WO2023193389A1 - Nanoparticule de resvératrol-lécithine, procédé de préparation de cette dernière, et utilisation associée - Google Patents

Nanoparticule de resvératrol-lécithine, procédé de préparation de cette dernière, et utilisation associée Download PDF

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WO2023193389A1
WO2023193389A1 PCT/CN2022/114615 CN2022114615W WO2023193389A1 WO 2023193389 A1 WO2023193389 A1 WO 2023193389A1 CN 2022114615 W CN2022114615 W CN 2022114615W WO 2023193389 A1 WO2023193389 A1 WO 2023193389A1
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resveratrol
lecithin
rsv
lec
nanoparticles
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姚燕丹
蔡佩娥
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中山大学孙逸仙纪念医院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to the field of medical technology, and more specifically, to resveratrol lecithin nanoparticles and their preparation methods and uses.
  • Resveratrol (3,5,4-trihydroxystilbene, RSV) is a natural polyphenolic flavonoid that is rich in grapes, red wine, mulberries, peanuts, rhubarb and other plants. RSV is known to have anti-inflammatory, anti-obesity, and protective effects on the heart and brain. In neurological diseases, resveratrol has been found to reduce neuronal oxidation and apoptosis and has neuroprotective effects. Currently, a common method of systemic administration of resveratrol is intravenous injection.
  • resveratrol has poor water solubility and is chemically unstable. It will be isomerized and degraded when exposed to high temperatures, pH changes, UV light or certain types of enzymes, which is also not conducive to the realization of resveratrol. Storage and use of alcohol.
  • PEG Polyethylene glycol
  • the existing technology urgently needs a drug delivery system or corresponding preparations and drugs that can improve the storage performance and drug action performance of resveratrol and have high safety, and provide its therapeutic use in related diseases.
  • the present invention aims to overcome at least one of the deficiencies of the above-mentioned prior art, provide resveratrol lecithin nanoparticles and preparation methods and uses thereof, and overcome the difficulty of storing resveratrol, low bioavailability, and curative effect in the prior art. It has limited defects and is used in anti-oxidation and anti-cancer as a nano drug delivery system to provide alternative, effective and safe treatment strategies for corresponding diseases.
  • the technical solution adopted by the present invention is a resveratrol lecithin nanoparticle, which includes resveratrol and lecithin wrapped and/or coupled to resveratrol.
  • Resveratrol lecithin nanoparticles are hereinafter referred to as Lec(RSV).
  • the lecithin is a liposome extracted from soybeans.
  • the present invention uses lecithin and resveratrol to form a completely natural nano-delivery drug delivery and treatment system with high safety. And the use of nano-preparations can make the shelf life of resveratrol longer. In more than one embodiment of the present invention, it can be stably maintained at room temperature and 4°C for twelve months.
  • resveratrol and lecithin are also beneficial to improving the drug delivery effect.
  • resveratrol is sustained-released in the nanoparticles, which can overcome the problem of resveratrol in the prior art.
  • the defect of low bioavailability of intravenous injection of retitol increases the duration of action in the body; on the other hand, in more than one embodiment of the present invention, the resveratrol lecithin nanoparticles provided by the application can significantly improve the antioxidant and anti-oxidation effects.
  • resveratrol lecithin nanoparticles achieve a synergistic effect between the two, and the effect is significant.
  • the resveratrol lecithin nanoparticles provided by the present invention can overcome the shortcomings of the existing technology, improve the storage performance and bioavailability of resveratrol, and provide anti-oxidation and anti-cancer uses, which is a new addition to the existing technology.
  • Antioxidant diseases and cancers need to provide new treatment strategies and drugs, especially for cancer treatment, which can provide an alternative, cost-effective, low-side-effect anti-cancer therapy.
  • the resveratrol is wrapped between the inner and outer layers of lecithin.
  • the mass ratio of resveratrol and lecithin is (9-11):1.
  • the mass ratio of resveratrol to lecithin is 10:1.
  • the particle size range of the nanoparticles is 128 to 174 nm. Nanoparticles with this particle size are not only stable, but also have excellent loading capacity and good tumor penetration ability. As an anti-cancer drug with potential for clinical application, stability plays a crucial role in its storage and delivery capabilities.
  • the size of nanoparticles significantly affects their therapeutic and diagnostic applications. Treatment aspects, including drug half-life, targeting ability, cellular uptake and tumor penetration, are all affected by the size of nanoparticles; nanoparticles must be larger than 10nm in order to Avoid renal filtration, but the diameter should not be too large. For example, particles larger than 200nm will activate the complement system and be quickly removed from the blood and accumulate in the liver and spleen.
  • the particle size of nanoparticles will directly affect the effect of nanoparticles, and being too large or too small is not conducive to exerting its effect.
  • the particle size range of the resveratrol lecithin nanoparticles is 128-174nm, and the average particle size is 151nm, which can appropriately prevent the nanoparticles from being too small or too large, while ensuring their load. Abilities and effects.
  • the above-mentioned resveratrol lecithin nanoparticles are prepared and formed by a nanoprecipitation method.
  • Another object of the present invention is to provide the use of the above-mentioned resveratrol lecithin nanoparticles in the preparation of drugs for scavenging free radicals and/or killing tumor cells.
  • the resveratrol lecithin nanoparticles described in this application have a significant killing effect on tumor cells. Compared with resveratrol directly applied to tumor cells, resveratrol Alcohol lecithin nanoparticles have a synergistic killing effect and the killing ability is more significant.
  • tumor cells include breast cancer cells.
  • the tumor cells used are breast cancer cells.
  • Another object of the present invention is to provide a tumor cell killing drug, including the above-mentioned resveratrol lecithin nanoparticles.
  • Another object of the present invention is to provide a method for preparing the above-mentioned resveratrol lecithin nanoparticles, which includes the steps:
  • A1 Dissolve resveratrol and lecithin in an organic solvent miscible with water to obtain a resveratrol organic phase and a lecithin organic phase. Add the lecithin organic phase to the resveratrol organic phase. Then add organic solvent to obtain a mixed solution;
  • the organic solvent is dimethyl sulfoxide.
  • the mass ratio of resveratrol and lecithin in the mixed solution is (9-11):1;
  • the concentration of resveratrol in the mixed solution is 0.9-1.1 mg/ml
  • volume ratio of the mixed solution to the water phase is (0.05-0.15):10.
  • volume ratio of the mixed liquid to the water phase is 0.1:10.
  • step A3 the nanosuspension is added to the Amincon filter and centrifuged to remove the organic solvent.
  • step A3 includes:
  • A31 Centrifuge the nanosuspension for the first time to separate the organic solvent
  • step A33 Repeat step A32 two or more times to obtain resveratrol lecithin nanoparticles.
  • Another object of the present invention is to provide the use of resveratrol and/or lecithin in the preparation of drugs for scavenging free radicals and/or killing tumor cells.
  • resveratrol or lecithin alone also has certain free radical scavenging and tumor killing effects, and resveratrol lecithin nanoparticles containing resveratrol and lecithin simultaneously Have more significant synergistic effects.
  • the beneficial effects of the present invention are: the components of the nanoparticles in this application are of natural origin and are safe, and the nano-delivery system formed by resveratrol and lecithin has sustained-release characteristics, which is not only convenient for It improves the bioavailability of resveratrol in the body and enhances the duration of its action in the body. Moreover, the lecithin coating also facilitates the storage of the main drug resveratrol when it is not in use. More importantly, the formed resveratrol lecithin nanoparticles have significant effects in tumor killing.
  • the nanodelivery system facilitates the improvement of resveratrol bioavailability and promotes the targeting of tumor tissues, improving tumor cell Killing effect.
  • the nanoparticles formed by resveratrol and lecithin also have a synergistic killing effect, and the anti-tumor and antioxidant effects are more significant. They are expected to be used in tumor treatment to provide new therapeutic drugs and treatment strategies. , to delay the survival of cancer patients.
  • Lec(RSV) directly killing tumor cells Lec(RSV) also has more stable properties and is easy to store, overcoming the storage problems caused by the instability of resveratrol in the existing technology. question.
  • Figure 1 shows the Lec(RSV) synthesis schematic and characteristics.
  • A Schematic diagram of using lecithin and resveratrol to form Lec(RSV) nanoparticles;
  • B Nanoprecipitation method to obtain soluble Lec(RSV).
  • Figure 2 shows the sizes of empty Lec nanoparticles and Lec(RSV) nanoparticles.
  • A Transmission electron microscopy analysis of empty Lec nanoparticles;
  • B Transmission electron microscopy analysis of Lec(RSV) nanoparticles;
  • C The average size of the nanoparticles is (Lec(RSV 151.0 ⁇ 22.93nm vs. empty Lec 128.4 ⁇ 19.88nm) );
  • D RSV encapsulation effect.
  • Figure 3 shows the stability of Lec and Lec(RSV) nanoparticles.
  • A The particle size of lecithin nanoparticles and Lec(RSV) nanoparticles does not change significantly within 48 hours at room temperature;
  • B The particle size of lecithin nanoparticles and Lec(RSV) nanoparticles within 60 days at 4°C There is no obvious change;
  • C Lec(RSV) nanoparticles were placed for 3, 6, 9, and 12 months respectively, and no obvious turbidity and sediment were found;
  • D In vitro release test of Lec(RSV), the accumulation within 12 hours Release 55%.
  • Figure 4 shows the in vitro absorption capacity and cytotoxicity of Lec and Lec(RSV) nanoparticles.
  • A-B BT474 breast cancer cells take up Lec and Lec(RSV) wrapped with FITC;
  • C In vitro cytotoxicity test to observe the killing ability of Lec, RSV and Lec(RSV) against cancer cells respectively;
  • D Lec, RSV and ROS scavenging ability of Lec(RSV).
  • Figure 5 shows the effect of Lec(RSV) on tumor uptake in vivo.
  • the BT474 tumor-bearing model was used to conduct in vivo tumor uptake experiments.
  • test samples and test processes used in the following examples include the following (if the specific experimental conditions are not specified in the examples, they are usually in accordance with conventional conditions, or in accordance with the conditions recommended by the reagent company; the conditions used in the following examples Reagents, consumables, etc., can be obtained from commercial sources unless otherwise specified).
  • Resveratrol purchased from Aladdin (Shanghai, China); lecithin, purchased from Sigma Aldrich (St. Louis, MO, USA), FITC, purchased from Sigma Aldrich (St. Louis, MO, USA), Alma Blue kit, purchased from Organic solvents (DMF, DMSO, 75% alcohol) were purchased from Sigma Aldrich (St. Louis, Missouri, USA).
  • the experimental water was treated with Millipore and Milli-Q systems. The remaining substances were All are using analysis level.
  • Lec(RSV) was prepared using nanoprecipitation method.
  • DMSO was used as the solvent to prepare resveratrol (RSV) (100 mg/mL) and lecithin (Lec) (100 mg/mL) solutions.
  • RSV resveratrol
  • Lec lecithin
  • Take a clean glass vial add 10 mL of ultrafiltered water, and stir continuously at 12,000 rpm at room temperature. The mixed solution was slowly added into the vial and the nanosuspension was obtained after stirring for five minutes.
  • the solution was transferred to an Amicon filter (Merck, Kenilworth, NJ, USA) and centrifuged at 4000 rpm for 15 minutes. The remaining solution was washed with 5 ml of water and centrifuged again at 4000 rpm for 10 min; repeat twice to remove any remaining DMSO. Lec(RSV) was stored at 4°C until further use.
  • the mass ratio of resveratrol to lecithin in the mixed solution is 10:1
  • the concentration of resveratrol in the mixed solution is 1 mg/ml
  • the volume ratio of the mixed solution to the water phase is 0.1:10.
  • the particle size and zeta potential of Lec and Lec(RSV) particles were determined by dynamic light scattering (DLS) analysis at Malvern Panalytical (MA, USA). Each sample data comes from 3 repeated experiments.
  • Lec(RSV) (10mg/mL) was dropped on the TEM grade carbon mesh copper grid. Place the pellets on the grid and leave at ambient temperature for 5 minutes. Wash each compartment 5 times with distilled water. Specimens were then negatively stained with 2% uranyl acetate and left at ambient temperature for 2 minutes. Then rinse with distilled water three times and air dry. Specimens were observed with a TECNAI F20 electron microscope (Philips Electronic Instruments Corp, Mahwah, 103NJ).
  • the encapsulated amount of RSV in Lec was determined using UV-visible spectrophotometry. After Lec(RSV) purification, samples were rehydrated in PBS to a volume of 1 ml. Take 10 ⁇ l of Lec(RSV) sample and add it to 90 ⁇ l DMSO. Take 10 ⁇ l of the original resveratrol-liposome working solution as a positive control group. RSV has specific UV absorbance at 330nm, which can be used to determine RSV concentration. In order to determine the encapsulation efficiency (EE) of RSV, the inventors calculated the encapsulation amount of RSV in the Lec(RSV) conjugate compared with the encapsulation amount of RSV initially used, and obtained the following formula:
  • Lec and Lec(RSV) were synthesized at a concentration of 10 mg/mL. Lec and Lec(RSV) particles were then stored in closed vials at 37°C. At preset time points (1, 2, 4, 8, 12, 24, 48 h), the DLS method was used to determine the Lec and Lec(RSV) particle sizes and record them.
  • Human breast cancer cells BT474 were purchased from ATCC and cultured according to the provided procedure. The temperature is 37°C. Use RPMI-1640/F-12K medium containing 10% fetal bovine serum (FBS), 100 U/mL penicillin and 100 g/mL streptomycin, and culture in a humidified cell culture room with 5% CO2.
  • FBS fetal bovine serum
  • Lec was fluorescently labeled with FITC at half the mass of the liposomes.
  • BT474 cells were grown on glass coverslips (12 ⁇ 12 mm; Fisher Scientific, Texas, USA) to ⁇ 80%. Before adding 200 g/mL Lec (FITC)-containing medium, the cells were incubated with serum-free medium for 1 hour, washed twice with PBS, and fixed with 4% (w/v) paraformaldehyde (PFA). Fixed cells were mounted on glass slides containing Dako mounting medium and detected using an Olympus Fluoview 1000 confocal microscope (Olympus Imaging Co, Tokyo, Japan).
  • Lec(RSV) was synthesized as a synergistic anti-tumor therapeutic platform ( Figure 1).
  • Resveratrol is soluble in organic solvents but not in water or buffers, a property that greatly limits the bioavailability of resveratrol.
  • Figure 1B (left) simply mixing lecithin with resveratrol does not automatically encapsulate RSV and form nanoparticles. Only through the nanoprecipitation method described above, Lec(RSV) nanoparticles can be prepared, and a transparent Lec(RSV) solution can be observed, as shown in Figure 1B (right).
  • nanoparticles significantly affects their therapeutic and diagnostic applications; therapeutic aspects including drug half-life, targeting ability, cellular uptake and tumor penetration are all affected by the size of nanoparticles; nanoparticles must be larger than 10nm to Avoid renal filtration, but the diameter should not be too large. For example, particles larger than 200nm will activate the complement system and be quickly removed from the blood and accumulate in the liver and spleen. Therefore, only nanoparticles of appropriate size can achieve the technical effect to be achieved by this application.
  • the particle size range of Lec(RSV) nanoparticles is 128 ⁇ 174nm, and the average size is 151nm, which is close to the ideal size and stable. , large load capacity, and good tumor penetration ability.
  • Lec(RSV) The stability of nanoparticles in nanodelivery systems is critical because nanoparticles need to circulate in the body for long periods of time. Both Lec and Lec(RSV) nanoparticles were stable for 48 hours.
  • Lec(RSV) the inventor measured the size of Lec(RSV) particles on days 1/4/8/5/30/60. As shown in Figure 3B, the size of Lec(RSV) was measured under DLS. Within 60 days, the nanometer size fluctuated very little, ranging from 100 to 200 nanometers, proving that Lec(RSV) has good stability.
  • Lec(RSV) can be stored at 4°C for a long time, proving that this nanosystem has good stability. Furthermore, RSV can achieve slow release after being wrapped by Lec, with only 55% of the cumulative release amount within 12 hours.
  • stability plays a crucial role in its storage and delivery capabilities.
  • the nanoparticle delivery system requires nanoparticles to circulate in the body for a long time, so the stability of Lec(RSV) plays a key role.
  • Lec(RSV) size was measured using DSL and found only slight size changes over 60 days. It is proved that Lec(RSV) has good stability. Lec(RSV) can be stored for 12 months at 4°C without aggregation or coagulation, which also shows that the nanoplatform has good stability. Combined with the aforementioned characteristics of Lec(RSV), Lec(RSV) shows greater advantages than other drugs or nano-delivery systems, and also has the potential for clinical application to treat related diseases.
  • Lec(RSV) was encapsulated into Lec and Lec(RSV) particles, and they were added to BT474 cells and cultured for 4 hours. After 4 hours of co-incubation, both Lec and Lec(RSV) showed significant uptake into the cytoplasm ( Figures 4A and 4B).
  • RSV treatment was highly toxic to cells (IC50 ⁇ 18 ⁇ M). As an antioxidant, Lec also has inherent tumor killing ability, but it is not as significant as RSV (IC50>40 ⁇ M).
  • Lec compared with using Lec or RSV alone, Lec (RSV) has a significant synergistic effect on the killing ability of tumor cells (IC50 ⁇ 11 ⁇ M). Similarly, compared with the control group or Lec, RSV had a significant scavenging effect on ROS (p ⁇ 0.001), and encapsulating RSV did not affect the biological activity of RSV (Figure 4D).
  • RSV As an ideal anti-cancer drug, in addition to the aforementioned particle size and stability, another important indicator is tumor cell enrichment ability and cytotoxicity.
  • the inventors used natural lecithin to encapsulate resveratrol to form nanoparticles, and tested its cellular uptake and cytotoxicity on BT474 breast cancer cells in vitro. After 4 hours of co-culture, both Lec and Lec(RSV) were obviously absorbed into the cytoplasm of the cells. Then, the inventors conducted an in vitro cytotoxicity test to observe the killing ability of RSV on tumor cells, and found that RSV (IC 50 , 11 ⁇ M) has obvious toxicity to cells. As an antioxidant, Lec also has a certain tumor-killing ability, but it is not as obvious as RSV (IC 50 , 40 ⁇ M).
  • Lec and RSV when Lec and RSV are combined to form nanoparticles, they have better tumor killing effect than Lec alone or RSV alone. The same is true in terms of antioxidants.
  • Lec(RSV) has a synergistic effect between components and has a significant effect.
  • encapsulating RSV will not change its biological activity, which further demonstrates the stability of the nanoparticles of the present application for encapsulating the main drug.
  • Lec(RSV) has excellent stability and biocompatibility, has an inhibitory effect on BT474 breast cancer cells, has less cytotoxicity, and is safe. Lec(RSV) is expected to be used clinically to become an effective clinical anti-tumor drug.
  • the inventor in the process of preparing resveratrol lecithin nanoparticles using nanoprecipitation method, the inventor also used DMSO to prepare resveratrol (RSV) (100 mg/mL) and lecithin (Lec) (100 mg/mL). ) solution, and add 9 ⁇ L or 11 ⁇ L of Lec to 1 ⁇ L of RSV, add DMSO to 100 ⁇ L, and use the same steps to prepare the white quinoa under the condition that the volume ratio of the mixed solution to the water phase is (0.05 ⁇ 0.15):10. Retinol lecithin nanoparticles.
  • RSV resveratrol
  • Lec lecithin

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Abstract

L'invention concerne une nanoparticule de resvératrol-lécithine comprenant du resvératrol et de la lécithine encapsulant et/ou conjuguée au resvératrol. La nanoparticule de resvératrol-lécithine présente une libération sûre et prolongée, et peut améliorer la biodisponibilité in vivo du resvératrol, améliorer le temps d'exposition in vivo, favoriser la performance de ciblage de tissus tumoraux, et améliorer l'effet de destruction sur des cellules tumorales, ayant ainsi des effets anti-tumoraux et antioxydants plus significatifs.
PCT/CN2022/114615 2022-04-08 2022-08-24 Nanoparticule de resvératrol-lécithine, procédé de préparation de cette dernière, et utilisation associée WO2023193389A1 (fr)

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