum were determined by ELISA kits (Abeam) according to the manufacturer's instructions.
  • the drug release profiles of Li/CC-Ce6 were evaluated as previously reported.
  • 20 ⁇ L of LDPF (10 mM) was incubated with Li/CC-Ce6 aqueous solution.
  • the solution was then irradiated with laser light (680 nm, 1 W/cm 2 ), and the UV absorption peak of DPBF at 418 nm was monitored to reflect the production of ROS.
  • the UV absorption of the solution at 418 nm was normalized with the untreated solution.
  • Li/CC-Ce6 (5-100 ⁇ g/mL) or Li/CC-Ce6 (Ce6 concentration, 0.25-5 ⁇ g/mL, 680 nm, 400 mW/cm for 10 min) were incubated with CT26 cells without laser irradiation. Forty-eight hours after incubation, standard MTT analysis was performed as previously reported. Furthermore, MCTS were incubated with different formulations at a Ce6 concentration of 5 ⁇ g/mL for 24 h before laser irradiation. The MCTS volume was monitored for 5 days.
  • CT26 cells were pretreated with/without FA (1 mM) for 2 h and then incubated with free Ce6, CC-Ce6 and Li/CC-Ce6. At predetermined time points, cells were harvested and assessed for intracellular accumulation of Ce6 by flow cytometry (FCM, DxFLEX, Beckman Coulter, Miami, USA).
  • Intracellular ROS levels were measured with a fluorescent probe (DCFH-DA). Briefly, cells (1 ⁇ 10 6 ) were treated differently (Ce6 concentration: 5 ⁇ g/mL) for 4 h and then loaded with DCFH-DA (25 mM, 30 min). Afterwards, cells were treated with/without laser irradiation (1 W/cm 2 , 5 min), and intracellular ROS levels were controlled by a confocal laser scanner (CLSM, FV3000, Olympus, Tokyo, Japan).
  • CLSM confocal laser scanner
  • CT26 tumor-bearing mice with only primary tumors were injected intravenously with CC-Ce6 and Li/CC-Ce6 (5 mg/kg Ce6). 48 hours after distribution, mice were sacrificed for major organs and tumors. The levels of Ce6 in these tissues were assessed by in vivo imaging (In-Vivo Xtreme, Bruker, German).
  • Primary tumors were irradiated with a 680 nm laser at 100 mW/cm2 for 20 minutes. Dosing was performed twice every two days at a Ce6 concentration of 5 mg/kg, while irradiation was performed 24 hours after administration. Tumor volumes were measured in all animals for 15 days every 3 days.
  • Li/CC-Ce6 The preparation of Li/CC-Ce6 involves two steps. First, the CC core is formed in a size-controlled microemulsion, during which Ce6 is loaded into the CC matrix through the complexation between the Ca2 + of CC and the carboxyl group of Ce6. To facilitate the surface modification of Li, CC-Ce6 was surface-modified using DOPA to generate a hydrophobic layer to further immobilize Li. Combining these two components (Li and CC-Ce6) into a system finally constructs Li/CC-Ce6. As shown in Figure 1A, the obtained Li/CC-Ce6 are nanoparticles with a narrow size distribution of 60-120 nm and the highest peak at 100 nm. Previous reports reported that nanoparticles with a size of about 100 nm were best suited to exploit tumor-based EPR effects relative to other size ranges for targeted drug delivery.
  • Li/CC-Ce6 To test the long-term stability of Li/CC-Ce6, we cultured Li/CC-Ce6 in PBS and plasma for 48 h and monitored the change in particle size during this period to determine its stability. As shown in Fig. 1B, the diameter of Li/CC-Ce6 exhibits only small fluctuations (less than 10%) throughout the process, which indicates that the stability of Li/CC-Ce6 can be well obtained under physiological conditions save. Applicable to be a promising DDS in cancer treatment.
  • Li/CC-Ce6 hardly adsorbs onto BSA, while the change in OD278 is small.
  • DPBF a detector of ROS in our experiments to evaluate the ability of Li/CC-Ce6 to generate ROS under laser stimulation. According to previous reports, DPBF can react with ROS to quench its UV absorption peak at 418 nm, and the degree of quenching is positively correlated with the ROS concentration in the environment. This is a convenient method to determine the ROS-producing capacity of a formulation.
  • DCFH-DA can easily penetrate into the cell interior and is not fluorescent.
  • DCF is produced after intracellular lipase degradation.
  • the fluorescence of the probe was greatly increased compared with the unreacted probe, which provided the possibility to evaluate the intracellular ROS generation profile of Li/CC-Ce6.
  • Figure 4A in the absence of stimulation, the fluorescence generated in the free Ce6 group was weak. The increase in fluorescence upon exposure to light indicated that laser stimulation was an important factor in the generation of ROS.
  • the intracellular fluorescence of the Li/CC-Ce6 group was higher than that of the free Ce6 group without laser irradiation, indicating that more Ce6 was absorbed into the cells with the help of DDS.
  • MCTS composed of fibroblasts and tumor cells
  • MCTS are widely used to mimic solid tumors and evaluate the therapeutic effect of DDS.
  • the saline group without any treatment showed a sustained increase in the volume of MCTS, which was almost 3 times its original size at the end of the experiment and was representative of the development of solid tumors.
  • the amount of MCTS was significantly reduced in all PDT groups.
  • Li/CC-Ce6 exhibits the most robust anticancer properties, supported by the MCTS volume results, which are only 72% of the original size.
  • the optical observations in Figure 7B also show similar conclusions. MCTS after PDT treatment were observed to have structural damage and apoptosis, and MCTS in the Li/CC-Ce6 group had the smallest volume and the most significant structural damage.

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Abstract

La présente invention concerne le domaine technique des préparations pharmaceutiques, et en particulier une préparation d'un support de carbonate de calcium enrobé d'un lipide chargé en Ce6, son procédé de préparation et son application. Li/CC-Ce6 selon la présente invention présente une bonne stabilité, une bonne biocompatibilité et un bon ciblage tumoral, et peut générer efficacement des espèces réactives de l'oxygène (ROS) sous stimulation laser. Les ROS peuvent déclencher l'apoptose pour exposer un antigène associé à une tumeur (TAA), et des cellules dendritiques (DC) seront avec bon espoir recrutées dans des tissus tumoraux au moyen d'un mécanisme de simulation d'inflammation. Les DC sont activées in situ pour libérer une inflammation correspondante (comprenant IL-6 et TNF-α) et déclencher une cascade de réponse immunitaire ultérieure. Des expériences in vitro et in vivo montrent toutes deux qu'une plateforme a une forte capacité à améliorer la vaccination des DC, et peut inhiber efficacement la croissance de tumeurs primaires et distantes croissantes, de sorte qu'une nouvelle méthode de traitement efficace du cancer peut être fournie.
PCT/CN2021/137048 2021-01-25 2021-12-10 Préparation d'un support de carbonate de calcium enrobé d'un lipide chargé en ce6, son procédé de préparation et son application WO2022156419A1 (fr)

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