WO2020258584A1 - 作用于小肠的辐射防护纳米药物及其制备方法 - Google Patents

作用于小肠的辐射防护纳米药物及其制备方法 Download PDF

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WO2020258584A1
WO2020258584A1 PCT/CN2019/110565 CN2019110565W WO2020258584A1 WO 2020258584 A1 WO2020258584 A1 WO 2020258584A1 CN 2019110565 W CN2019110565 W CN 2019110565W WO 2020258584 A1 WO2020258584 A1 WO 2020258584A1
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drug
nanomedicine
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basic amino
small intestine
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华道本
张钰烁
王璐
杨森
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Suzhou University
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention relates to a nanometer medicine acting on the small intestine, in particular to a radiation protection nanometer medicine acting on the small intestine and a preparation method thereof.
  • Injectable small intestine radiation protection drugs are mainly antioxidants (DOI:10.1016/j.freeradbiomed.2018.10.) and mercaptans that remove free radicals generated by ionizing radiation.
  • Class preparations DOI: 10.1634/theoncologist.12-6-738; small molecule drugs that inhibit radiation-induced apoptosis of intestinal epithelial cells (DOI: 10.1053/gast.2002.34209; DOI: 10.1093/jrr/rrs001) and protein preparations ( DOI: 10.1126/science.1154986); and cytokine preparations (DOI: 10.1084/jem.173.5.1177; DOI: 10.1097/00002820-200308000-00012) that can promote the regeneration and reconstruction of small intestinal stem cells and secretory vesicles from bone marrow ( DOI: 10.1038/ncomms13096) etc.
  • the above drugs are all designed to distribute the drugs throughout the body through invasive operations (such as intravenous injection, intraperitoneal injection, etc.) to achieve the small intestinal radiation protection effect.
  • Oral preparations such as intestinal flora transplantation (DOI:10.15252/emmm.201606932), amifostine microcapsules (DOI:10.1016/j.ijpharm.2013.06.019) and Ex- (DOI:10.1269/jrr.11191), etc., it is necessary to make biologically active agents (such as transplanted flora) survive in the intestinal lumen, or to make the radiation protection drugs absorb into the blood to reach the effective concentration of the whole body to play the role of small intestine radiation protection.
  • injection drugs may cause serious side effects (such as protein preparations induce immune response, etc.), and intravenous administration is difficult to ensure that the drugs reach the small intestine tissue with high radiation sensitivity (research has found that drugs tend to be concentrated in the liver and spleen ).
  • Oral preparations may be decomposed by the extreme pH environment of the gastrointestinal tract and digestive enzymes. Most importantly, most drugs cannot resist the rapid flow of digestive juices. Therefore, oral drugs are often difficult to stay in the small intestine tissues with high radiation sensitivity, so they cannot exert effective radiation protection effects.
  • the purpose of the present invention is to provide a radiation protection nanomedicine that acts on the small intestine and a preparation method thereof.
  • the present invention provides a nanomedicine with intestinal adhesion, which can tolerate the gastrointestinal tract. Acid-base environment, high biocompatibility, and the ability to penetrate the intestinal mucus barrier, can effectively concentrate the drugs on the small intestinal crypt stem cells.
  • the first object of the present invention is to provide a method for preparing nanomedicine, which includes the following steps:
  • the acid buffer solution is morpholine ethanesulfonic acid solution, glacial acetic acid or hydrochloric acid solution.
  • step (1) the activation time is 2-6 hours.
  • the small molecule catalyst is N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; both The molar ratio is 1:1.
  • step (1) the molar ratio of basic amino acid, N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 1 : 4:4.
  • the basic amino acids are arginine, lysine, histidine and the like.
  • the polysaccharide is a hydrophobic polysaccharide, and the polysaccharide is preferably chitosan, dextran, alginic acid, cellulose, etc.; the molar ratio of the carboxyl group of the basic amino acid to the amino group of the polysaccharide is 1:1.
  • the molecular weight of the polysaccharide is preferably 20-200kD, and the degree of deacetylation of chitosan is 75%-95%.
  • the solvent of the polysaccharide solution is morpholine ethanesulfonic acid solution.
  • step (1) when preparing the amphiphilic polymer, the reaction solution needs to be continuously stirred and reacted for 24-48 hours, and the pH of the buffer solution is maintained at 4.5-5.5. After the reaction is completed, an alkaline solution is added to terminate the reaction.
  • step (1) in the prepared amphiphilic polymer, basic amino acids and polysaccharides are connected by covalent bonds. Since the molecular weight of polysaccharides is much larger than that of basic amino acids, the polymer is formed by polysaccharides. In the internal structure of the nanoparticles, basic amino acids are evenly distributed on the outside of the nanoparticles.
  • the drug is a hydrophobic drug, preferably thalidomide, cysteamine thiosulfate, amifostine, genistein, genistein, resveratrol , 3,3-diindolylmethane, Entolimod, Ex-RAD, etc.; the concentration of the drug solution is 1.0 mg/mL; the mass ratio of the drug to the amino acid-coated polysaccharide is 1:100.
  • the solvent of the drug solution is a mixed solvent of water and an organic solvent, the volume ratio of the two is 1:1, and the organic solvent is preferably acetonitrile.
  • step (1) when preparing the drug-containing nanoparticles, the reaction is continuously stirred under a protective atmosphere for 24 hours, the solvent is removed after the reaction is completed, and the drug is lyophilized after centrifugation. Further, in step (2), the concentration of the dopamine solution is 2.0 mg/mL; the mass ratio of the nanoparticles to dopamine is 1:4.
  • step (2) the reaction is stirred for 3-12 hours.
  • the second object of the present invention is to provide a nanomedicine prepared by the above preparation method.
  • the nanomedicine includes nanoparticles and polydopamine modified on the surface of the nanoparticles, and the nanoparticles include hydrophobic polysaccharides, hydrophilic
  • the basic amino acid and the hydrophobic drug, the polysaccharide and the basic amino acid are connected by a covalent bond, the drug is located inside the nanoparticle and is positively charged in the gastric acid environment, and the particle size of the nano drug is 100-500nm .
  • the surface of the nanomedicine In gastric acid, the surface of the nanomedicine is positively charged (the polydopamine and basic amino acids on the surface are protonated), and the small molecule drug contained in it is also positively charged and cannot be released due to charge repulsion.
  • the surface of the nanomedicine is close to neutrality (negative charge of the deprotonation of the dopamine hydroxyl group and positive charge of the basic amino acid), the charge repulsion effect is relieved, so that the internal medicine is slowly released, ensuring that most medicines are radiation sensitive Released in the small intestine with higher sex.
  • the medicine prepared by the present invention has the characteristics of being more suitable for penetrating the small intestinal mucus layer network structure, and can quickly reach the small intestinal crypt site below the mucus layer, which is the most susceptible part of the small intestine to be damaged by radiation. At present, there is no small intestine radiation.
  • the protective drugs can be delivered directly to the crypts by oral administration.
  • the third objective of the present invention is to claim the application of the above-mentioned nano-medicine of the present invention in the field of preparing small intestine radiation protection.
  • the preparation is an oral drug.
  • the radiation is X-ray radiation, ⁇ -ray ( 60 Co source, 137 Cs source).
  • the radiation site is the abdomen, and the radiation dose is 2-15 Gy.
  • the above-mentioned protective preparation has good adhesion to small intestinal crypts and has the best radiation protection effect.
  • the preparation principle of the nano medicine of the present invention is as follows:
  • the interior is hydrophobic and the surface is hydrophilic. water.
  • dopamine can undergo oxidative self-polymerization, and the formed polydopamine tends to coat the surface of the nanoparticle in the water environment of the drug-loaded nanoparticle, forming a polydopamine coating structure, and then forming the nano drug.
  • the present invention can realize the intestinal delivery of the drug, and while increasing the effective concentration of the local drug through the adhesion effect of polydopamine, it reduces the systemic side effects of the drug.
  • the polydopamine modified on the surface of the nano-medicine makes it have intestinal adhesion, and in the small intestine, the polysaccharide in the nano-medicine swells after absorbing water, allowing the drug to be released slowly.
  • the present invention has at least the following advantages:
  • the present invention provides a nanomedicine that acts on the small intestine. Similar concepts can be used to optimize other small intestinal administration methods, which are different from traditional intravenous and oral administration methods.
  • the nanomedicine can tolerate the acid-base environment of the gastrointestinal tract and has good biocompatibility.
  • the suitable particle size and surface charge of the nanomedicine make it have the ability to penetrate the intestinal mucus barrier, and the nanomedicine has adhesion in the small intestinal liquid environment. Ability, can significantly improve the time and utilization efficiency of drugs acting on the small intestine.
  • Oral radiation protection nano-drugs are used for small intestine radiation protection, which can efficiently and stably deliver the radiation protection drugs to the small intestinal crypt area, ensuring that the drug directly acts on the small intestinal crypt stem cells with high radiation sensitivity.
  • Figure 1 is the SEM test image of the prepared radiation protection nanomedicine
  • Figure 2 is the test result of the hydrated particle size of the radiation protection nanomedicine
  • Figure 3 is the standard curve of UV absorption value of the contained drug thalidomide and the test result of drug loading rate of nano drug;
  • Figure 4 is a schematic diagram of the structure of the radiation protection nanomedicine
  • Figure 5 is the test result of in vitro radiation protection effect of radiation protection nanomedicine
  • Figure 6 is the test results of intestinal adhesion of radiation protection nanomedicine
  • Figure 7 is a schematic diagram of the action mode of radiation protection nanomedicine delivered by oral means
  • Figure 8 is the effect of radiation protection nano-medicine to relieve radiation-induced intestinal injury
  • 1-chitosan 2-arginine; 3-thalidomide; 4-polydopamine; 5-radioprotective nanomedicine; 6-small intestinal mucus barrier layer; 7-small intestinal villi; 8-small intestinal crypts.
  • Arginine (0.867g, 4.997mmol) was dissolved in 40mL morpholine ethanesulfonic acid solution (25mM, pH 5.0), and then N-hydroxysuccinimide (2.291g, 19.908mmol), 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.816g, 19.908mmol) was activated for 2 hours, and then a chitosan solution (1.0g, 4.977 mmol) was added to the above mixture. After stirring and reacting at room temperature for 24 hours, sodium hydroxide (0.1M) was added to terminate the reaction.
  • sodium hydroxide 0.1M
  • the lyophilized sample (20.0 mg) was transferred into a dopamine solution (2 mg/mL, 40 mL, pH 8.5), stirred at room temperature for 3 hours, washed with deionized water and centrifuged to collect the supernatant to obtain the nano drug.
  • Figure 1 is the SEM test image of the prepared radiation protection nanomedicine. The results show that the nanomedicine has a small particle size and good dispersibility. The nanomedicine is close to a circular structure and the surface is relatively smooth. It can be seen that polydopamine is formed through The coating form uniformly covers the surface of the nanoparticles.
  • Figure 2 is the test results of the hydrated particle size of the radiation protection nanomedicine. The results show that the above-mentioned nanomedicine has a smaller hydrated particle size, about 214nm, and a PDI of 0.584. Its particle size is suitable for penetrating the small intestinal mucus barrier. It helps nanomedicine play a radioprotective effect in the crypts of the small intestine.
  • Figure 3 shows the standard curve of the UV absorption value of the contained thalidomide and the test results of the drug loading rate of the radiation protection nano-drug.
  • FIG. 4 Schematic diagram of the structure of the radiation protection nanomedicine prepared above, including chitosan 1, arginine 2, thalidomide 3 and polydopamine 4; chitosan 1 forms a network structure with arginine 2 attached to its surface , Thalidomide 3 is contained in a network structure, and Polydopamine 4 is located on the surface of the nanomedicine.
  • nanomedicine (11.237 ⁇ g/mL) prepared in Example 1 was dispersed in the small intestinal crypt organoid culture medium, and the small intestinal crypt organoids of C57BL/6J mice were cultured in vitro. After 12 hours, a 14Gy dose of X Radiation is used to calculate the small intestinal crypts separated and disintegrated after radiation damage (as shown in Figure 5A) and the crypts with intact shape and sharp edges (as shown in Figure 5B). As shown in Figure 5C, the crypts after irradiation with nanomedicine The survival rate is about 42.67%, which is significantly higher than that of the control group (*p ⁇ 0.05). The results show that the above-mentioned nanomedicine has a good radiation protection effect.
  • the radiation protection nanomedicine prepared in Example 1 was labeled with Cy5.5 fluorescent dye, and then resuspended in phosphate buffer. After fasting for 12 hours on C57BL/6J mice, the dye-labeled nanomedicine solution (4 mg /mL, 0.5mL) were administered to each group of mice by gavage. After the mice were euthanized 6 hours and 24 hours after the administration, the small intestine tissue was taken for in vitro fluorescence imaging. The instrument used was the Kodak FX Pro in vivo fluorescence imaging system. The excitation light was 630 nm and the emission light was 700 nm.
  • FIG. 7 is a schematic diagram of the mode of action of radioprotective nanomedicine delivered by oral route.
  • Radiation protection nanomedicine 5 is resistant to the acid-base environment of the gastrointestinal tract, and can be prevented from being decomposed and absorbed into the blood under the action of gastric acid. Because of its adhesion ability in the small intestinal liquid environment, the nanomedicine can penetrate the small intestinal mucus barrier Layer 6 reaches the small intestine villi 7 and can reach the small intestine crypt 8 deeply.
  • Example 4 Test to relieve the intestinal injury induced by radiation
  • C57BL/6J mice male, 8 weeks old were given radioprotective nano-drugs (22.98wt.%, containing 100mg/kg thalidomide, solvent 500 ⁇ L phosphate buffer) by gavage 12 hours before irradiation, The irradiation group was given the same dose of phosphate buffer solvent.
  • X-RAD 320i X-ray machine was used to irradiate the abdomen of mice with a dose of 14Gy and a dose rate of 1Gy/min. Five days after the exposure, the mouse small intestine tissue was taken to make paraffin sections and stained with hematoxylin and eosin.
  • the main evaluation index of radiation-induced intestinal injury is pathological detection of the number of crypts in the intestinal sample, and the regeneration and repair of the intestine after irradiation mainly rely on stem cells in the crypt site, so the survival and integrity of the small intestine crypts after irradiation can be reflected Severity of small intestine radiation injury.
  • the normal small intestinal crypt structure is shown in Figure 8A, and the crypt structure almost disappeared 5 days after the irradiation group (Figure 8B), indicating that ionizing radiation caused serious intestinal damage and a large reduction in crypt structure.
  • the nest is unable to perform regeneration and repair functions, which will cause the body to die.
  • the radiation protection nanomedicine group Figure 8C
  • there are still some small intestinal crypts maintaining the original contour and regenerating Figure 8C, the arrow points to the survival crypts), indicating that the small intestine tissue still has Repair the regenerative ability, so the radiation protection nano medicine can greatly alleviate the radiation-induced intestinal damage.

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Abstract

一种具有小肠黏附性的纳米药物构建方法：利用小分子催化剂活化碱性氨基酸，然后向其中加入多糖溶液，反应后得到两亲性高分子聚合物；然后向其中加入药物溶液，混匀后得到包载有药物的纳米颗粒，纳米颗粒包括亲水部分和疏水部分；药物具有辐射防护性能或对电离辐射诱导的细胞死亡有抑制效果；将所得包载有药物的纳米颗粒加入多巴胺溶液中反应，反应完全后得到表面为碱性氨基酸和聚多巴胺的纳米药物。同时提供一种具有肠道黏附性的口服纳米药物，该纳米药物生物相容性高，可耐受胃肠道酸碱环境，具有小肠黏附性能及肠道粘液屏障穿透能力。

Description

作用于小肠的辐射防护纳米药物及其制备方法 技术领域
本发明涉及作用于小肠的纳米药物，尤其涉及作用于小肠的辐射防护纳米药物及其制备方法。
背景技术
随着核工业与核技术的发展及广泛应用，核安全的重要性日渐突出，如何有效防治急性辐射损伤已经成为核安全领域的重要研究内容。机体在短时间内受到剂量大于10Gy的电离辐射将引起严重的胃肠道综合征，可使患者出现腹泻、血便、肠道炎症等症状，并在数周内导致患者死亡。虽然现有的辐射防护药物虽能发挥一定的辐射防护效果，然而其较低的靶向性及严重的副作用常导致其肠道辐射损伤救治效果不甚理想。目前针对小肠的辐射防护手段主要为注射类制剂和口服制剂两类，注射类小肠辐射防护药物主要为清除电离辐射产生自由基的抗氧化剂(DOI:10.1016/j.freeradbiomed.2018.10.)及硫醇类制剂(DOI:10.1634/theoncologist.12-6-738)；抑制辐射诱导肠上皮细胞凋亡的小分子药物(DOI:10.1053/gast.2002.34209；DOI:10.1093/jrr/rrs001)及蛋白类制剂(DOI:10.1126/science.1154986)；以及可促进小肠干细胞再生重建的细胞因子制剂(DOI:10.1084/jem.173.5.1177；DOI:10.1097/00002820-200308000-00012)和骨髓来源的分泌型囊泡(DOI:10.1038/ncomms13096)等。以上药物均旨在通过侵入性操作(如静脉注射，腹腔注射等)使药物分布于全身，以达到小肠辐射防护效果。而口服类制剂如肠道菌群移植(DOI:10.15252/emmm.201606932)、氨磷汀微胶囊(DOI:10.1016/j.ijpharm.2013.06.019)及Ex-
Figure PCTCN2019110565-appb-000001
(DOI:10.1269/jrr.11191)等，需使生物活性制剂(如移植菌群)存活于肠腔内，或使辐射防护药物吸收入血达到全身有效浓度以发挥小肠辐射防护作用。但胃肠道蠕动、消化液的快速流动、胃肠道极端酸碱环境和消化酶，使口服制剂难以长久且有效地停留在胃肠道内，降低了口服制剂的辐射防护效果。目前尚未发明在消化道液体环境下仍可黏附于小肠组织，通过在小肠局部缓慢持久地释放药物以达到辐射防护效果的纳米药物。
由于注射类药物可能引起严重的毒副作用(如蛋白类制剂诱发机体免疫反应等)，且静脉给药难以保证药物到达辐射敏感性较高的小肠组织(研究发现药物常倾向于集中在肝脏、脾脏)。而口服类制剂则可能被胃肠道极端的pH环境及消化酶分解。最重要的是，多数药物均无法抵抗消化液的快速流动，因此口服药物常难以停留在辐射敏感性较高的小肠组织内，故 无法发挥高效辐射防护作用。
发明内容
为解决上述技术问题，本发明的目的是提供一种作用于小肠的辐射防护纳米药物及其制备方法，本发明提供了一种具有肠道黏附性的纳米药物，该药物可耐受胃肠道酸碱环境，生物相容性高，且具有肠粘液屏障地穿透能力，可将药物有效集中于小肠隐窝干细胞部位。
本发明的第一个目的是提供一种纳米药物的制备方法，包括以下步骤：
(1)在酸性缓冲溶液中，利用小分子催化剂活化亲水性的碱性氨基酸，然后向其中加入多糖溶液，在pH＝4.5-5.5，20-30℃条件下混匀并反应，得到两亲性高分子聚合物；然后向其中加入药物溶液，混匀后，得到包载有药物的纳米颗粒，所述纳米颗粒包括亲水部分和疏水部分，所述亲水部分为碱性氨基酸，疏水部分为多糖和药物；其中，药物具有辐射防护性或具有抑制电离辐射诱导的细胞死亡(如凋亡、焦亡等)效果且药物在胃酸环境中带正电荷；
(2)将步骤(1)所得包载有药物的纳米颗粒加入多巴胺溶液中，在pH＝8.0-10.0条件下于25-50℃下反应，反应完全后得到表面为碱性氨基酸和聚多巴胺的纳米药物。
进一步地，在步骤(1)中，酸性缓冲溶液为吗啉乙磺酸溶液、冰醋酸或盐酸溶液。
进一步地，在步骤(1)中，活化时间为2-6小时。
进一步地，在步骤(1)中，所述小分子催化剂为N-羟基琥珀酰亚胺和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；二者摩尔比为1:1。
进一步地，在步骤(1)中，碱性氨基酸、N-羟基琥珀酰亚胺和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的摩尔比为1：4：4。
进一步地，在步骤(1)中，所述碱性氨基酸为精氨酸、赖氨酸、组氨酸等。
进一步地，在步骤(1)中，所述多糖为疏水性多糖，多糖优选为壳聚糖、葡聚糖、海藻酸、纤维素等；所述碱性氨基酸的羧基与多糖的氨基摩尔比为1:1。多糖的分子量优选为20-200kD，其中壳聚糖脱乙酰化程度为75％-95％。
优选地，在步骤(1)中，多糖溶液的溶剂为吗啉乙磺酸溶液。
进一步地，在步骤(1)中，制备两亲性高分子聚合物时，反应液需持续搅拌反应24-48小时，保持缓冲液pH 4.5-5.5，反应结束后加入碱性溶液终止反应。
进一步地，在步骤(1)中，所制备的两亲性高分子聚合物中，碱性氨基酸与多糖依靠共价键连接，由于多糖分子量远大于碱性氨基酸的分子量，该聚合物依靠多糖形成纳米颗粒内部结构，碱性氨基酸则均布于纳米颗粒外部。
进一步地，在步骤(1)中，所述药物为疏水性药物，优选为沙利度胺、半胱胺硫代硫酸酯、氨磷汀、染料木素、金雀异黄酮、白藜芦醇、3，3-二吲哚基甲烷、Entolimod、Ex-RAD等；所述药物溶液的浓度为1.0mg/mL；所述药物与所述氨基酸包裹的多糖的质量比为1:100。
进一步地，在步骤(1)中，药物溶液的溶剂为水和有机溶剂的混合溶剂，二者体积比为1:1，有机溶剂优选为乙腈。
进一步地，在步骤(1)中，制备包载有药物的纳米颗粒时，在保护气氛下持续搅拌反应24小时，反应完全后除去溶剂，离心后冻干。进一步地，在步骤(2)中，所述多巴胺溶液的浓度为2.0mg/mL；所述纳米粒子与多巴胺的质量比为1:4。
进一步地，在步骤(2)中，搅拌反应3-12小时。
本发明的第二个目的是提供一种采用上述制备方法所制备的纳米药物，该纳米药物包括纳米颗粒以及修饰于纳米颗粒表面的聚多巴胺，所述纳米颗粒包括疏水性的多糖、亲水性的碱性氨基酸和疏水性的药物，所述多糖和碱性氨基酸通过共价键连接，所述药物位于所述纳米颗粒内部且在胃酸环境中带正电荷，纳米药物的粒径为100-500nm。
在胃酸中本纳米药物表面带正电(表面的聚多巴胺及碱性氨基酸发生质子化)，其内部包载的小分子药物也带正电，由于电荷排斥作用而无法释放。抵达小肠后，由于纳米药物表面接近电中性(多巴胺羟基去质子化的负电与碱性氨基酸正电中和)，电荷排斥作用解除，从而使内部药物缓慢释放，保证了多数药物都在辐射敏感性较高的小肠内释放。
本发明所制备的药物具有更适合穿透小肠黏液层网状结构的特点，可快速抵达黏液层下方的小肠隐窝部位，该部位为小肠中最易受到辐射损伤的部位，目前尚未有小肠辐射防护类药物可达到通过口服直接递送至隐窝的效果。
本发明的第三个目的是要求保护本发明的上述纳米药物在制备小肠辐射防护领域中的应用。
进一步地，制剂为口服药物。
进一步地，辐射为X射线辐射，γ射线( 60Co源， 137Cs源)。
进一步地，辐射部位为腹部，辐射剂量为2-15Gy。
进一步地，上述防护制剂对小肠隐窝的黏附性较好且辐射防护作用最佳。
本发明的纳米药物的制备原理如下：
活化后的碱性氨基酸与多糖混合后，在缓冲溶液中发生酰胺反应，使得氨基酸的羧基与多糖上的氨基相连，形成两亲性高分子聚合物。由于多糖的分子量远高于氨基酸，多糖形成类似无规线团样结构，氨基酸则分布于多糖形成的无规线团样结构的外部。再向其中缓慢滴 加药物的有机水溶液，由于药物与多糖均为疏水性，根据相似相溶原理，药物将被包封入两亲性高分子聚合物内部，得到纳米颗粒，其内部疏水，表面亲水。在碱性水溶液中，多巴胺可发生氧化自聚合，形成的聚多巴胺在载药纳米颗粒的水环境内倾向于包覆在纳米颗粒表面，形成聚多巴胺涂层结构，进而形成所述纳米药物。
结合口服给药的方式，本发明的可实现药物肠道输送，在通过聚多巴胺的黏附作用提高局部药物有效浓度的同时，降低药物的全身毒副作用。在口服给药后，纳米药物表面修饰的聚多巴胺使其具备肠道黏附性，且在小肠内，纳米药物中的多糖吸水后发生溶胀，可使药物缓慢释放。
借由上述方案，本发明至少具有以下优点：
(1)本发明提供了一种作用于小肠的纳米药物，相似的概念可被用于其他作用于小肠给药方式的优化，有别于传统的静脉及口服给药方式。该纳米药物可耐受胃肠道酸碱环境，药物生物相容性好，纳米药物合适的粒径及表面电荷使其具有肠粘液屏障地穿透能力，并且纳米药物具备小肠液体环境下的黏附能力，可显著提高药物作用于小肠的时间及利用效率。
(2)口服辐射防护纳米药物用于小肠辐射防护，可将辐射防护药物高效、稳定地输送至小肠隐窝区域，保证药物直接作用于辐射敏感性较高的小肠隐窝干细胞。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1是所制备的辐射防护纳米药物的SEM测试图；
图2是辐射防护纳米药物的水合粒径测试结果；
图3是所包载药物沙利度胺的紫外吸收值标准曲线及纳米药物的载药率检测结果；
图4为该辐射防护纳米药物的结构示意图；
图5是辐射防护纳米药物的体外辐射防护效果测试结果；
图6是辐射防护纳米药物的肠道黏附性测试结果；
图7为使用口服方式递送的辐射防护纳米药物作用方式示意图；
图8是辐射防护纳米药物缓解辐射诱导的肠损伤效果；
附图标记说明：
1-壳聚糖；2-精氨酸；3-沙利度胺；4-聚多巴胺；5-辐射防护纳米药物；6-小肠黏液屏障层；7-小肠绒毛；8-小肠隐窝。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例1合成纳米药物
将精氨酸(0.867g，4.977mmol)溶解在40mL吗啉乙磺酸溶液(25mM，pH 5.0)中，然后依次加入N-羟基琥珀酰亚胺(2.291g，19.908mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(3.816g，19.908mmol)进行活化2小时，随后将溶解在吗啉乙磺酸中的壳聚糖溶液(1.0g，4.977mmol)加入上述混合物中，室温持续搅拌反应24小时后，加入氢氧化钠(0.1M)终止反应。随后将溶解在水和乙腈混合液(v/v＝1/1)中的沙利度胺(1.0mg/mL，10mL)缓慢滴入上述聚合物溶液(10mg/mL，100mL)内，持续搅拌并通氮气过夜除去乙腈，离心后取上清液冻干。将冻干样品(20.0mg)移入多巴胺溶液(2mg/mL，40mL，pH 8.5)中，室温搅拌3小时，用去离子水清洗后离心收集上清液，即得到纳米药物。
图1是所制备的辐射防护纳米药物的SEM测试图，结果表明，上述纳米药物具有较小的粒径及良好的分散性，纳米药物接近圆形结构，表面相对光滑，可见聚多巴胺是通过形成涂层的形式均匀包覆于纳米颗粒表面。
图2是辐射防护纳米药物的水合粒径测试结果，结果表明，上述纳米药物具有较小的水合粒径，约214nm左右，PDI为0.584，其粒径大小适于穿透小肠粘液屏障层，有助于纳米药物在小肠隐窝部位发挥辐射防护作用。
图3是所包载的沙利度胺的紫外吸收值标准曲线及辐射防护纳米药物的载药率检测结果。通过将超声破碎后的纳米药物溶液紫外吸光度(图3B)带入标准曲线所得计算公式(图3A，y＝0.2245x+0.051，R 2＝0.9975)，可得纳米药物的载药率约为22.98％左右。
图4上述制备的辐射防护纳米药物的结构示意图，包括壳聚糖1、精氨酸2、沙利度胺3和聚多巴胺4；壳聚糖1形成网状结构，其表面连接精氨酸2，沙利度胺3包载于网状结构中，聚多巴胺4位于纳米药物的表面。
实施例2体外辐射防护效果测试
将实施例1制备的适量纳米药物(11.237μg/mL)分散在小肠隐窝类器官培养基中，对C57BL/6J小鼠小肠隐窝类器官进行离体培养，12小时后进行14Gy剂量的X射线照射，对辐射损伤后分离崩解的小肠隐窝(如图5A)及保持形状完整、边缘锐利的隐窝(如图5B)进行计算，图5C所示，使用纳米药物的照后隐窝存活率约为42.67％，较对照组存活率有明显提高(*p<0.05),结果表明上述纳米药物具有良好的辐射防护效果。
实施例3肠道黏附性测试
利用Cy5.5荧光染料标记实施例1制备的辐射防护纳米药物，然后重悬于磷酸盐缓冲液中，对C57BL/6J小鼠进行12小时禁食处理后，将染料标记的纳米药物溶液(4mg/mL,0.5mL)使用灌胃法给予各组小鼠。分别于给药后6小时及24小时将小鼠安乐死后，取其小肠组织进行体外荧光成像，所使用仪器为Kodak FX Pro活体荧光成像系统，激发光为630纳米，发射光为700纳米。
如图6所示，给药后6小时(图6A)，小鼠小肠表现出较强荧光信号，表明药物已大部分聚集于小肠部位。给药后24小时(图6B)，小鼠小肠组织内荧光信号依然维持较强水平，表明纳米药物具有良好的小肠黏附性能。
图7为使用口服方式递送的辐射防护纳米药物作用方式示意图。辐射防护纳米药物5因其耐受胃肠道酸碱环境，可免于在胃酸作用下分解并吸收入血液，由于其具有小肠液体环境下的黏附能力，使得该纳米药物可穿透小肠黏液屏障层6到达小肠绒毛7，并可深入到达小肠隐窝8。
实施例4缓解辐射诱导的机体肠损伤测试
于照射前12小时通过灌胃法给予C57BL/6J小鼠(雄性，8周龄)辐射防护纳米药物(22.98wt.％,含100mg/kg沙利度胺，溶剂为500μL磷酸盐缓冲液)，单纯照射组则给予同等剂量的磷酸盐缓冲液溶剂。使用X-RAD 320iX射线机对小鼠进行腹部照射，照射剂量14Gy，剂量率1Gy/min。于照后5天取小鼠小肠组织制作石蜡切片，进行苏木精-伊红染色。放射性肠损伤的主要评价指标为病理学检测肠道样本中的隐窝数量，且照后肠道的再生修复主要依靠隐窝部位的干细胞，因此辐照后小肠隐窝的存活和完整情况可以反映小肠辐射损伤严重程度。
如图8所示，正常的小肠隐窝结构如图8A所示，单纯照射组照后5天隐窝结构几乎消失(如图8B)，表明电离辐射造成了严重的肠损伤，大量减少的隐窝无法发挥再生修复功能，从而将导致机体死亡。而服用辐射防护纳米药物组(图8C)，照后5天仍有部分小肠隐窝维持原有轮廓并进行再生(如图8C，箭头所指为存活隐窝)，表明辐射后小肠组织仍具备修复再生能力，因此辐射防护纳米药物可大大缓解辐射诱导的肠损伤。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。

Claims (10)

  1. 一种作用于小肠的纳米药物的制备方法，其特征在于，包括以下步骤：
    (1)在酸性缓冲溶液中，利用小分子催化剂活化亲水性的碱性氨基酸，然后向其中加入多糖溶液，在pH＝4.5-5.5，20-30℃条件下混匀并反应，得到两亲性高分子聚合物；然后向其中加入药物溶液，混匀后，得到包载有药物的纳米颗粒，所述纳米颗粒包括亲水部分和疏水部分，所述亲水部分为碱性氨基酸，疏水部分为多糖和药物；其中，药物具有辐射防护性或具有抑制电离辐射诱导的细胞死亡效果，药物在胃酸环境中带正电荷；
    (2)将步骤(1)所得包载有药物的纳米颗粒加入多巴胺溶液中，在pH＝8.0-10.0条件下于25-50℃下反应，反应完全后得到表面修饰有聚多巴胺的纳米药物。
  2. 根据权利要求1所述的制备方法，其特征在于：在步骤(1)中，所述小分子催化剂为N-羟基琥珀酰亚胺和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
  3. 根据权利要求2所述的制备方法，其特征在于：在步骤(1)中，所述碱性氨基酸、N-羟基琥珀酰亚胺和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的摩尔比为1：4：4。
  4. 根据权利要求1所述的制备方法，其特征在于：在步骤(1)中，所述碱性氨基酸为精氨酸、赖氨酸和组氨酸中的一种或几种。
  5. 根据权利要求1所述的制备方法，其特征在于：在步骤(1)中，多糖为壳聚糖、葡聚糖、海藻酸和纤维素中的一种或几种；所述碱性氨基酸的羧基与多糖的氨基摩尔比为1:1。
  6. 根据权利要求1所述的制备方法，其特征在于：在步骤(1)中，所述药物为沙利度胺、半胱胺硫代硫酸酯、氨磷汀、染料木素、金雀异黄酮、白藜芦醇、3，3-二吲哚基甲烷、Entolimod和Ex-RAD中的一种或几种；所述药物溶液的浓度为1.0mg/mL；所述药物与所述氨基酸包裹的多糖的质量比为1:100。
  7. 根据权利要求1所述的制备方法，其特征在于：在步骤(2)中，所述多巴胺溶液的浓度为2.0mg/mL；所述纳米颗粒与多巴胺的质量比为1:4。
  8. 权利要求1-7中任一项所述的制备方法所制备的作用于小肠的纳米药物，其特征在于：所述纳米药物包括纳米颗粒以及修饰于纳米颗粒表面的聚多巴胺，所述纳米颗粒包括疏水性的多糖、亲水性的碱性氨基酸和疏水性的药物，所述多糖和碱性氨基酸通过共价键连接，所述药物位于所述纳米颗粒内部且在胃酸环境中带正电荷，所述纳米药物的粒径为100-500nm。
  9. 权利要求8所述的作用于小肠的纳米药物在制备小肠辐射防护制剂中的应用。
  10. 根据权利要求9所述的应用，其特征在于：所述制剂为口服药物。
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