CN105833289A - Mitochondrion-targeting nano-drug delivery system and preparation method and application thereof - Google Patents
Mitochondrion-targeting nano-drug delivery system and preparation method and application thereof Download PDFInfo
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- CN105833289A CN105833289A CN201610371113.1A CN201610371113A CN105833289A CN 105833289 A CN105833289 A CN 105833289A CN 201610371113 A CN201610371113 A CN 201610371113A CN 105833289 A CN105833289 A CN 105833289A
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- 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
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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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
Abstract
The invention discloses a mitochondrion-targeting nano-drug delivery system, comprising polyethylene glycol connected with TPP and thioketal linker connected with a chemotherapeutic drug, the polyethylene glycol and the thioketal linker are connected with each other through amino and carboxyl condensation. This system also comprises DSPE-PEG and a photosensitizer; the chemotherapeutic drug forms a hydrophobic core inside, a hydrophilic shell layer is formed in the center of the polyethylene glycol, a mitochondrion-targeting crown is formed outside the TPP, and the photosensitizer is of hydrophobic structure distributed inside the core and/or around the core. TPP is selectively positioned to mitochondrion. This system is ROS responsive, the photosensitizer is laser excited to release ROS, and ROS cuts the thioketal linker to release the chemotherapeutic drug and can carry out photodynamic therapy at the same time, thus enabling synergic therapy of mitochondrion-targeting photodynamic therapy and chemotherapy. The invention also discloses a preparation method and application of the mitochondrion-targeting nano-drug delivery system.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly relate to a kind of Mitochondrially targeted Nano medication delivery system and
Preparation method and application.
Background technology
Mitochondrion is the main place that cell carries out aerobic respiration, is referred to as " power house ", and its diameter exists
0.5 to 1.0 microns.Mitochondrion also takes up important function in the apoptosis of cell.Mitochondrial function is disorderly
Disorderly generation and development with tumor have important relationship.Optical dynamic therapy is by converting light energy into of photosensitizer
Learning can reactive oxygen free radical (being abbreviated as ROS).Singlet oxygen (1O2) as a kind of ROS,
In optical dynamic therapy most commonly used, but its time of staying the shortest (< 0.1ms) in vivo, and spreading
Radius the least (< 20nm).Therefore, in optical dynamic therapy, photosensitizer enough must be pressed close to treatment site.
Mitochondrion is the main place of aerobic respiration.Therefore, the nanometer system energy of Mitochondrially targeted load photosensitizer
Upset the metabolism of ROS, the apoptosis of inducing cell, it is achieved the maximization of optical dynamic therapy efficiency.
The mitochondrial function of tumor cell and the function of normal tissue cell are different.The line grain of tumor cell
Body transmembrane potential is compared with the mitochondrial membrane potential of normal tissue cell, and mitochondrial membrane potential is more negative.This is the most favourable
Medicine or nano-particle in cation enter tumor cell.Someone studies and shows before, under the conditions of 37 DEG C,
It is Normocellular that the 60mV potential difference of normal cell and tumor cell may result in the amount of swallowing of tumor cell
About 10 times.Triphenylphosphine is positively charged, can be accumulated in transmembrane potential is negative mitochondrion by selectivity.Carefully
After birth is the most electronegative, and triphenylphosphine readily penetrates through, and entering cytoplasmic triphenylphosphine has more than 80% to accumulate
In mitochondrion.This characteristic of triphenylphosphine is explored for guiding imaging and medicine to enter mitochondrion, targeting
In mitochondrion for some acts on mitochondrial medicine, toxic and side effects can be reduced, improve curative effect, reduce
Multidrug resistance.
Chemotherapy is that tumor makes a definite diagnosis Therapeutic Method conventional afterwards, but chemotherapy is often with a lot of side effect, in order to obtain
Obtaining best therapeutic effect and avoid side effect, many nano materials are used for load slow release chemotherapeutics.These
Medicine generally can target tumor and drug release is controllable.Such as pH responsive type, reduction responsive type,
Responsive to temperature type, enzyme responsive type and photaesthesia type etc., but the drug release few people of ROS response research.
The ROS stimulation of light-operated generation has time and the advantage in space that can accurately control release.
The ROS pressure ratio normal cell of tumor cell wants height, and a part of reason is probably derived from the thorn of oncogene
Swash and add metabolic activity and mitochondrial dysfunction.Under identical ROS pressure, normal cell is than swollen
Oncocyte can process more ROS.Therefore, properly increase the level of ROS in cell and can reach selectivity
The effect of killing tumor cell.Optical dynamic therapy can produce ROS and kill cell, and photosensitizer ZnPc has higher
ROS productivity, be commonly used for optical dynamic therapy.
Summary of the invention
In order to obtain a kind of preferably drug delivery system, inventor is with mitochondrion as targeting, in conjunction with ROS
Stimulate and produce optical dynamic therapy and conventional chemotherapy, develop a kind of Mitochondrially targeted Nano medication and deliver system
System.This Mitochondrially targeted Nano medication delivery system is a kind of Mitochondrially targeted ROS (Reactive oxygen
Species) the Nano medication delivery system responded.
The invention discloses a kind of Mitochondrially targeted Nano medication delivery system, including block polymer；Described
Block polymer includes connecting to be had the Polyethylene Glycol of TPP and connects the contracting thioketone linker having chemotherapeutics, described
Connect and have the Polyethylene Glycol of TPP and described connection to have the contracting thioketone linker of chemotherapeutics to be contracted by amino and carboxyl
Close reaction forming.TPP is PPh3Br-(CH2)4The abbreviation of-COOH.TPP with the connection of Polyethylene Glycol is
It is connected with an amino condensation reaction on Polyethylene Glycol by the carboxyl on TPP.
Further, PEG-DSPE (DSPE-PEG) and photosensitizer are also included；
Chemotherapeutics forms hydrophobic core in inner side, and Polyethylene Glycol is formed in outside at the hydrophilic shell of intermediate formation, TPP
The mitochondrial hat of targeting, described photosensitizer is in hydrophobic structure is distributed in described core and/or around described core.
Further, the amount of the TPP on the surface of described Mitochondrially targeted Nano medication delivery system abundant with
Make the surface of described Mitochondrially targeted Nano medication delivery system positively charged and current potential >=40mV.
Further, the structural formula of described contracting thioketone linker (TL) is:
Wherein, described contracting thioketone linker is connected with chemotherapeutics by its carboxyl；Described contracting thioketone linker
It is that ROS is sensitive, can be cut off by ROS, thus discharge chemotherapeutics.
Further, described photosensitizer discharges ROS under 633-660nm laser excitation, for tumor
Optical dynamic therapy.
Further, described photosensitizer includes Phthalocyanine Zinc (Zinc phthalocyanine, ZnPc) and m-four
One or two kinds of in phenyl porphine, the structural formula of its correspondence is:
Wherein, the left side is Phthalocyanine Zinc, and the right is m-tetraphenylporphines.
Further, described chemotherapeutics includes that camptothecine (CPT), amycin (DOX), Yi Li replace
One or more in health, paclitaxel.
Further, the hydration particle diameter of described Mitochondrially targeted Nano medication delivery system is 80-150nm.
In a better embodiment of the present invention, described chemotherapeutics is CPT, and described photosensitizer is ZnPc,
Described block polymer is TL-CPT-PEG1K-TPP, TL-CPT-PEG1K-TPP and DSPE-PEG matter
Amount than for load capacity w/w in described Mitochondrially targeted Nano medication delivery system of 8:1, CPT is
14.91% ± 1%, CPT account for TL-CPT-PEG1KThe 17.52% ± 1% of-TPP molecule total amount, the institute of ZnPc
Stating load capacity w/w in Mitochondrially targeted Nano medication delivery system is 4.27% ± 0.5%.
The invention also discloses the preparation method of above-mentioned Mitochondrially targeted Nano medication delivery system, including following
Step:
Step one, the synthesis of contracting thioketone linker；
Step 2, contracting thioketone linker are connected with chemotherapeutics；
Step 3, connection have the contracting thioketone linker of chemotherapeutics to be connected with the amino of Polyethylene Glycol one end,
To complex one；
Step 4, the modification of triphenylphosphine: be heated to reflux in 5-bromine valeric acid and triphenylphosphine addition acetonitrile, cold
Freezing filtration, ethyl acetate is washed, the dried triphenylphosphine that must pass through modification, i.e. TPP；
Step 5, TPP are connected with the amino of the Polyethylene Glycol other end of described complex one, obtain block and gather
Compound；
Step 6, assemble complete Mitochondrially targeted Nano medication delivery system: by described block polymer,
PEG-DSPE and photosensitizer hybrid precast go out complete described Mitochondrially targeted
Nano medication delivery system.
Further, described step one is specifically: the synthesis of contracting thioketone linker: anhydrous 3-mercaptopropionic acid
With anhydrous acetone room temperature reaction 2-6h in the case of dry HCl gas is saturated, product crystallizes
Filtering, washing, vacuum lyophilization obtains product contracting thioketone linker (TL).
Described step 2 is specifically: contracting thioketone linker is connected with chemotherapeutics: contracting thioketone linker is anhydrous
Dimethylformamide in, be initially charged triethylamine, 2,4,6-trichloro-benzoyl chlorides, the feelings of dimethylamino naphthyridine
Under condition, stir 5-20min；Antineoplastic chemotherapy medicine is added, reaction 20-30h, crude product are stirred at room temperature
Cross silicagel column and must connect the antineoplastic chemotherapy medicine sterling having contracting thioketone linker；Chemotherapeutic as added is happiness
Tree alkali (CPT), this step product is TL-CPT.
Described step 3 is specifically: connects and has the contracting thioketone linker of chemotherapeutics and the ammonia of Polyethylene Glycol one end
Base connects, and obtains complex one: the connection being dissolved in anhydrous dimethyl formamide (DMF) has chemotherapeutics
Contracting thioketone linker, triethylamine, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate
(EDC.HCl) join after, I-hydroxybenzotriazole is stirred at room temperature 10min two ends be amino molecule amount about
It is Polyethylene Glycol (the i.e. NH of 10002-PEG1K-NH2In), reaction 24h is stirred at room temperature；After 24h,
Reactant liquor is slowly dropped in appropriate deionized water, and dropping limit, limit is stirred, and continues stirring 4h after dripping
Form it into micelle；After 4h, it is loaded into bag filter (MWCO=3.5kDa) dialysis 48h, has dialysed
After carry out lyophilization and obtain complex one.Medicine as modified is CPT, the complex obtained by the reaction of this step
One is TL-CPT-PEG1K-NH2。
Described step 4 is specifically: triphenylphosphine (PPh3) modification: 5-bromine valeric acid and triphenylphosphine add
Acetonitrile is heated to reflux 24h, the crude product that freezing and filtering must separate out, ethyl acetate wash 3 times dried
White powder product PPh3Br-(CH2)4-COOH (is abbreviated as TPP).
Described step 5 is specifically: TPP is connected with the amino of the Polyethylene Glycol other end of described complex one,
Obtain block polymer: TPP, triethylamine, EDC.HCl and I-hydroxybenzotriazole and 10min is stirred at room temperature
After join in the complex one that described step 3 obtains reaction 24h；After 24h, this reactant liquor is slowly added dropwise
In appropriate deionized water, dropping limit, limit is stirred, and continues stirring 4h to form micelle after being added dropwise to complete；4
After h, being loaded by this liquid in bag filter (MWCO=3.5kDa), dialyse 48h, postlyophilization of dialysing
Obtain described block polymer.Medicine as modified is CPT, and this step product is
TL-CPT-PEG1K-TPP。
Described step 6 is particularly as follows: assemble complete Mitochondrially targeted Nano medication delivery system: will be dissolved in two
The described block polymer of methyl sulfoxide (DMSO), it is dissolved in the DSPE-PEG of chloroform and is dissolved in DMSO
Photosensitizer mixing, be slowly dropped in deionized water, dropping limit, limit is ultrasonic, and ultrasonic power is 120-140W,
Continue ultrasonic 2-5min after dripping, obtain micellar solution；Precipitate is removed by centrifugal for described micellar solution, on
Clear liquid adds ultrafiltration in super filter tube and removes organic principle；0.45 μm sterilised membrane filter is crossed after adding deionized water dilution
Obtain aseptic micellar solution, the most described Mitochondrially targeted Nano medication delivery system.
Further, in step one, the addition of acetone is that excess, 3-mercaptopropionic acid and acetone add mol ratio
For 1:2, the hydrogen chloride gas being passed through is necessary for dry gas.
Further, in step 2, the addition of contracting thioketone linker is excess, it is preferable that contracting thioketone linker
Adding mol ratio with antineoplastic chemotherapy medicine is 2:1.
Further, in step 3, connection has chemotherapeutic and the NH of contracting thioketone linker2-PEG1K-NH2Add
Enter mole than for 1:1.
Further, the addition amount of skipping over of 5-bromine valeric acid in step 4, adding of 5-bromine valeric acid and triphenylphosphine
Enter mol ratio and be about 1.06:1.
Further, in step 5, the addition of TPP is excess, and the mole that TPP adds is complex one
More than 5 times.
The invention also discloses above-mentioned Mitochondrially targeted Nano medication delivery system as preparing antitumor drug system
The application of agent.This Mitochondrially targeted Nano medication delivery system is Mitochondrially targeted optical dynamic therapy and chemotherapy
The nanometer system combined, can be by optical dynamic therapy and chemotherapy combined treatment tumor eradication.
Ultimate principle: triphenylphosphine energy selectivity accumulates in mitochondrion, contracting thioketone linker (TL) is that ROS rings
Answering, ROS can cut TL and discharge chemotherapeutics.In this individual system, triphenylphosphine makes Selective feeding
It is positioned the mitochondrion of the mitochondrion of cell, especially tumor cell；633nm laser excitation photosensitizer is such as
ZnPc discharges ROS, ROS cutting TL and discharges chemotherapeutics.It is achieved thereby that optical dynamic therapy and chemotherapy
Synergistic therapeutic action.
Its beneficial effect:
(1) this Nano medication delivery system is Mitochondrially targeted, and mitochondrion is the field of cell aerobic respiration
Institute, is conducive to producing ROS and is used for optical dynamic therapy, and mitochondrion also takes up important function in the apoptosis of cell,
Mitochondrial dysfunction has important relationship with generation and the development of tumor.Therefore, the line of tumor cell is targeted
The optical dynamic therapy of plastochondria can realize the maximization of curative effect.
(2) ROS can cut contracting thioketone linker release antineoplastic chemotherapy medicine.Therefore, ROS is used
Drug release can be controlled by the Nano medication delivery system of response over time and space.
(3) cutting-release antineoplastic chemotherapy medicine of chemical bond sensitive for light-operated generation ROS and ROS,
Make the Nano medication delivery system utilizing ROS to respond can carry out optical dynamic therapy and chemotherapy combined is treated, one
Secondary by tumor eradication.
(4) good biocompatibility of this nanometer formulation.
(5) this nanometer formulation uniform particle sizes, good stability.
Accompanying drawing explanation
Fig. 1 is the block polymer TL-CPT-PEG in the better embodiment of the present invention1KThe synthesis of-TPP
Route map.
Fig. 2 is that the Mitochondrially targeted Nano medication delivery system in the better embodiment of the present invention is for light
Dynamic therapy and the mechanism figure of chemotherapy combined treatment.
Fig. 3 is the block polymer TL-CPT-PEG in the better embodiment of the present invention1K-TPP's1H
NMR schemes.
Fig. 4 is the hydration of the Mitochondrially targeted Nano medication delivery system in the better embodiment of the present invention
Grain size distribution.
Fig. 5 is the sensitivity of contracting thioketone linker sensitive for test ROS in the better embodiment of the present invention1H NMR schemes.
Fig. 6 is the Mitochondrially targeted Nano medication delivery system targeting detection in the better embodiment of invention
Streaming figure.
Fig. 7 is that the Mitochondrially targeted Nano medication delivery system in the better embodiment of invention is used in vitro
The therapeutic alliance design sketch to lung carcinoma cell NCI-H460 in light power and chemotherapy.
Fig. 8 is that the Mitochondrially targeted Nano medication delivery system in the better embodiment of invention moves for light
Power and the chemotherapy therapeutic alliance design sketch to pulmonary carcinoma NCI-H460 transplanted tumor in nude mice.
Detailed description of the invention
Below in conjunction with the accompanying drawings and specific embodiment, and with reference to data, the present invention is described in further detail.Ying Li
Solve, these embodiments present invention solely for the purpose of illustration, rather than limit the scope of invention by any way.
Experimental technique used in following embodiment if no special instructions, is conventional method.Used by following embodiment
Material, reagent etc., if no special instructions, the most commercially obtain.
Embodiment one
1. contracting thioketone linker (TL) step sensitive for synthesis ROS is as follows:
Anhydrous 3-mercaptopropionic acid (5.2g, 49.1mmol) and anhydrous acetone (5.8g, 98.2mmol) are with dry
Dry HCl gas is saturated, at room temperature reaction 4h.Product crystallization is filtered, and washs with hexane and cold water,
Mercaptan linker vacuum lyophilization obtains product.
2. synthesis TL-CPT experimental procedure is as follows:
TL (252.1mg, 1.0mmol) is dissolved in anhydrous 10mL DMF, be sequentially added into triethylamine (TEA,
3.0mmol), 2,4,6-trichloro-benzoyl chlorides (241.9mg, 1.0mmol), dimethylamino naphthyridine (DMAP,
24.4mg, 0.2mmol), stir 10min.Be dissolved in 10mL DMF camptothecine (CPT, 174.1mg,
Add after 0.5mmol), reaction 24h is stirred at room temperature.Go out reaction with shrend, with CH2Cl2Extract 5 times.
Crude product is crossed silicagel column and is obtained sterling TL-CPT.
3.TL-CPT is as follows with the Connection Step of Polyethylene Glycol one Amino End Group:
TL-CPT (232.8mg, 0.4mmol) is dissolved in the anhydrous DMF of 10mL, triethylamine (triethylamine,
TEA, 1.8mmol), EDC.HCl (134.19mg, 0.7mmol) and I-hydroxybenzotriazole
(hydroxybenzotriazole, HOBT, 94.6mg, 0.7mmol) is dissolved in the DMF of 3mL and drips
In TL-CPT solution, dropping limit, limit is stirred, and after reaction 10min is stirred at room temperature, is dissolved in 2mL DMF
NH2-PEG1K-NH2(400mg, 0.4mmol) joins in reactant liquor, and reaction 24h is stirred at room temperature.
After 24h, reactant liquor is slowly dropped in 100mL deionized water, and dropping limit, limit is stirred, and drips follow-up
Continuous stirring 4h.After 4h, it is loaded into bag filter (MWCO=3.5kDa) dialysis 48h.Dialyse laggard
Row lyophilization obtains product TL-CPT-PEG1K-NH2。
4. the modification step of triphenylphosphine is as follows:
5-bromine valeric acid (3.1g, 17.1mmol) and triphenylphosphine (PPh3,4.24g, 16.1mmol) add
40mL acetonitrile is heated to reflux 24h.The crude product that freezing and filtering must separate out, ethyl acetate is washed 3 times and is done
White powder product PPh is obtained after dry3Br-(CH2)4-COOH (is abbreviated as TPP).
5. the triphenylphosphine (TPP) after modifying is as follows with the Connection Step of Polyethylene Glycol other end amino:
TPP (173.1mg, 0.66mmol) is dissolved in the anhydrous DMF of 3mL, is dissolved in 3mL dry DMF
Triethylamine (triethylamine, TEA, 2mmol), EDC.HCl (153mg, 0.8mmol) and 1-
Hydroxybenzotriazole (hydroxybenzotriazole, HOBT, 108mg, 0.8mmol) adds containing TPP
Solution in be stirred at room temperature reaction 10min.After 10min, containing TL-CPT-PEG1K-NH2(200mg, 0.133
Mmol) 4mL dry DMF adds above-mentioned solution room temperature reaction 24h.After 24h, this reactant liquor delays
Slowly being added drop-wise in 70mL deionized water, dropping limit, limit is stirred, and continues stirring 4h to be formed after being added dropwise to complete
Micelle.After 4h, being loaded by this liquid in bag filter (MWCO=3.5kDa), dialyse 48h.After dialysis
Lyophilization obtains product TL-CPT-PEG1K-TPP.Product TL-CPT-PEG1KThe synthetic route of-TPP is shown in
Fig. 1, that sees the structure detection of this product sees Fig. 3.
6. the process of assembling composite micelle ZnPc-CPT-TPPNPs is as follows:
It is that 50mg/mL, ZnPc are dissolved in the dense of DMSO mother solution that DSPE-PEG is dissolved in the mother liquid concentration of chloroform
Degree is 0.4mg/mL.Nano-particle contains the ratio difference of composition but manufacture method is identical.With
CPT-PEG1KAs a example by-TPP:DSPE (8:1), the 8mg of 0.1mL DMSO will be dissolved in
CPT-PEG1K-TPP, 1mg DSPE-PEG and 0.4mg being dissolved in chloroform are dissolved in the ZnPc of DMSO
Solution mixing, be slowly dropped in 10mL deionized water, dropping limit, limit is ultrasonic, and ultrasonic power is 130W,
Ultrasonic 3min is continued after dripping.Micellar solution after ultrasonic centrifugal (5000rpm/min, 3min) goes precipitation
Thing, centrifuged supernatant adds ultrafiltration in super filter tube and removes organic principle 3-4 time.After adding deionized water dilution
Cross 0.45 μm sterilised membrane filter and obtain aseptic micellar solution, the most Mitochondrially targeted Nano medication delivery system, here
It is specially ZnPc-CPT-TPPNPs.
The line grain of the present invention is described as a example by the Mitochondrially targeted Nano medication delivery system that embodiment one obtains
The Nano medication delivery system of body targeting is for optical dynamic therapy and the mechanism (see Fig. 2) of chemotherapy combined treatment.
The structure of the Mitochondrially targeted Nano medication delivery system assembled is: chemotherapeutics CPT is Mitochondrially targeted
The inner side of Nano medication delivery system form hydrophobic core, Polyethylene Glycol (PEG1K) hydrophilic at intermediate formation
Shell, in TPP forms the mitochondrial hat of targeting, photosensitizer ZnPc core in outside and around core.TPP makes
The surface of Mitochondrially targeted Nano medication delivery system is positively charged, beneficially permeates cell membranes, and be conducive to
Mitochondrion is target, drives Mitochondrially targeted Nano medication delivery system to reach mitochondrion, especially tumor cell
Mitochondrion.633nm laser irradiates and makes photosensitizer ZnPc release ROS, ROS cut discharging of TL
Treat medicine CPT.It is achieved thereby that targeting, optical dynamic therapy and the synergistic therapeutic action of chemotherapy.Here change
Treat medicine and can also is that other anti-tumor chemotherapeutic medicines, such as amycin (DOX), irinotecan, paclitaxel.
Photosensitizer is also not necessarily limited to ZnPc, can be m-tetraphenylporphines.The wavelength that laser irradiates is also not necessarily limited to 633nm,
Can be 633-660nm.
Fig. 4 is shown in the hydration particle diameter distribution of the Mitochondrially targeted Nano medication delivery system that embodiment one obtains, its
Hydration particle diameter is concentrated mainly near 100nm.
The contracting thioketone linker sensitivity Detection to ROS: from figure 5 it can be seen that after adding ROS, contracting
Thioketone linker (TL) is cut off, and double methyl peaks (δ 1.47,1.54ppm) of contracting thioketone linker disappear,
Prove that this TL has ROS sensitivity.
Mitochondrially targeted property detects: contaminates cell with mitochondrial membrane potential fluorescent probe JC-1, has positive charge
After nano-particle enters mitochondrion, mitochondrial nagative potential is made to change.In NM, JC-1 gathers
Collection forms polymer in mitochondrial matrix, and polymer sends red fluorescence；Mitochondrion is if owing to transmembrane potential
Decline or forfeiture, JC-1 can only presented in monomer in endochylema, produce green fluorescence.Therefore face
The change of color the most directly reflects the change of mitochondrial membrane potential.Mitochondrial degree of depolarization can also
Weighed by the ratio of red green fluorescence intensity.As can be seen from Figure 6 with normal healthy controls, ZnPc, CPT
Comparing with ZnPc-CPT-NH2NPs, ZnPc-CPT-TPPNPs is the best to mitochondrial targeting.
Examination of curative effect:
(1) Mitochondrially targeted Nano medication delivery system ZnPc-CPT-TPPNPs under laser excitation at body
Therapeutic effect to lung carcinoma cell NCI-H460 is considerably better than and does not has the situation of exciting light outward, irradiates at laser
Under, ZnPc-CPT-TPPNPs is also better than non-thread plastochondria targeting to the therapeutic effect of NCI-H460
ZnPc-CPT-NH2NPs, is shown in Fig. 7.
(2) under laser excitation, Mitochondrially targeted Nano medication delivery system ZnPc-CPT-TPPNPs
It is best in several therapeutic scheme to the therapeutic effect of pulmonary carcinoma NCI-H460 transplanted tumor in nude mice, sees Fig. 8.
Embodiment two
Contracting thioketone linker (TL) synthesis step sensitive for 1.ROS is identical with embodiment one, the most superfluous
State.
2. synthesis TL-DOX experimental procedure is as follows:
TL (252.1mg, 1.0mmol) is dissolved in anhydrous 10mL DMF, be sequentially added into triethylamine (TEA,
303.6mg, 3.0mmol), 2,4,6-trichloro-benzoyl chlorides (241.9mg, 1.0mmol), dimethylamino naphthyridine
(DMAP, 24.4mg, 0.2mmol), stirs 10min.Be dissolved in 10mL DMF amycin (DOX,
271.76mg, 0.5mmol) add afterwards, reaction 24h is stirred at room temperature.Go out reaction with shrend, crude product mistake
Silicagel column obtains sterling.
3.TL-DOX is identical with embodiment one with the Connection Step of Polyethylene Glycol one Amino End Group, the most superfluous
State.
4. the modification step of triphenylphosphine is identical with embodiment one, repeats no more here.
5. the triphenylphosphine after modifying is identical with embodiment one with the Connection Step of Polyethylene Glycol other end amino,
Here repeat no more.
6. the process of assembling ZnPc-DOX-TPPNPs is identical with embodiment one, repeats no more here.
The preferred embodiment of the present invention described in detail above.Should be appreciated that the ordinary skill of this area without
Creative work just can make many modifications and variations according to the design of the present invention.Therefore, all in the art
Technical staff passes through logical analysis, reasoning, or a limited experiment the most on the basis of existing technology
Available technical scheme, all should be in the protection domain being defined in the patent claims.
Claims (10)
1. a Mitochondrially targeted Nano medication delivery system, it is characterised in that include block polymer；Institute
State block polymer to include connecting the Polyethylene Glycol having TPP and connecting the contracting thioketone linker having chemotherapeutics, institute
Stating to connect has the Polyethylene Glycol of TPP and described connection to have the contracting thioketone linker of chemotherapeutics by amino and carboxyl
Condensation reaction connects.
The most Mitochondrially targeted Nano medication delivery system, it is characterised in that also
Including PEG-DSPE and photosensitizer；Chemotherapeutics forms hydrophobic core in inner side,
Polyethylene Glycol is at the hydrophilic shell of intermediate formation, and TPP forms the mitochondrial hat of targeting in outside, and described photosensitizer is
In hydrophobic structure is distributed in described core and/or around described core.
The most Mitochondrially targeted Nano medication delivery system, it is characterised in that described
The amount of the TPP on the surface of Mitochondrially targeted Nano medication delivery system is abundant so that described Mitochondrially targeted
The surface of Nano medication delivery system is positively charged and current potential >=40mV.
The most Mitochondrially targeted Nano medication delivery system, it is characterised in that described
The structural formula of contracting thioketone linker is:
Wherein, described contracting thioketone linker is connected with chemotherapeutics by its carboxyl；Described contracting thioketone linker
It is that ROS is sensitive, can be cut off by ROS, thus discharge chemotherapeutics.
The most Mitochondrially targeted Nano medication delivery system, it is characterised in that institute
Stating photosensitizer and include the one or two kinds of in Phthalocyanine Zinc and m-tetraphenylporphines, the structural formula of its correspondence is:
Wherein, the left side is Phthalocyanine Zinc, and the right is m-tetraphenylporphines.
The most Mitochondrially targeted Nano medication delivery system, it is characterised in that described
The hydration particle diameter of Mitochondrially targeted Nano medication delivery system is 80-150nm.
The most Mitochondrially targeted Nano medication delivery system, it is characterised in that described
Chemotherapeutics is CPT, and described photosensitizer is ZnPc, and described block polymer is TL-CPT-PEG1K-TPP,
TL-CPT-PEG1K-TPP and DSPE-PEG mass ratio are that 8:1, CPT are in described Mitochondrially targeted nanometer
Load capacity w/w in drug delivery system is 14.91% ± 1%, and CPT accounts for TL-CPT-PEG1K-TPP divides
The 17.52% ± 1% of sub-total amount, the load capacity in the described Mitochondrially targeted Nano medication delivery system of ZnPc
W/w is 4.27% ± 0.5%.
8. such as the preparation of the claim 1 or 2 Mitochondrially targeted Nano medication delivery system as described in any one
Method, it is characterised in that comprise the following steps:
Step one, the synthesis of contracting thioketone linker；
Step 2, contracting thioketone linker are connected with chemotherapeutics；
Step 3, connection have the contracting thioketone linker of chemotherapeutics to be connected with the amino of Polyethylene Glycol one end,
To complex one；
Step 4, the modification of triphenylphosphine: be heated to reflux in 5-bromine valeric acid and triphenylphosphine addition acetonitrile, cold
Freezing filtration, ethyl acetate is washed, the dried triphenylphosphine that must pass through modification, i.e. TPP；
Step 5, TPP are connected with the amino of the Polyethylene Glycol other end of described complex one, obtain block and gather
Compound；
Step 6, assemble complete Mitochondrially targeted Nano medication delivery system: by described block polymer,
PEG-DSPE and photosensitizer hybrid precast go out complete described Mitochondrially targeted
Nano medication delivery system.
The preparation method of the most Mitochondrially targeted Nano medication delivery system, it is special
Levying and be, described step 6 is particularly as follows: assemble complete Mitochondrially targeted Nano medication delivery system: by molten
In DMSO described block polymer, be dissolved in the DSPE-PEG of chloroform and be dissolved in the photosensitizer of DMSO
Mixing, is slowly dropped in deionized water, and dropping limit, limit is ultrasonic, and ultrasonic power is 120-140W, dropping
Continue ultrasonic 2-5min after complete, obtain micellar solution；Precipitate, supernatant is removed by centrifugal for described micellar solution
Add ultrafiltration in super filter tube and remove organic principle；Cross 0.45 μm sterilised membrane filter after adding deionized water dilution and obtain nothing
Bacterium micellar solution, the most described Mitochondrially targeted Nano medication delivery system.
10. the Mitochondrially targeted Nano medication delivery system as described in any one of claim 1-7 is as preparation
The application of anti-tumor medicinal preparation.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1282334A (en) * | 1997-11-25 | 2001-01-31 | 奥塔戈大学 | Mitochondrially targeted antioxidants |
| US20070270381A1 (en) * | 2000-05-25 | 2007-11-22 | Antipodean Pharmaceuticals, Inc. | Mitochondrially targeted antioxidants |
| CN103536919A (en) * | 2013-10-24 | 2014-01-29 | 天津市肿瘤研究所 | Tumor-targeted photodynamic medicine carrying nanoparticle as well as preparation method and application thereof |
| KR101580251B1 (en) * | 2015-04-14 | 2015-12-29 | 가톨릭대학교 산학협력단 | TPP-PCL-TPP polymer and nano-drug delivery composition for targeting mitochondria using the same |
-
2016
- 2016-05-30 CN CN201610371113.1A patent/CN105833289B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1282334A (en) * | 1997-11-25 | 2001-01-31 | 奥塔戈大学 | Mitochondrially targeted antioxidants |
| US20070270381A1 (en) * | 2000-05-25 | 2007-11-22 | Antipodean Pharmaceuticals, Inc. | Mitochondrially targeted antioxidants |
| CN103536919A (en) * | 2013-10-24 | 2014-01-29 | 天津市肿瘤研究所 | Tumor-targeted photodynamic medicine carrying nanoparticle as well as preparation method and application thereof |
| KR101580251B1 (en) * | 2015-04-14 | 2015-12-29 | 가톨릭대학교 산학협력단 | TPP-PCL-TPP polymer and nano-drug delivery composition for targeting mitochondria using the same |
Non-Patent Citations (7)
| Title |
|---|
| CAIXIA YUE ET AL: "Near-Infrared Light Triggered ROS-activated Theranostic Platform based on Ce6-CPT-UCNPs for Simultaneous Fluorescence Imaging and Chemo-Photodynamic Combined Therapy", 《THERANOSTICS》 * |
| MELANI A. SOLOMON ET AL: "In Vitro assessment of the utility of stearyl triphenyl phosphonium modified liposomes in overcoming the resistance of ovarian carcinoma Ovcar-3 cells to paclitaxel", 《MITOCHONDRION》 * |
| MIN SUK SHIM DR ET AL: "A Reactive Oxygen Species (ROS)-Responsive Polymer for Safe, Efficient, and Targeted Gene Delivery in Cancer Cells", 《ANGEW CHEM INT ED ENGL》 * |
| SEAN MARRACHE ET AL: "Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics", 《PNAS》 * |
| ZHENGZE YU ET AL: "A Near-Infrared Triggered Nanophotosensitizer Inducing Domino Effect on Mitochondrial Reactive Oxygen Species Burst for Cancer Therapy", 《ACS NANO》 * |
| 丁兰兰等: "酞菁在光动力治疗中的应用", 《无机化学学报》 * |
| 潘凌立: "线粒体靶向抗肿瘤药物及其分类", 《化学与生物工程》 * |
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