CN111821280B - Construction method of pH-responsive sericin-adriamycin nano drug carrier - Google Patents
Construction method of pH-responsive sericin-adriamycin nano drug carrier Download PDFInfo
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- CN111821280B CN111821280B CN202010712370.3A CN202010712370A CN111821280B CN 111821280 B CN111821280 B CN 111821280B CN 202010712370 A CN202010712370 A CN 202010712370A CN 111821280 B CN111821280 B CN 111821280B
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- 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
- A61K9/5169—Proteins, e.g. albumin, gelatin
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- 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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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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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
- A61K47/50—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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
Abstract
The invention discloses a preparation method of a construction method of a pH responsive sericin-adriamycin nano drug carrier, which mainly comprises the following steps: (1) preparation of ZIF-8, loading of an adriamycin medicament and modification of sericin, and (2) washing and purification of ZIF-8@ DOX @ SS. The obtained drug is named as ZIF-8@ DOX @ SS. The obtained inorganic nano-particles can form a nano-particle aqueous solution which is uniformly distributed in water, have the advantages of high stability, low toxic and side effects, good controlled release of the drug and the like, effectively solve the problem of low solubility of hydrophobic drug molecules and provide an efficient drug delivery system.
Description
Technical Field
The invention belongs to the field of drug delivery, and particularly relates to a construction method of a pH-responsive sericin-adriamycin nano drug carrier.
Background
Sericin is a hydrophilic glycoprotein extracted from silk, and is composed of 18 kinds of amino acids including serine, glycine, glutamic acid, etc. The chemical element composition is as follows: carbon (46.5%), oxygen (31%), nitrogen (16.5%), hydrogen (6%). Through research, the sericin has various good efficacies of anti-inflammation, antibiosis, antioxidation and the like. Zeolitic imidazolate framework-8 (ZIF-8) is the most commonly used MOF for pH-responsive drug release. It has a Sodalite (SOD) type structure, has large pores (11.6 a), and exhibits improved drug loading capacity and pH-responsive drug release due to its porosity and acid sensitivity.
Because the molecular size of the adriamycin medicine is small and the solubility in water is extremely low, the problems of nonspecific selectivity, low medicine utilization rate, high kidney clearance rate, strong toxic and side effects and the like are urgently solved in the medicine delivery process, so that the improvement of the water solubility and the biocompatibility of the adriamycin medicine has important scientific significance. By loading the adriamycin medicine on the ZIF-8 and utilizing sericin to wrap the periphery of the medicine, when the nano particles reach a tumor microenvironment, the medicine is released from the carrier to play the medicine effect. The drug-loaded system increases the stability and biocompatibility of the drug, forms a nano solution in water and also shows good cell permeation and retention Effects (EPR), so that the uptake of the drug by tumor cells is greatly increased, and meanwhile, the defects of high toxic and side effects on normal tissues and the like of the adriamycin are overcome, and the targeting property and excellent controllable release of the drug-loaded particles are realized.
Disclosure of Invention
Aiming at the defects that the existing inorganic nanoparticles have poor selectivity, the loading capacity of the drug is low, the selective controllable release of the drug is difficult to ensure and the like, the invention aims to provide a construction method of a pH-responsive sericin-adriamycin nano drug carrier and application thereof in the field of drug treatment of cancers.
The technical scheme of the invention is as follows:
a construction method of a pH-responsive sericin-adriamycin nano drug carrier is characterized by comprising the following steps:
(1) dissolving sericin powder in deionized water, and fully dissolving sericin by using a vortex instrument; standing the obtained sericin protein solution for 5 minutes, and taking supernatant for later use;
(2) dissolving doxorubicin hydrochloride in deionized water to obtain a doxorubicin hydrochloride aqueous solution;
(3) mixing the sericin aqueous solution obtained in the step (1) and the step (2) with adriamycin hydrochloride aqueous solution, and stirring for 5 minutes at room temperature for later use;
(4) adding imidazole-2-pyrrole formaldehyde into the adriamycin hydrochloride and sericin mixed solution obtained in the step (3), continuously stirring at room temperature for 15 minutes, and then adding zinc nitrate hexahydrate;
(5) stirring the solution obtained in the step (4) at room temperature overnight in a dark place;
(6) centrifuging the solution which is completely reacted, and taking a precipitate; and dissolving the precipitate in deionized water, centrifuging again to obtain the precipitate, and washing for three times to obtain the ZIF-8@ DOX @ SS nanoparticle aqueous solution.
Further, the mass concentration range of the sericin in the step (1) is 30-45 mg/ml.
Further, the mass concentration range of the doxorubicin hydrochloride in the step (2) is 0.3-0.6 mg/ml.
Further, in the step (3), the mass ratio of the adriamycin to the sericin is controlled to be 1: 150.
further, in the step (4), the mass ratio of imidazole-2-pyrrole formaldehyde to zinc nitrate hexahydrate is 54: 25.
further, the overnight stirring in the step (5) is carried out in a dark place for 12-16 hours.
Further, in the step (6), the centrifugal speed is 8000 rpm, and the diameter of the ZIF-8@ DOX @ SS nano particle is 120-300 nm.
The main advantages of the invention are:
1. aiming at the problems of the existing inorganic nanoparticle delivery system, the project creatively provides the delivery system of the construction method of the pH-responsive sericin-adriamycin nano drug carrier, which can effectively achieve the aim of selective release, solve the problems of the stability of the existing inorganic nanoparticle delivery system and the selective and controllable release of drugs and promote the accurate diagnosis and the efficient treatment of tumors.
2. In the project, sericin has various effects of good antibiosis, anti-inflammation, oxidation resistance and the like, is a pure natural hydrophilic glycoprotein, and is one of the greatest characteristics of the project for application of sericin.
Drawings
In order to make the purpose, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings:
FIG. 1 is a graphical representation of DLS and PDI and stability of ZIF-8@ DOX @ SS from example 1.
FIG. 2 is an infrared schematic of ZIF-8@ DOX @ SS from example 1.
FIG. 3 is a schematic fluorescence of ZIF-8@ DOX @ SS in example 1.
FIG. 4 is a schematic in vitro release of ZIF-8@ DOX @ SS as described in example 1.
FIG. 5 is a graph comparing the toxicity of ZIF-8@ DOX @ SS on 4T1 cells in example 1.
FIG. 6 is a graph showing the in vitro phagocytosis of 4T1 cells by ZIF-8@ DOX @ SS in example 1.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1 preparation of a pH-responsive sericin-doxorubicin biopharmaceutical carrier
The preparation method of the pH-responsive sericin-adriamycin nano drug carrier mainly comprises the following steps:
(1) 150mg of sericin powder was dissolved in 4ml of deionized water, and sericin was sufficiently dissolved using a vortex apparatus. And standing the obtained sericin solution for 5 minutes, and taking a supernatant for later use.
(2) Doxorubicin hydrochloride was dissolved in 2ml of deionized water to obtain an aqueous doxorubicin hydrochloride solution.
(3) And (3) mixing the sericin aqueous solution obtained in the steps (1) and (2) with an adriamycin hydrochloride aqueous solution, metering to 6ml, and stirring at room temperature for 5 minutes for later use.
(4) Adding 108mg of imidazole-2-pyrrole formaldehyde into the mixture of the doxorubicin hydrochloride and the sericin aqueous solution obtained in the step (3), continuously stirring at room temperature for 15 minutes, and then adding 50mg of zinc nitrate hexahydrate.
(5) And (5) stirring the solution obtained in the step (4) at room temperature overnight in a dark place (12-16 h).
(6) The solution which has completed the reaction is centrifuged to take the precipitate. And dissolving the precipitate in deionized water, centrifuging again to obtain the precipitate, washing for three times, and fixing the volume to 6ml to obtain the ZIF-8@ DOX @ SS nanoparticle aqueous solution. FIG. 1 is a schematic diagram of DLS and PDI and their stability, and it can be seen that the nanoparticles are successfully synthesized, and their stability and dispersibility are good. FIGS. 2 and 3 are schematic infrared and ultraviolet diagrams, respectively, illustrating the successful synthesis of ZIF-8@ DOX @ SS. FIG. 4 is a graph comparing the toxicity of ZIF-8@ DOX @ SS against 4T1 cells, and it can be seen that the drug has strong toxicity to tumor cells and low toxicity to normal cells. FIG. 5 is a schematic in vitro release of ZIF-8@ DOX @ SS, showing that the drug has excellent DOX release effect in the in vitro simulated tumor part. FIG. 6 is a schematic diagram of phagocytosis showing very high phagocytosis efficiency and degree.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (4)
1. A construction method of a pH-responsive sericin-adriamycin nano drug carrier is characterized by comprising the following steps:
(1) dissolving sericin powder in deionized water, and fully dissolving sericin by using a vortex instrument; standing the obtained sericin protein solution for 5 minutes, and taking supernatant for later use; the mass concentration range of the sericin in the step (1) is 30-45 mg/ml;
(2) dissolving doxorubicin hydrochloride in deionized water to obtain a doxorubicin hydrochloride aqueous solution; the mass concentration range of the doxorubicin hydrochloride in the step (2) is 0.3-0.6 mg/ml;
(3) mixing the sericin aqueous solution obtained in the step (1) and the step (2) with adriamycin hydrochloride aqueous solution, and stirring for 5 minutes at room temperature for later use;
(4) adding imidazole-2-pyrrole formaldehyde into the adriamycin hydrochloride and sericin mixed solution obtained in the step (3), continuously stirring at room temperature for 15 minutes, and then adding zinc nitrate hexahydrate;
(5) stirring the solution obtained in the step (4) at room temperature overnight in a dark place;
(6) centrifuging the solution which is completely reacted, and taking a precipitate; and dissolving the precipitate in deionized water, centrifuging again to obtain the precipitate, and washing for three times to obtain the ZIF-8@ DOX @ SS nanoparticle aqueous solution.
2. The method for constructing a pH-responsive sericin-doxorubicin nano-drug carrier according to claim 1, wherein: the mass ratio of imidazole-2-pyrrole formaldehyde to zinc nitrate hexahydrate in the step (4) is 54: 25.
3. the method for constructing a pH-responsive sericin-doxorubicin nano-drug carrier according to claim 1, wherein: and (4) stirring overnight in the step (5) in a dark place for 12-16 hours.
4. The method for constructing a pH-responsive sericin-doxorubicin nano-drug carrier according to claim 1, wherein: in the step (6), the centrifugal speed is 8000 rpm, and the diameter of the ZIF-8@ DOX @ SS nano-particles is 120-300 nm.
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| CN114712519A (en) * | 2022-04-15 | 2022-07-08 | 青岛科技大学 | Preparation method and application of sericin-based water-insoluble drug delivery system |
| CN115120721A (en) * | 2022-07-27 | 2022-09-30 | 西南大学 | Preparation method of sericin/manganese dioxide compound loaded with phthalocyanine and adriamycin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105148286A (en) * | 2015-09-07 | 2015-12-16 | 华中科技大学同济医学院附属协和医院 | Natural sericin encapsulated mesoporous silicon nano-carrier and preparation method and application thereof |
| WO2017078609A1 (en) * | 2015-11-05 | 2017-05-11 | Su Holding Ab | One-pot synthesis of metal-organic frameworks with encapsulated target-molecule and their use |
| CN107245243A (en) * | 2017-05-17 | 2017-10-13 | 浙江大学 | A kind of method of the fibroin induction synthesis nanoparticles of ZIF 8 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105148286A (en) * | 2015-09-07 | 2015-12-16 | 华中科技大学同济医学院附属协和医院 | Natural sericin encapsulated mesoporous silicon nano-carrier and preparation method and application thereof |
| WO2017078609A1 (en) * | 2015-11-05 | 2017-05-11 | Su Holding Ab | One-pot synthesis of metal-organic frameworks with encapsulated target-molecule and their use |
| CN107245243A (en) * | 2017-05-17 | 2017-10-13 | 浙江大学 | A kind of method of the fibroin induction synthesis nanoparticles of ZIF 8 |
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