CN112439080B - Diagnosis and treatment magnetic bacteria and preparation method thereof - Google Patents

Diagnosis and treatment magnetic bacteria and preparation method thereof Download PDF

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CN112439080B
CN112439080B CN201910814388.1A CN201910814388A CN112439080B CN 112439080 B CN112439080 B CN 112439080B CN 201910814388 A CN201910814388 A CN 201910814388A CN 112439080 B CN112439080 B CN 112439080B
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bacteria
inps
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CN112439080A (en
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蔡林涛
邢婕华
尹婷
郑明彬
罗英梅
陈泽
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Shenzhen Institute of Advanced Technology of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0097—Cells, viruses, ghosts, red blood cells, viral vectors, used for imaging or diagnosis in vivo
    • 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
    • A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides diagnosis and treatment magnetic bacteria AMB-1-INPs and a preparation method thereof, and particularly relates to a nano fluorescence labeling method for magnetotactic bacteria, which is strong in specificity, rapid and simple. The invention selects the magnetotactic bacteria AMB-1 with high safety and strong targeting as a bacterial biological carrier, carries out chemical crosslinking on the magnetotactic bacteria AMB-1 rich in free-SH and a phospholipid-polymer nano probe (INPs) loaded with ICG and provided with maleimide groups on the surface, and constructs the diagnosis and treatment magnetic bacteria AMB-1-INPs with fluorescence imaging capability. According to the method, the nano fluorescent probe INPs are stably marked on the surface of the magnetotactic bacteria AMB-1, so that the efficiency of reaction between the nano probe and the surface of the bacteria can be prevented from being reduced due to cross-linking, and the obtained diagnosis and treatment magnetic bacteria AMB-1-INPs can penetrate through tumors deeply under the control of an external magnetic field to carry out fluorescence tracking, so that the practical requirements of basic research and clinical real-time evaluation on the treatment effect of the tumors are met.

Description

Diagnosis and treatment magnetic bacteria and preparation method thereof
Technical Field
The invention relates to the field of nano medicine, in particular to diagnosis and treatment magnetic bacteria, and a preparation method and application thereof.
Background
Liposomes have been known for the past few decades to have good biocompatibility, low immunogenicity, high flexibility, controlled release kinetics, and drug loading (e.g., hydrophilic or hydrophobic drugs, imaging agents, chemotherapeutics, etc.). However, liposomes suffer from unavoidable drawbacks such as insufficient pharmacokinetics, poor local targeting (non-specific biodistribution), lack of deep tissue penetration, etc., which limit their further clinical application. In recent years, bacteria have been focused on researchers for their good tumor anaerobic targeting ability and autonomous driving ability, and it has been shown that bacteria including E.coli, magnetotactic bacteria and other genera accumulate preferentially in tissues through anaerobic chemotaxis, thus suggesting potential applications of bacterial-based therapeutics. While bacteria may be used as therapeutic agents to address the above problems, they are not compatible with computer-based tumor area navigation, which is considered to be the most likely to enhance targeting. However, studies have shown that the magnetotactic properties of the magnetotactic bacterium AMB-1 can be combined with computer navigation to enhance its targeting, which is alleviated by deep penetration of the tumor through flagellum and external magnetic field controlled propulsion.
The magnetotactic bacteria AMB-1 is a facultative microaerophilic microorganism, can form nano magnetic particles in vivo and can perform directional movement under the action of an external magnetic field, mainly survives in an aerobic-anaerobic transition zone in water and can timely and effectively find a zone with specific oxygen concentration in water, so that targeted delivery to the deep part of an anoxic tumor becomes a current research hotspot by combining the magnetotactic bacteria AMB-1 with an in-vitro controllable magnetic field, such as Xie Maobin (the magnetic targeting anticancer drug delivery system is constructed by the magnetic bodies of the magnetotactic bacteria AMB-1), and the magnetic targeting anticancer drug delivery system is constructed by using the separated and purified magnetic bodies in AMB-1 as carriers and connecting methotrexate to the magnetic bodies through genipin.
In the prior art, it has been reported that adding nano material on the surface of bacteria provides a protective layer for bacteria, and the preparation of nano probe is aromatic, for example, CN200910188814 discloses a nano particle and its preparation method, in which an intermediate layer formed by polylactic acid-glycolic acid copolymer (PLGA) is used to form an inner core, and phospholipid surrounds the inner core surface, and a shell portion formed by distearoyl phosphatidylethanolamine-polyethylene glycol containing amino or carboxyl is inserted in the intermediate layer. This document does not relate to labeling of fluorescent probes and has a limited range of use. CN201010607708 discloses a fluorescent nano probe, which is also an intermediate layer formed by forming an inner core by polylactic acid-glycolic acid copolymer and phospholipid around the surface of the inner core, wherein an outer shell part formed by distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG) containing amino or carboxyl is inserted in the intermediate layer, indocyanine green (ICG) is dispersed in the inner core, and the fluorescent probe can identify tumor cells, but can only be used for early diagnosis of tumors. The preparation methods of the nano particles in the two prior arts adopt a stirring and mixing mode, so that the preparation efficiency is low and the time consumption is long. CN201210424026 and CN201210574535 also disclose two kinds of nano-drug particles and their preparation methods, and the two methods combine the advantages of nano-encapsulation technology, chemotherapeutic drugs and near-infrared photothermal conversion reagents for hyperthermia, and the two technical problems to be solved are the combined action of hyperthermia and chemotherapy, and the slow release technical problems of loading the two drugs of near-infrared photothermal conversion reagents and chemotherapeutic drugs. None of the above prior art uses attenuated bacteria for targeted treatment of tumors, and even less relates to the magnetotactic bacteria AMB-1.
The object of the present invention is to develop a new drug delivery strategy, namely a method of bacterial vector, while maintaining its deep targeting capability to solid tumors. The nanometer fluorescent probe INPs are efficiently and stably marked on the surface of the magnetotactic bacteria AMB-1 to prepare the diagnosis and treatment magnetic bacteria AMB-1-INPs, and the diagnosis and treatment magnetic bacteria AMB-1-INPs penetrate deep into tumors to carry out fluorescence tracking under the control of an external magnetic field, so that the treatment effect of the bacteria can be evaluated in real time, and great convenience is provided for the development of tumor generation and clinical treatment and the research of related antitumor drugs.
Disclosure of Invention
The invention provides a diagnosis and treatment magnetic bacterium, wherein the surface of the diagnosis and treatment magnetic bacterium is marked with nano fluorescent probes (INPs), and the INPs are chemically crosslinked with sulfhydryl groups on the surface of the magnetotactic bacterium after being treated by a reducing agent through maleimide groups on the surface; the INPs include amphiphilic compounds, monolayer lipid molecules, near infrared light-to-heat converting agents, and hydrophobic polymers; the amphoteric compound contains maleimide groups; the bacteria are magnetotactic bacteria.
The invention also provides a method for marking diagnosis and treatment magnetic bacteria by using the nano fluorescent probe with strong specificity, rapidness and convenience, which comprises the steps of chemically crosslinking maleimide groups on the surface of the nano fluorescent probe (INPs) with sulfhydryl groups on the surface of the magnetotactic bacteria after being treated by a reducing agent, wherein the INPs comprise a hydrophilic outer shell, an intermediate layer and a hydrophobic inner shell, the hydrophilic outer shell contains amphoteric compounds, the intermediate layer contains single-layer lipid molecules, and the hydrophobic inner shell contains a near infrared light heat conversion reagent and a hydrophobic polymer; the amphoteric compound is inserted in the middle layer to form a hydrophobic shell; the near infrared light-to-heat conversion agent is adsorbed on the hydrophobic polymer to form a hydrophobic inner shell.
Preferably, the amphoteric compound is distearoyl phosphatidylethanolamine-carboxypolyethylene glycol (DSPE-PEG) or distearoyl phosphatidylethanolamine-polyethylene glycol-maleic amide (DSPE-PEG-Mal), preferably DSPE-PEG-Mal; preferably, the monolayer lipid molecule comprises lecithin or cephalin, preferably vegetable lecithin, further preferably soy lecithin.
Preferably, the shell comprises soybean lecithin and DSPE-PEG-Mal, and the mass ratio of the soybean lecithin to the DSPE-PEG-Mal is 2:3.
preferably, the near infrared light-to-heat conversion reagent comprises any one or more of indocyanine green (ICG), gold nanorods, and carbon nanotubes, preferably ICG; preferably, the hydrophobic polymer is selected from polylactic acid-glycolic acid copolymer (PLGA), polylactic acid, polycaprolactone, preferably PLGA.
Preferably, the INPs further comprise a chemotherapeutic agent adsorbed to the lipid end of the amphiphilic compound and to the monolayer lipid molecules; preferably, the chemotherapeutic drug comprises any one or more of doxorubicin, epirubicin, taxol, norvinca alkaloid and platinum drugs.
Preferably, the diagnosis and treatment magnetic bacteria are magnetotactic bacteria AMB-1 strain; preferably, the reducing agent is tris (2-carboxyethyl) phosphine (TCEP).
The invention also provides a preparation method of INPs, which comprises the following steps:
(1) Soy lecithin ethanol solution and DSPE-PEG-Mal ethanol solution were mixed at 2:3, wherein the total weight of lecithin and DSPE-PEG-Mal is 15% of the total weight of PLGA;
(2) ICG 4% ethanol solution was added to 2mL4% ethanol solution;
(3) Mixing the solutions in the steps (1) and (2) to obtain a mixed solution, and ultrasonically dispersing the mixed solution for 5 minutes by using an ultrasonic crusher;
(4) In the ultrasonic process of the step (3), dropwise adding PLGA acetone solution into the mixed solution to form nano probe dispersion liquid;
(5) Transferring the nano probe dispersion liquid in the step (4) into a 3500kDa dialysis bag for dialysis and concentration to obtain purified INPs.
The invention also provides a preparation method of the diagnosis and treatment magnetic bacteria, which comprises the following steps:
(1) Preparing INPs according to the method;
(2) Will have a density of 10 7 -10 8 The CFU/mL magnetotactic bacteria were collected in centrifuge tubes and centrifuged at 3500rpm gravity;
(3) Resuspending the magnetotactic bacteria in 20-30mM TCEP in PBS and incubating for 20-120 min at 37 ℃;
(4) Washing the bacteria twice with PBS;
(5) Adding 1mL of the INPs prepared in the step (1) into the magnetotactic bacteria obtained in the step (4), and incubating for 20-120 minutes at 37 ℃;
(6) And (5) centrifugally washing to obtain the diagnosis and treatment magnetic bacteria marked by the nano fluorescent probe.
The invention also provides the nanometer fluorescent probe-labeled diagnosis and treatment magnetic bacteria AMB-1-INPs prepared by any one of the methods.
The invention also provides application of the magnetotactic bacteria or diagnosis and treatment magnetic bacteria AMB-1-INPs in preparing or screening medicaments for treating and/or preventing tumor.
The invention has the technical principle and beneficial effects that:
the aim of the invention is to develop a new drug delivery strategy, namely a method for bacterial vectors, while maintaining the deep targeting capability of the bacterial vectors on solid tumors and simultaneously realizing effective fluorescent tracing on artificial magnetotactic bacterial vectors. The invention selects the magnetotactic bacteria AMB-1 with high safety and strong targeting as a bacterial biological carrier, adopts a reducing agent of tris (2-carboxyethyl) phosphine (TCEP) to gently reduce disulfide bonds (S-S) on the surface of outer membrane proteins of the magnetotactic bacteria AMB-1 into sulfhydryl groups (SH); then, the free-SH enriched magnetotactic bacteria AMB-1 and phospholipid-polymer nano probes (INPs) loaded with near infrared fluorescent dye ICG and provided with maleimide groups (Mal) on the surface are subjected to chemical crosslinking to construct the AMB-1-INPs with fluorescence imaging capability. The method disclosed by the invention is quick, simple, safe and efficient, the nano fluorescent probe INPs are stably marked on the surface of the magnetotactic bacteria AMB-1, the efficiency of the reaction between the nano probe and the surface of the bacteria can be prevented from being reduced due to cross-linking, and the prepared diagnosis and treatment magnetic bacteria AMB-1-INPs can meet the practical requirements of basic research and clinical on tracking and monitoring bacteria and evaluating the tumor treatment effect in real time.
Drawings
FIG. 1 is an SEM image of magnetotactic bacterium AMB-1 and diagnostic magnetic bacterium AMB-1-INPs.
FIG. 2 shows hysteresis curves (A) of magnetotactic bacteria AMB-1 and magnetotactic bacteria AMB-1-INPs, and aggregation of magnetotactic bacteria AMB-1-INPs after 15min of external magnetic field.
Detailed Description
The present invention will be further described in detail by the following examples, which are not intended to limit the scope of the invention, so that those skilled in the art can better understand the invention and practice it.
The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents and the like used, unless otherwise specified, are all commercially available.
Example 1
INPs are prepared by a one-step ultrasonic method. First, soybean lecithin ethanol solution (10 mg/mL, 12. Mu.L) and DSPE-PEG-Mal ethanol solution (10 mg/mL, 18. Mu.L) were mixed at a ratio of 2:3 (total weight of lecithin and DSPE-PEG-Mal 15% of total weight of PLGA), ICG 4% ethanol solution (1 mg/mL,1 mL) was added to 2mL of 4% ethanol solution. Then, the above mixed solution was ultrasonically dispersed at a frequency of 20kHz and a power of 130W using a VCX130 ultrasonic breaker for 5 minutes, and PLGA acetone solution (4 mg/mL,0.5 mL) was dropwise added to the above mixed solution during the ultrasonic process, to form a microprojection dispersion. Finally, transferring the nano-probe dispersion liquid into a 3500kDa dialysis bag for dialysis and concentration, thus obtaining purified INPs.
Will have a density of 10 8 CFU/mL of magnetotactic bacteria AMB-1 were collected in centrifuge tubes, centrifuged at 3500rpm under gravity, and resuspended in 30mM TCEP in PBS. The bacteria were then washed twice with PBS after incubation at 37 ℃ for 20 minutes. 1mL of INPs at a concentration of 100mg/mL was then added to 10 8 Incubating the CFU/mL bacteria at 37 ℃ for 2 hours, and centrifugally washing to obtain the nano fluorescent probe-marked magnetic micro-robot AMB-1-INPs.
Example 2
INPs are prepared by a one-step ultrasonic method. First, soybean lecithin ethanol solution (10 mg/mL, 12. Mu.L) and DSPE-PEG-Mal ethanol solution (10 mg/mL, 18. Mu.L) were mixed at a ratio of 2:3 (total weight of lecithin and DSPE-PEG-Mal 15% of total weight of PLGA), ICG 4% ethanol solution (0.9 mg/mL,1 mL) was added to 2mL of 4% ethanol solution. Then, the above mixed solution was ultrasonically dispersed at a frequency of 20kHz and a power of 130W using a VCX130 ultrasonic breaker for 5 minutes, and PLGA acetone solution (4 mg/mL,0.5 mL) was dropwise added to the above mixed solution during the ultrasonic process, to form a microprojection dispersion. Finally, transferring the nano-probe dispersion liquid into a 3500kDa dialysis bag for dialysis and concentration, thus obtaining purified INPs.
Will have a density of 10 7 CFU/mL of magnetotactic bacteria AMB-1 were collected in centrifuge tubes, centrifuged at 3500rpm under gravity, and resuspended in 30mM TCEP in PBS. The bacteria were then washed twice with PBS after incubation at 37 ℃ for 30 minutes. 1mL of INPs at a concentration of 50mg/mL was then added to 10 7 Incubating the CFU/mL bacteria at 37 ℃ for 2 hours, and centrifugally washing to obtain the nano fluorescent probe-marked magnetic micro-robot AMB-1-INPs.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.

Claims (5)

1. A method of labeling magnetotactic bacteria with a nano-fluorescent probe, the method comprising chemically cross-linking maleimide groups on the surface of the nano-fluorescent probe (inp) with thiol groups on the surface of magnetotactic bacteria after treatment with a reducing agent, the inp comprising a hydrophilic outer shell comprising an amphiphilic compound comprising maleimide groups, an intermediate layer comprising a monolayer of lipid molecules, and a hydrophobic inner shell comprising a near infrared light-to-heat converting agent and a hydrophobic polymer; the amphoteric compound is inserted in the middle layer to form a hydrophobic shell; the near infrared light-heat conversion reagent is adsorbed on the hydrophobic polymer to form a hydrophobic inner shell; the amphoteric compound is distearoyl phosphatidylethanolamine-polyethylene glycol-maleic amide (DSPE-PEG-Mal); the monolayer lipid molecule is soybean lecithin; the near infrared light-to-heat conversion reagent is indocyanine green (ICG); the hydrophobic polymer is polylactic acid-glycolic acid copolymer (PLGA);
the magnetotactic bacteria are AMB-1 strains; the reducing agent is tris (2-carboxyethyl) phosphine (TCEP);
the preparation method of the INPs comprises the following steps:
(1) Soy lecithin ethanol solution and DSPE-PEG-Mal ethanol solution were mixed at 2:3, wherein the total weight of the soybean lecithin and the DSPE-PEG-Mal is 15% of the total weight of PLGA;
(2) ICG 4% ethanol solution was added to 2mL4% ethanol solution;
(3) Mixing the solutions in the steps (1) and (2) to obtain a mixed solution, and ultrasonically dispersing the mixed solution for 5 minutes by using an ultrasonic crusher;
(4) In the ultrasonic process of the step (3), dropwise adding PLGA acetone solution into the mixed solution to form nano probe dispersion liquid;
(5) Transferring the nano probe dispersion liquid in the step (4) into a 3500kDa dialysis bag for dialysis and concentration to obtain purified INPs.
2. The method of claim 1, wherein the inp further comprises a chemotherapeutic agent adsorbed to the lipid end and monolayer lipid molecules of the amphiphilic compound, wherein the chemotherapeutic agent comprises any one or more of doxorubicin, epirubicin, paclitaxel, norvinca alkaloid, and platinum drugs.
3. A method of preparing a diagnostic magnetic bacterium comprising the steps of:
(1) Preparing INPs according to the method of claim 1;
(2) Will have a density of 10 7 -10 8 The CFU/mL magnetotactic bacteria were collected in centrifuge tubes and centrifuged at 3500rpm gravity;
(3) Resuspending the magnetotactic bacteria in a PBS solution of 20-30mM tris (2-carboxyethyl) phosphine, and incubating for 20-120 minutes at 37 ℃;
(4) Washing the bacteria twice with PBS;
(5) Adding the INPs prepared in the step (1) of 1mL into the magnetotactic bacteria obtained in the step (4), and incubating for 20-120 minutes at 37 ℃;
(6) And (5) centrifugally washing to obtain the diagnosis and treatment magnetic bacteria marked by the nano fluorescent probe.
4. A nano-fluorescent probe-labeled magnetotactic bacterium prepared according to the method of claim 1 or 2 or a diagnostic magnetic bacterium prepared according to the method of claim 3.
5. Use of a nanofluorescent probe-labeled magnetotactic bacterium prepared according to the method of claim 1 or 2 or a diagnostic magnetic bacterium prepared according to the method of claim 3 in the preparation of a medicament for screening treatment and/or prevention of tumors.
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