CN107049955A - A kind of multistage targeting hyaluronan nanoparticle for carrying methotrexate (MTX) and preparation method thereof - Google Patents
A kind of multistage targeting hyaluronan nanoparticle for carrying methotrexate (MTX) and preparation method thereof Download PDFInfo
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- CN107049955A CN107049955A CN201611060375.2A CN201611060375A CN107049955A CN 107049955 A CN107049955 A CN 107049955A CN 201611060375 A CN201611060375 A CN 201611060375A CN 107049955 A CN107049955 A CN 107049955A
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- 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
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Abstract
The invention discloses a kind of multistage targeting hyaluronan nanoparticle for carrying methotrexate (MTX) and preparation method thereof, belong to pharmaceutical technology field, it is characterized in that the daiamid dendrimers for wrapping up small particle (~5nm) by the sodium hyaluronate grain of rice of big particle diameter (~200nm) are constituted, and (envelop rate and drugloading rate are respectively using methotrexate (MTX) as antineoplastic：71.62 ± 3.159%, 6.46 ± 0.518%), it is prepared for a kind of multistage targeting hyaluronan nanoparticle intravenous injection drug-delivery preparation for carrying methotrexate (MTX).Multistage targeting hyaluronan nanoparticle constructed by the present invention enters after body circulation, passive target and concentration of the nanoparticle in tumor tissues can be realized by the high osmosis effect of tumor blood vessels, simultaneously, the hyaluronidase that can be expressed further responsive to tumor tissues height, realize the degraded of the sodium hyaluronate grain of rice, so as to discharge wrapped daiamid dendrimers, and utilize daiamid dendrimers particle diameter small and surface lotus positive electricity characteristic, realize the depth of penetration and the medicine delivery across tumour cell of tumor tissues.
Description
Technical field：
The present invention relates to pharmaceutical technology field, particularly a kind of multistage targeting of tumor depth infiltration for carrying methotrexate (MTX) is transparent
Matter acid nano particle/polymer and its preparation.
Background technology：
Polyamide-amide (polyamidoyamine, PAMAM) dendrimers are a kind of features of novel high branch
Material, there is small particle, functional end-group can modify because of it, good water solubility, with height geometrical symmetry and larger inside
The advantages such as hydrophobic cavity, cause concern in numerous areas such as material, analytical chemistry, biology and medical science at present.Especially in doctor
Medicine field, due to PAMAM under physiological environment lotus positive electricity, be easily combined with electronegative tumor cell membrane, therefore possess good
Enter born of the same parents' ability, simultaneously because its PAMAM particle diameter be 5~10nm, be conducive to the barrier across tumor tissues, so that mediate drug
Penetrate deep into tumor locus, through tumour cell and play curative effect, and be considered as that most promising cancer target nanometer passs medicine
One of system.However, PAMAM is primarily due to unmodified also because the shortcoming of itself make it that its application is limited significantly
PAMAM surface enrichment positive charges, it is easy to erythrocyte binding so as to causing the destruction of haemocyte, cause serious poison is secondary to make
With, and the PAMAM of small particle is more easy to quickly be recognized and swallowed by macrophage during body circulation.
Nanometer drug delivery system refers to drug delivery system of the particle diameter in 1~1000nm, including the less tree-shaped polymerization of particle diameter
Thing, CNT, and the relatively large micella of particle diameter, liposome, nanoparticle etc..The concept of multi-stage nano delivery system occurs
In 2008, proposed at first by Mauro Ferrari seminars.The seminar constructs mesoporous silica gel and contains quantum dot and single wall
Carbon nano tube multistage administration nano-drug administration system.After this, it is Jenner's grain of rice, polymer micelle, fat that endothecium structure is occurred in that in succession
The multi-stage nano drug delivery system of plastid.Multi-stage nano delivery system refers to what is collectively formed by various sizes of a variety of nano units
Each nano unit is designed to across one or more biological barriers in drug delivery system, system.With swelling for single size
Knurl targeted nano system is compared, and multi-stage nano delivery system is different due to the size of unit, causes it to be distributed spy in vivo
Property it is different, so as to give play to the advantage of multiple nano units.
Hyaluronic acid (hyaluronic acid, HA) is a kind of polyanion polymer, is widely present in body fluid, such as
Extracellular matrix, body connection tissue, cell surface of most cells etc..HA has excellent physicochemical properties are for example non-to exempt from
Epidemic focus, good biocompatibility and biodegradability, therefore it is widely used in biomedicine field.It is worth noting that,
Under body fluid neutral environment, HA is negatively charged, by wrapping up PAMAM, so as to effectively cover the positive charge on PAMAM surfaces.
In addition, most of tumor tissues altimeter reaches hyaluronidase, and this enzyme can effectively degrade HA, so as to discharge internal band
The PAMAM of positive electricity, then, PAMAM can carry medicine and realize penetrating deep into for further tumor tissues.
Therefore, the characteristics of quasi-step matrix PAMAM dendrimers of the present invention and multi-stage nano system advantage, with hyaluronic acid
(hyaluronic acid, HA) is that material wraps up PAMAM dendrimers, and structure obtains a kind of new oozed with tumor depth
Multistage targeting hyaluronan nanoparticle for the purpose of thoroughly.Meanwhile, as a kind of pharmaceutical carrier of oncotherapy, the present invention is with first ammonia
Pterin (MTX) is prepared for a kind of multistage targeting hyaluronan nanometer of the tumor depth infiltration for carrying methotrexate (MTX) as antineoplastic
Grain intravenous injection drug-delivery preparation, had both remained PAMAM as the advantage of pharmaceutical carrier, and enzyme responsive type multi-stage nano grain is combined again
The advantage of drug delivery system.
The content of the invention：
The purpose of the present invention is to overcome the deficiencies in the prior art there is provided a kind of mesenchyma stroma of tumors enzyme responsive type dendrimers are many
Level nanoparticle and preparation method thereof, multi-stage nano grain can not only realize that medicine, to the targeted delivery of tumor tissues, reduces tumour
The toxic side effect of normal tissue in medicine delivery process, while the enzyme degraded of tumor tissues can also be responded, promotes dendrimer pair
Tumor tissues are penetrated deep into, so as to increase accumulation of the medicine in tumour cell to improve curative effect.
A kind of mesenchyma stroma of tumors enzyme responsive type targets dendrimers, and formula is：HA/PAMAM/X, wherein, HA is hyalomitome
Acid, PAMAM is the cationic PAM AM dendrimers in 4 generations, and X is methotrexate (MTX), the particle diameters of the dendrimers for 100~
200nm.The hyaluronan molecule amount is 500~600kDa.
The preparation method of the multistage targeting hyaluronan nanoparticle of tumor depth infiltration of above-mentioned load methotrexate (MTX), including it is following
Step：
Step 1：15mg PAMAM are weighed, 3ml purified waters are dissolved in, ultrasound is uniformly mixed so as to obtain the PAMAM aqueous solution.PAMAM
MTX powder 25mg are gradually added into the aqueous solution, at room temperature after 1000rpm lucifuges stirring 3h, with 0.45 μm of cellulose acetate film mistake
Unreacted MTX powder is filtered out, gained filtrate freeze-drying 72h obtains outward appearance yellow powder, to carry medicine PAMAM kernels, i.e.,
PAMAM/MTX。
Step 2：10mg hyaluronic acid is weighed, is dissolved in appropriate purified water, ultrasound dissolves hyaluronic acid.1mg
PAMAM/MTX is dissolved into the aqueous solution, is added dropwise in hyaluronic acid solution.It is added dropwise into above-mentioned hyaluronic acid system
6.8ml acetone solns, magnetic agitation 15min.4mg adipic dihydrazides and 2mg carbodiimides are dissolved in 100 μ l water, plus
Enter above-mentioned hyaluronic acid system, magnetic agitation 30min.Above-mentioned hyaluronic acid system is added dropwise in 6.55ml acetone, continues magnetic force
Stir 3h.Rotary evaporation removes acetone, and reaction solution is centrifuged, and takes centrifugation inner tube liquid, is freeze-dried to obtain Yellow nanometer grain.
In normal physiological context (pH 7.4), HA bears electricity is wrapped in PAMAM dendrimers by nanoprecipitation method
Macromolecular surface, so as to reduce cationic polymer PAMAM toxicity.Once reach in mesenchyma stroma of tumors environment (pH 6.5), outside
Layer HA can be degraded by the hyaluronidase (hyaluronidase, HAase) of mesenchyma stroma of tumors high concentration, and PAMAM recovers electropositive,
Promote PAMAM particles penetrating deep into tumour cell, strengthen the antitumor action of methotrexate (MTX).
The invention by HA nanoprecipitation method methods, it is combined with PAMAM, can be optionally in tumour
Depart under the enzyme environment of interstitial with PAMAM, so as to play the characteristic that multi-stage nano grain targets selection.
The present invention can not only realize medicine to the targeted delivery of tumor tissues, and reduction cancer target medicine carrying delivery system is aligned
The toxic side effect often organized, while dendrimer carrier can also be promoted to penetrate deep into tumour, increase medicine is in tumour cell
Interior accumulation and improve curative effect.
Brief description of the drawings：
Accompanying drawing 1：The multistage targeting hyaluronan nanoparticle HA/PAMAM/MTX of load methotrexate (MTX) prepared by specific embodiment 2
Transmission electron microscope picture.
Accompanying drawing 2：The multistage targeting hyaluronan nanoparticle of fluorescence labeling prepared by specific embodiment 1 is taken the photograph to A549 cells
Take situation.
Accompanying drawing 3：The multistage targeting hyaluronan nanoparticle of load methotrexate (MTX) prepared by specific embodiment 2 is small to H22 lotus knurls
Mouse in-vivo tumour suppresses situation.
Embodiment：
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.In addition, it is to be understood that after the content of the invention lectured has been read, people in the art
Member can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited
Scope.
Specific embodiment 1
Step 1：The preparation of fluorescence labeling dendrimers
PAMAM is in itself without fluorescence, and for its cellular uptake situation of later observation, we design and connect different on PAMAM
Thiocyanic acid fluorescein (Fluorescein isothiocyanate isomer, FITC).In simple terms, 6.7mg FITC dissolve
In 5ml dimethyl sulfoxide (DMSO)s (Dimethyl sulfoxide, DMSO), the 5ml bis- of the 50.2mg containing PAMAM is then slowly added to
In the envelope solution of first Asia.Mixed liquor stirs 12h, and following reaction liquid is at room temperature using deionized water as dialysis medium lucifuge dialysis 48h.
Last dialyzate freeze-drying obtains purified product PAMAM-FITC.
Step 2：The preparation of fluorescence labeling multistage targeting hyaluronan nanoparticle
The hyaluronic acid for weighing 10mg is dissolved in appropriate deionized water, and ultrasonic disperse dissolves hyaluronic acid, dropwise
Add the PAMAM-FITC solution that content is 1mg.6.8ml acetone solns, magnetic agitation are added dropwise in hyaluronic acid system
15min.4mg adipic dihydrazides and 2mg carbodiimides are dissolved in 100 μ l water, add above-mentioned hyaluronic acid system, magnetic force
Stir 30min.Above-mentioned hyaluronic acid system is added dropwise in 6.55ml acetone, continues magnetic agitation 3h.Rotary evaporation removes acetone,
Reaction solution is poured into centrifuge tube (Ultrafree-CL@centrifuge tubes, 100nm), 3220 × g rotating speeds centrifugation 30min.Discard outer tube
Liquid, inner tube liquid adds deionization to rinse nanoparticle, continues to repeat above-mentioned centrifugation step centrifugation, centrifuges 3 times altogether.Inner tube liquid is taken, is freezed
The nanoparticle HA/PAMAM-FITC of dry fluorescence labeling.
Specific embodiment 2
Step 1：The preparation of pastille dendrimers
15mg PAMAM are weighed, 3ml purified waters are dissolved in, ultrasound is uniformly mixed so as to obtain the PAMAM aqueous solution.The PAMAM aqueous solution
In be gradually added into MTX powder 25mg, at room temperature 1000rpm lucifuges stirring 3h after, be filtered to remove with 0.45 μm of cellulose acetate film
Unreacted MTX powder, gained filtrate freeze-drying 72h obtains outward appearance yellow powder, to carry medicine PAMAM kernels, i.e. PAMAM/
MTX。
Step 2：Carry the preparation of the multistage targeting hyaluronan nanoparticle of tumor depth infiltration of methotrexate (MTX)
10mg hyaluronic acid is weighed, is dissolved in appropriate purified water, ultrasound dissolves hyaluronic acid.PAMAM/MTX
The aqueous solution is dissolved into, 1mg PAMAM/MTX solution is added dropwise.6.8ml acetone is added dropwise into above-mentioned hyaluronic acid solution
Solution, magnetic agitation 15min.4mg adipic dihydrazides and 2mg carbodiimides are dissolved in 100 μ l water, add above-mentioned body
System, magnetic agitation 30min.Above-mentioned hyaluronic acid system is added dropwise in 6.55ml acetone, continues magnetic agitation 3h.Rotary evaporation is removed
Acetone is removed, reaction solution is poured into centrifuge tube (Ultrafree-CL@centrifuge tubes, 100nm) 3220 × g rotating speeds centrifugation 30min.Abandon
Outer tube liquid is removed, inner tube liquid adds deionization, repeats above-mentioned centrifugation step, centrifuges 3 times altogether.Take inner tube liquid, be freeze-dried yellow is received
The grain of rice.Transmission electron microscope observing is carried out after freshly prepared nanoparticle is diluted, accompanying drawing 1 is referred to.
Specific embodiment 3
Fluorescence labeling multistage targeting hyaluronan nanoparticle refers to accompanying drawing 2 to the intake situation of A549 cells.
Take the logarithm the human lung carcinoma cell line A549 cells in growth period, with the RPMI1640 culture mediums containing serum after pancreatin digestion
Dilution, transfer cell is cultivated into 24 orifice plates, and culture medium is changed in each hole after adding about 50,000 cells, adhere-wall culture 24h, and
PAMAM-FITC, HA/PAMAM-FITC and HA/PAMAM-FITC (HAase, 50U/mL are added in culture medium) are separately added into, is made
Its ultimate density is 15 μM of PAMAM, in 5%CO2, 37 DEG C of culture 6h, discard culture medium, PBS is washed 3 times, and fluorescence is inverted aobvious
Micro mirror observes cellular uptake situation.
Specific embodiment 4
The measure for carrying the multistage targeting hyaluronan nanoparticle drugloading rate of methotrexate (MTX) tumor depth infiltration and envelop rate is fresh
The HA/PAMAM/MTX nanoparticles solution of preparation is removed after acetone, pour into centrifuge tube (Ultrafree-CL@centrifuge tubes,
100nm), 3220 × g rotating speeds centrifugation 30min.HA/PAMAM/MTX nanoparticles will be left in centrifuge tube inner tube, and free drug and water
It can be present in centrifuge tube outer tube etc. small particle molecule, realize the separation of nanoparticle and free drug.Take in centrifuge tube outer tube
The μ l of filtered fluid 50 are to 10ml volumetric flasks, with 0.01MNaOH constant volumes, using 0.01MNaOH as blank control, using deionized water as pair
According to using its light absorption value is determined at UV, visible light spectrophotometer 303nm, reference standard curvilinear equation calculates unentrapped and enters nanometer
MTX content in grain, and then the drugloading rate (DLE) and envelop rate (EE) of HA/PAMAM/MTX nanoparticles are calculated according to the following formula, with
Upper experiment is repeated 3 times.
Specific embodiment 5
Internal pharmacodynamics tumor suppression experiment, using commercially available methotrexate (MTX) solution as control, investigates the gained of embodiment 2 and carries first ammonia
The targeting and mouse interior tumor rejection ability of pterin multistage targeting hyaluronan nanoparticle.Refer to accompanying drawing 3.
The 37 DEG C of recoveries of H22 cells are taken, normal saline dilution is subcutaneously injected to mouse peritoneal into cell suspension.After 7 days, choosing
Take belly to swell obvious ascites mouse, put to death and extract ascites, physiological saline after extracting 3mL mouse with syringe under super-clean bench
It is diluted to 1: 3 cell suspension, inoculated with subcutaneous injections to the subcutaneous 0.2mL of mouse left fore armpit.Tumour length is to 100~300mm3
When, well-grown 20 are taken, 4 groups are randomly divided into, using physiological saline as negative control, methotrexate (MTX) normal saline solution is sun
Property control, tail vein injection administration, each group is respectively：Physiological saline group, MTX groups, HA/PAMAM/MTX groups, PAMAM/MTX groups,
Administration 0.2mL (dosage presses MTX 5mg/kg), is administered once for every 3 days respectively, is administered 3 times altogether.Surveyed daily with slide measure
Gross tumor volume is measured, calculation formula is as follows：Mouse tumor volume=d1 × (d2)2× 0.5, d1 are knurl major diameter, and d2 is knurl minor axis.
Claims (7)
1. a kind of multistage targeting hyaluronan nanoparticle intravenous injection delivery system for carrying methotrexate (MTX), it is characterised in that by big grain
Footpath (~200nm) the sodium hyaluronate grain of rice parcel small particle (~5nm) polyamide-amide (polyamidoyamine,
PAMAM) dendrimers are constituted.
2. the multistage targeting hyaluronan nanoparticle for carrying methotrexate (MTX) (methotrexate, MTX) according to claim 1 enters
Enter after body circulation, can be by high osmosis effect (the enhanced permeability and of tumor blood vessels
Retention effect, EPR effect) passive target and concentration of the nanoparticle in tumor tissues are realized, meanwhile, one can be entered
The hyaluronidase of step response tumor tissues height expression, realizes the degraded of the sodium hyaluronate grain of rice, so as to discharge wrapped
PAMAM dendrimers, and utilize PAMAM dendrimers particle diameters small and surface lotus positive electricity characteristic, realize tumor tissues
Depth of penetration and the medicine delivery across tumour cell, so as to play MTX antitumor curative effect.
3. a kind of preparation method of hyaluronic acid parcel PAMAM dendrimers multi-stage nano grain, it is characterised in that using following
Step：
A. 15mg PAMAM are weighed, 3ml purified waters are dissolved in, ultrasound is uniformly mixed so as to obtain the PAMAM aqueous solution.
MTX powder 25mg are gradually added into the b.PAMAM aqueous solution, at room temperature after 1000rpm lucifuges stirring 3h, with 0.45 μm of acetic acid
Cellulose membrane is filtered to remove unreacted MTX powder, and filtrate freeze-drying 72h obtains yellow and carries medicine PAMAM kernels, i.e. PAMAM/
MTX。
C. 10mg hyaluronic acid is weighed, is dissolved in appropriate purified water, ultrasound dissolves hyaluronic acid.
D.PAMAM/MTX is dissolved into the aqueous solution, and 1mg PAMAM/MTX solution is added dropwise.
E. 6.8ml acetone solns, magnetic agitation 15min are added dropwise into above-mentioned hyaluronic acid solution.
F.4mg adipic dihydrazide and 2mg carbodiimides are dissolved in 100 μ l water, are added to above-mentioned hyaluronic acid system, magnetic
Power stirs 1000rpm, 30min.
G.6.55ml above-mentioned hyaluronic acid system is added dropwise in acetone, continues magnetic agitation 3h.Rotary evaporation removes acetone, will be anti-
Answer liquid to pour into centrifuge tube (Ultrafree-CL@centrifuge tubes, 100nm), 30min is centrifuged with 3220 × g rotating speeds.
H. discarding nanoparticle in outer tube liquid, inner tube liquid adds deionization to wash, and repeats above-mentioned centrifugation step, centrifuges 3 times altogether.Take inner tube
Liquid, is freeze-dried to obtain Yellow nanometer grain.
4. hyaluronic acid parcel PAMAM dendrimers multi-stage nano grain according to claims 2 to 3, it is characterised in that
PAMAM dendrimers and medicine MTX mass ratio are 15: 15-15: 25.
5. hyaluronic acid parcel PAMAM dendrimers multi-stage nano grain according to claims 2 to 3, it is characterised in that
Hyaluronan molecule amount is 500-600kDa, and hyaluronic acid is 10: 1-20: 1, final hyaluronic acid concentration with PAMAM mass ratioes
For 0.57mg/mL.
6. hyaluronic acid parcel PAMAM dendrimers multi-stage nano grain according to claims 2 to 3, it is characterised in that
Acetone will be added in two times, and the mass ratio of water/acetone will be controlled in 200/80-300/80.
7. hyaluronic acid parcel PAMAM dendrimers multi-stage nano grain according to claims 2 to 3, it is characterised in that
The mol ratio of crosslinking agent adipic dihydrazide and carbodiimides will be controlled 2.2: 1-1.8: 1.
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Cited By (5)
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| CN107510849A (en) * | 2017-08-16 | 2017-12-26 | 暨南大学 | A kind of glutathione response type dual drug carrier and its preparation method and application |
| CN111821470A (en) * | 2020-09-01 | 2020-10-27 | 中南大学 | Methotrexate-entrapped iron-tannic acid complex and preparation method and application thereof |
| CN112618516A (en) * | 2021-01-05 | 2021-04-09 | 四川大学华西医院 | Preparation method and application of particles for adjusting concentration of nitric oxide at tumor part |
| CN115227683A (en) * | 2022-08-01 | 2022-10-25 | 重庆大学 | Inhalation type composite microsphere for treating lung diseases and preparation method thereof |
| CN115554411A (en) * | 2022-09-26 | 2023-01-03 | 中国药科大学 | Enzyme-responsive tumor step-by-step targeted drug delivery system |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107510849A (en) * | 2017-08-16 | 2017-12-26 | 暨南大学 | A kind of glutathione response type dual drug carrier and its preparation method and application |
| CN107510849B (en) * | 2017-08-16 | 2020-02-07 | 暨南大学 | Glutathione response type dual drug carrier and preparation method and application thereof |
| CN111821470A (en) * | 2020-09-01 | 2020-10-27 | 中南大学 | Methotrexate-entrapped iron-tannic acid complex and preparation method and application thereof |
| CN111821470B (en) * | 2020-09-01 | 2022-08-12 | 中南大学 | Methotrexate-entrapped iron-tannic acid complex and preparation method and application thereof |
| CN112618516A (en) * | 2021-01-05 | 2021-04-09 | 四川大学华西医院 | Preparation method and application of particles for adjusting concentration of nitric oxide at tumor part |
| CN115227683A (en) * | 2022-08-01 | 2022-10-25 | 重庆大学 | Inhalation type composite microsphere for treating lung diseases and preparation method thereof |
| CN115227683B (en) * | 2022-08-01 | 2023-12-19 | 重庆大学 | Inhalation type composite microsphere for treating pulmonary diseases and preparation method thereof |
| CN115554411A (en) * | 2022-09-26 | 2023-01-03 | 中国药科大学 | Enzyme-responsive tumor step-by-step targeted drug delivery system |
| CN115554411B (en) * | 2022-09-26 | 2024-05-28 | 中国药科大学 | Enzyme-response tumor step-by-step targeting drug delivery system |
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Application publication date: 20170818 |