CN108452303A - It is a kind of to carry double medicine nanometer formulations and preparation method thereof - Google Patents
It is a kind of to carry double medicine nanometer formulations and preparation method thereof Download PDFInfo
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- 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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Abstract
The invention discloses a kind of double medicine nanometer formulations of load and preparation method thereof being effectively improved the weary oxygen of tumor tissues to enhance optical dynamic therapy, the double medicine nanometer formulations itself of load prepared by the present invention have the small advantage of grain size, there is deeper tumor tissues permeability relative to other nanometer formulations, so as to enhance drug effect.Reduction cell consumption rate drug used in said preparation, the degree of anoxic cell consumption oxygen, increases the oxygen concentration of cell indirectly inside changeable tumor tissues, achievees the purpose that improve the weary oxygen of inside tumor, and then enhance optical dynamic therapy for the lethality of tumour cell, keep treatment more complete.The pharmaceutical composition has preferable safety and significant collaboration drug effect, can significantly increase optical dynamic therapy effect, reach killing tumor cell, tumour is inhibited to increase the effect for even being eliminated tumour.
Description
Technical field
Double medicine nanometer formulations are carried the present invention relates to a kind of, more particularly to a kind of tumor hypoxia that improves enhances optical dynamic therapy
Carry double medicine nanometer formulations and its preparation and application.
Background technology
Cancer is to threaten one of the first cause of human health, is existed according to National Cancer Center《2017 Chinese tumour Entry yeaies
Report》In issued Chinese newest cancer data, kainogenesis cases of cancer 4,290,000, tumour associated death 2,810,000, cancer is anti-
It controls and allows of no optimist, one, 20 year following, cancer morbidity can also Continued.The mode for the treatment of cancer includes that operation is controlled at present
It treats（For infantile tumour, there is larger risk of recurrence）, chemotherapy（Cell toxicity medicament）, radiotherapy（Ionising radiation）, optical dynamic therapy
（Photosensitizer）, biotherapy（Monoclonal antibody etc.）.In existing therapeutic modality, photodynamic therapy（Photodynamic
therapy, PDT）It is the oncotherapy new technology that last century late nineteen seventies initially form, it has also become oncotherapy
One conventional means.It has huge application potential, receives the extensive concern of researcher.The treatment basis of PDT is that light is dynamic
Force effect, the needs that play a role have standby three fundamentals simultaneously：Photosensitizer（Photosensitizer）, exciting light
（Light）With molecular oxygen（Oxygen）.The basic principle of PDT treatment tumours is system or the photosensitizer administered locally to pass through it is certain
Bioprocess or preparation auxiliary make photosensitizer tumor tissues selectivity be detained, under the action of specific wavelength exciting light,
Simultaneously in the presence of molecular oxygen, singlet oxygen is generated（singlet oxygen）And other levels of reactive oxygen species
（Reactive oxygenspecies, ROS）, since tumour lacks active oxygen consumption system, DNA, lipid in cell,
The important substances such as protein are aoxidized, and cellular damage is caused, and further result in tumor cell necrosis and apoptosis；Secondly, PDT can also
The capilary in tumor tissues is destroyed, ischemic hypoxia is caused and then leads to cell death；Finally, PDT can induce a variety of exempt from
Quickly infiltration to tumor by local, complement activation system and promotes the generation of cytokine profiles/chemokines and releases epidemic disease cell
It puts, it is final to start body immune response to kill tumour.The excitation of light is needed just because of optical dynamic therapy, therefore it has
Standby extremely strong selectivity, controllability.In addition to this, also there is preferably repeatability, wound is small, and toxic side effect is small, can protect appearance
The advantage of looks and vitals increasingly becomes a kind of oncotherapy means having much foreground.For older, constitution is poor, merges
Other organic diseases etc. are not resistant to or are reluctant to undergo surgery, radiotherapy, chemotherapy patient, PDT is also a kind of to substitute well
Treatment means.
However, in tumor microenvironment, the mad proliferation of tumour cell makes cell increase at a distance from interstitial blood vessel, causes
Hydraulic pressure increases in its internal environment anoxic and mesenchyma stroma of tumors.The decline of this oxygen content can lead to optical dynamic therapy significant effect
It reduces, is unable to reach expected therapeutic effect；And the increase of interstitial internal pressure can cause nano-carrier diffusivity and permeability to drop
It is low so that drug is only trapped in tumor tissues surface, and the ability for killing tumor tissues is had a greatly reduced quality.Therefore, micro- to improve tumour
For the purpose of environmental hypoxia, the drawbacks of to make up solution that researchers have proposed, such as direct delivering oxygen, but oxygen transportation
It is less efficient to target area；Prepared nanometer particle size is larger to cause its permeability restriction；It delivers catalyst and generates oxygen,
But the drawbacks such as oxygen generation efficiency is limited, inorganic material is difficult to degrade.The above problem of the present invention constructs one kind and is oozed in tumor tissues
Permeability is strong and can imitate the novel nano delivery system for improving anoxic in tumor.
Cell consumption rate（Oxygen consumption rate, OCR）It refer to the rate that cell consumes oxygen.It reduces
Cell consumption rate can improve oxygen content indirectly.This method can more effectively improve tumor microenvironment anoxic conditions first；Its
Secondary, horizontal due to reducing cell oxygen consumption, cell is in similar " suspend mode ", reduces the resistance for radiotherapy, can be improved
The effect of radiotherapy.Atovaquone（Atovaquone, ATO）For the anti-malaria medicaments of FDA approvals.Some researches show that it to have
The effect of cell consumption rate is reduced, the anoxic zones of tumour are completely eliminated under a certain concentration.The drug is mainly by acting on
Mitochondrial complex III, cuts off the normal respiratory chain of cell, that is, interrupts the respiration of cell, and cell oxygen consumption is reduced to reach
The effect of rate.Verteporfin（Verteporfin, VER）For the photosensitizer listed, currently used for eye disease such as macula lutea
The optical dynamic therapy of disease.Tumour, due to needing a large amount of nutriment, can spontaneously form new blood during growing multiplication
Pipe is to achieve the purpose that meet itself needs.And Verteporfin is mainly transported by lipoprotein in blood, new vessels are rich in
Lipoprotein receptor, therefore Verteporfin has the new vessels in tumor tissues certain targeting.Joint reduces cell
Consumption rate drug Atovaquone and photosensitizer Verteporfin can generate synergistic effect enhancing optical dynamic therapy effect.
Invention content
Purpose：In order to overcome the deficiencies in the prior art, it is dynamic that the present invention provides a kind of improvement tumor hypoxia enhancing light
The double medicine nanometer formulations of load of power treatment.
Technical solution：In order to solve the above technical problems, the technical solution adopted by the present invention is：
It is a kind of to carry double medicine nanometer formulations, it is characterised in that：The carrier of the nanometer formulation is amphipathic nature polyalcohol, by amphipathic
Polymer is mounted with oxygen consumption inhibitor and photosensitizer simultaneously.
The amphipathic nature polyalcohol is selected from poly-（Lactic acid-polyglycolic acid）Polyethylene glycol（PLGA-PEG）, polylactic acid-is poly-
Ethylene glycol（PLA-PEG）, polyglycolide-polyethylene glycol（PGA-PEG）, polycaprolactone-polyethylene glycol（PCL-PEG）, polyphenyl second
Alkene-bPolymethyl tert-butyl acrylate (PS-b- PtBMA), poly- (vinyl pyrrolidone-bTert-butyl methacrylate)（P
(NVP-b-tBMA)）, poly benzyl glutamate-polyethylene glycol oxide（PBLG-PEO）, poly-aspartate benzyl ester-polyethylene glycol oxide
（PBLA-PEO）, phosphatide.PEG herein and PEO is the different form of same substance, alternatively.
Preferably, the double medicine nanometer formulations of the load, it is characterised in that：Hydrophobic patch in amphipathic nature polyalcohol
Molecular weight ranges are 2000-50000, and the molecular weight ranges of hydrophilic segment are 400-10000.
Further, the oxygen consumption inhibitor is biguanides or respiratory chain inhibitor drug；Biguanides include
Atovaquone；Insoral, melbine, buformin.Respiratory chain inhibitor drug includes rotenone, and amytal kills white butterfly poison
Element, antimycin A, cyanide, azide.
Further, photosensitizer is chlorin e 6, hematoporphyrin derivative, dihematoporphyrin ethers, and hematoporphyrin monomethyl ether is m-
Tetrahydroxy phenyl chlorin, etioporphyrin (ETIO) tin, benzene porphyrin, texaphyrin, N- lucid asparagus acyl group chlorins, metal phthalocyanine class
Deng compound and phytochrome II with photosensitizer quality, stupid and derivatives of porphyrin mono-acid ring A, Verteporfin, 5- amino ketones penta
Acid, the photosensitizer drugs such as Porfimer Sodium.
Preferably, in the nanometer formulation, oxygen consumption inhibitor, photosensitizer drugloading rate 0.5-20 % it
Between, the particle size of nanometer formulation is 10-200 nm.
It is as follows the present invention also provides the preparation method of the double medicine nanometer formulations of the load：Using film dispersion method, by oxygen consumption
Inhibitor and photosensitizer are codissolved in amphipathic nature polyalcohol in organic solvent, and rotary evaporation makes oxygen consumption inhibitor and photosensitive under water-bath
Agent and the adherent formation organic phase film of amphipathic nature polyalcohol, are added aqueous solution, in 30-60 oCLower ultrasonic 30 minutes, and in 3000
Rev/min be centrifuged off impurity to get.
Further, the organic solvent is in tetrahydrofuran, acetonitrile, ethyl acetate, acetone, dichloromethane, ethyl alcohol
One or more of mixtures.
Further, the aqueous solution be glucose solution, physiological saline, phosphate buffer, acetate buffer,
Ammonia-ammonium chloride buffer, hanks' balanced salt solution, borate buffer solution, barbital sodium-hydrochloride buffer, trihydroxy methyl ammonia
Methylmethane-hydrochloride buffer, Glycine-NaOH buffer solution, ammonium sulphate buffer, Triethanolamine buffer, sodium chloride-Chinese holly
Rafter acid sodium buffer solution, Triethanolammonium chloride buffer solution.
The present invention also requires the double medicine nanometer formulations of the load preparing the application in treating tumor disease drug.
Advantageous effect：Pair medicine nanometer formulations provided by the invention that carry have the following advantages compared with prior art：
1, novelty of the present invention proposes a kind of by reducing tumour cell consumption rate to improve tumor hypoxia situation, reduces tumour
Weary oxygen region is to improve the thinking of optical dynamic therapy.Since one of three elements required greatly of optical dynamic therapy are oxygen, and entity
Weary oxygen region inside tumor can cause the situation of optical dynamic therapy engineering noise, pass through oxygen consumption of the reduction in anoxic zones cell
Rate, it is opposite to increase cells oxygen content, achieve the effect that improve active oxygen yield under the excitation of light, is finally reached raising light
Dynamic therapy killing tumor cell treats the purpose of tumour.
2, the present invention builds enhanced optical dynamic therapy delivery system, which is two using biocompatibility
Parent's property copolymer wraps up two kinds of drugs by film dispersion method.Be primarily based on the solid tumor of nanoparticle itself high-permeability and
Retention effect（EPR effects）, accumulation of the nanoparticle in tumor locus, content of the raising nanoparticle in tumor locus can be enhanced；Its
It is secondary that 50nm is less than based on made nanoparticle, its permeability in tumor tissues is enhanced, two drugs can be improved in tumor group
Knit interior distribution；Finally, Atovaquone can reduce cell consumption rate, after being delivered to tumor tissues inside, can pass through opposite raising
Tumor microenvironment oxygen content improves tumor hypoxia problem, to enhance optical dynamic therapy effect.Therefore, which is tumour
Optical dynamic therapy pratical and feasible, safe and efficient pharmaceutical composition mode is provided, also the targeted therapy for hypoxic tumor tissue is ground
Study carefully and valuable reference is provided.
3, drug of the present invention is the drug that FDA ratifies or listed, and drug is safe and effective.Pass through novelty
In conjunction with developing the new role of drug, maximize the therapeutic effect of two kinds of drugs of collaboration.In the premise for not bringing other side effects
Under, effectively increase the effect of optical dynamic therapy.By result early period as it can be seen that the combination generates apparent tumor killing effect,
Tumour is completely eliminated in a certain range, there is potential clinical value.
Description of the drawings
Fig. 1 is the diameter characterization for the double medicine nanoparticles of load that the present invention is prepared according to embodiment 1, the load obtained by the preparation method
Double medicine nanoparticle grain sizes are within 50 nanometers；
Fig. 2 is the nanoparticle of the invention carried out according to embodiment 2 about the infiltrative characterization of tumour ball；It is small by characterization result, 12
When have it is apparent to center permeate, penetration depth dramatically increases within 24 hours；
Fig. 3 is that the present invention characterizes the improvement anaerobic condition for carrying double medicine nanoparticles according to embodiment 3；It is produced by oxygen with comparing
Raw active oxygen amount indirect proof drug can improve the amount of oxygen of anoxic cell, to enhance lethal effect of the photosensitizer to it.
As a result in, green fluorescence represents active oxygen, deep, shallow and region the large and small cell represented after the drug-treated of color
The active oxygen generated after illumination it is more, few；
Fig. 4 is the cell survival rate experimental result that the present invention is carried out according to embodiment 4, and the reduction of cell survival rate demonstrates the hair
Bright double medicines synergistic effect；
Fig. 5 is that the present invention is tested according to the cell survival rate that embodiment 5 carries out, by the double medicine nanoparticle group complete cell deaths of load
Other organize the synergistic effect that not dead or Mortality demonstrates two drugs；
Fig. 6 is that the present invention is characterized according to the internal pharmacodynamics of embodiment 6；
Fig. 7 is that the present invention is characterized according to the treatment results of embodiment 7.
Specific implementation mode
The present invention is further described in the following with reference to the drawings and specific embodiments.
The present invention is realized by following technical solution, is as follows：
By oxygen consumption inhibitor and photosensitizer with 1:1 is codissolved in tetrahydrofuran, and addition is dissolved in the PLGA-PEG of tetrahydrofuran
（Drugloading rate is 2.5 %）, 40oC water-baths revolving removes organic solvent, forms it into film, and the water-soluble of pH 8.6 is then added
Liquid, 40oUltrasound forms it into nanoparticle under C.3000 revs/min of centrifugations, remove the drug not wrapped up, as target nanometer system
Agent.
The double medicine nanometer formulations of the made load of above-mentioned film dispersion method, measure its embodiments.
Application of the double medicine nanometer formulations of above-mentioned load in treatment breast cancer.
Embodiment 1
It is specific as follows to carry double medicine nanoparticle preparation methods：2.5 milligrams of drug Verteporfin is weighed, is dissolved in 1 milliliter of tetrahydrofuran；
2.5 milligrams of Atovaquone is weighed, is dissolved in 1 milliliter of tetrahydrofuran；200 milligrams of PLGA-PEG is weighed, 2 milliliters of tetrahydrochysene furans are dissolved in
In muttering.Three kinds of liquids are mixed, and keep transfer complete using 2 milliliters of tetrahydrofuran rinses.In 40oC water-baths revolving removes organic molten
Agent makes its adherent formation film.2.5 milliliters of the glucose injection of pH 8.6 is then added, in 40oUltrasound makes its shape under C
At nanometer turbid.Nanometer turbid centrifuges 3 minutes under 3000 revs/min, collects supernatant to obtain the final product.Load prepared by the present embodiment
The dynamic laser light scattering experimental method measurement result of double medicine nanoparticles is as shown in Figure 1, the grain size of nanoparticle is 37.8nm.The present embodiment
In, copolymer noted in the disclosure is amphipathy macromolecule material, having the same with PLGA-PEG in the present embodiment
Property can be used as carrier material and be replaced；Oxygen consumption inhibitor noted in the disclosure, with the Atovaquone in the present embodiment
With similar drug effect, it can be used as respiration inhibitor and be replaced；Photosensitizer drug noted in the disclosure, with the present embodiment
In Verteporfin be photosensitizer, there is similar optical dynamic therapy effect, it is replaceable to use.
Embodiment 2
The infiltration situation that double medicine nanoparticles are carried in tumour ball characterizes.Tumour ball is transferred to the culture solution containing a certain concentration preparation
In, it cultivates 12,24 hours respectively.Penetration depth for drug in tumour ball characterizes.The present embodiment is copolymerized by laser
Burnt shooting result has apparent to center infiltration, 24 hours infiltration depths for 12 hours as shown in Fig. 2, being found out by characterization result
Degree dramatically increases.
Embodiment 3
Double medicine nanoparticle groups and control group are carried after illumination for the characterization of enhancing cell ROS abilities.Cell respectively in normal oxygen and
Administration intake 4 hours, illumination 10 minutes under anoxia condition.ROS probes are added and characterize ROS yields.The present embodiment is by falling
It sets fluorescence microscope and shoots final result as shown in figure 3, can be changed by the active oxygen amount indirect proof drug that oxygen generates to compare
The amount of oxygen of kind anoxic cell, to enhance lethal effect of the photosensitizer to it.As a result in, green fluorescence represents active oxygen,
The active oxygen generated after deep, shallow and region the large and small cell illumination represented after the drug-treated of color it is more, few.
Embodiment 4
Carry the characterization that hypoxic tumor cells cytotoxicity is remarkably reinforced relative to control group for double medicine nanoparticle groups.Cell is in anoxic item
After being cultivated under part, administration intake 4 hours under anoxia condition are continued at.After illumination 30 minutes, restore 24 hours in normoxic condition, it is right
Its final survivaling cell ratio is characterized.The present embodiment passes through cell tetrazolium bromide（MTT）Dyeing measures absorbance value calculating and deposits
Motility rate, the results are shown in Figure 4.
Embodiment 5
Cell is handled with embodiment 4.After illumination cell dyeing is carried out using propidium iodide/calcium flavin AM.Red area represents dead
Cell, green area represent living cells.The present embodiment uses inverted fluorescence microscope shooting result as shown in figure 5, by carrying double medicines
Nanoparticle group complete cell death and other groups are not dead or Mortality demonstrates the synergistic effects of two kinds of drugs.
Embodiment 6
Processing tumor-bearing mice is administered by tail vein using double medicine nanometer formulations and its control formulation is carried.Illumination 20 divides after 6 hours
Clock.One course for the treatment of is treated 4 times altogether, is characterized to mouse-borne tumor size variation during a course for the treatment of.The present embodiment measures live body
The results are shown in Figure 6 for tumor size.
Embodiment 7
Tumor-bearing mice is handled with embodiment 6.Tumor tissue is taken out after one course for the treatment of of treatment, accurate table is carried out to its size and weight
Sign.The present embodiment measures the tumor size taken out and weight, and the results are shown in Figure 7, to treat the size and again of final tumor of breast
Scale levies treatment results.
Amphipathilic block polymer PLGA-PEG used in the present embodiment as nanoparticulate carriers deliver altogether photosensitizer dimension to replace
Pool is fragrant and reduces cell consumption rate drug Atovaquone, makes its one side since EPR effects are gathered in tumor locus, on the other hand
Since smaller grain size penetrates into the weary oxygen region of inside tumor, realize that drug improves the purpose of internal anoxic, to enhance
The comprehensive lethal effect to tumour cell of photosensitizer.
The above is only a preferred embodiment of the present invention, it should be pointed out that：For the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of carrying double medicine nanometer formulations, it is characterised in that：The carrier of the nanometer formulation is amphipathic nature polyalcohol, passes through amphiphilic
Property polymer simultaneously be mounted with oxygen consumption inhibitor and photosensitizer.
2. according to claim 1 carry double medicine nanometer formulations, it is characterised in that：The amphipathic nature polyalcohol is selected from poly-（Breast
Acid-polyglycolic acid）Polyethylene glycol（PLGA-PEG）, polylactic acid-polyglycol（PLA-PEG）, polyglycolide-polyethylene glycol
（PGA-PEG）, polycaprolactone-polyethylene glycol（PCL-PEG）, polystyrene-bPolymethyl tert-butyl acrylate (PS-b-
PtBMA), poly- (vinyl pyrrolidone-bTert-butyl methacrylate)（P(NVP-b-tBMA)）, poly benzyl glutamate-polyoxy
Change ethylene（PBLG-PEO）, poly-aspartate benzyl ester-polyethylene glycol oxide（PBLA-PEO）, phosphatide.
3. according to claim 1 carry double medicine nanometer formulations, it is characterised in that：Point of hydrophobic patch in amphipathic nature polyalcohol
The molecular weight ranges of son amount ranging from 2000-50000, hydrophilic segment are 400-10000.
4. according to claim 1 carry double medicine nanometer formulations, it is characterised in that：The oxygen consumption inhibitor is biguanides
Or respiratory chain inhibitor drug；
Biguanides include Atovaquone；Insoral, melbine, buformin；
Respiratory chain inhibitor drug includes rotenone, and amytal kills white butterfly toxin, antimycin A, cyanide, azide.
5. according to claim 1 carry double medicine nanometer formulations, it is characterised in that：The photosensitizer is tool photosensitizer quality
Compound, photosensitizer drug；
The compound of tool photosensitizer quality includes chlorin e 6, hematoporphyrin derivative, dihematoporphyrin ethers, hematoporphyrin monomethyl ether,
M- tetrahydroxy phenyl chlorin, etioporphyrin (ETIO) tin, benzene porphyrin, texaphyrin, N- lucid asparagus acyl group chlorins, metal phthalein
Cyanines class；
Photosensitizer drug includes phytochrome II, stupid and derivatives of porphyrin mono-acid ring A, Verteporfin, 5-ALA, porphines nurse
Sodium.
6. according to claim 1 carry double medicine nanometer formulations, it is characterised in that：In the nanometer formulation, oxygen consumption inhibitor,
For the drugloading rate of photosensitizer between 0.5-20 %, the particle size of nanometer formulation is 10-200 nm.
7. the preparation method of double medicine nanometer formulations is carried according to claim 1-6 any one of them, it is as follows：Disperseed using film
Oxygen consumption inhibitor and photosensitizer are codissolved in amphipathic nature polyalcohol in organic solvent by method, and rotary evaporation makes oxygen consumption press down under water-bath
Preparation and photosensitizer and the adherent formation organic phase film of amphipathic nature polyalcohol, are added aqueous solution, in 30-60 oCLower ultrasound, centrifugation
Remove impurity to get.
8. the preparation method according to claim 7 for carrying double medicine nanometer formulations, it is characterised in that：The organic solvent is four
One or more of hydrogen furans, acetonitrile, ethyl acetate, acetone, dichloromethane, ethyl alcohol.
9. the preparation method according to claim 7 for carrying double medicine nanometer formulations, it is characterised in that：The aqueous solution is grape
Sugar juice, physiological saline, phosphate buffer, acetate buffer, ammonia-ammonium chloride buffer, hanks' balanced salt solution, boron
Phthalate buffer, barbital sodium-hydrochloride buffer, tris-HCI buffer, Glycine-NaOH are slow
Fliud flushing, ammonium sulphate buffer, Triethanolamine buffer, sodium chloride-sodium citrate buffer, Triethanolammonium chloride buffer solution.
10. claim 1-6 any one of them carries double medicine nanometer formulations and is preparing the application in treating tumor disease drug.
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| CN111053900A (en) * | 2019-11-19 | 2020-04-24 | 南京大学射阳高新技术研究院 | Platelet drug-loading system for targeting tumor and improving radiotherapy sensitivity and preparation method thereof |
| CN111744014A (en) * | 2020-05-29 | 2020-10-09 | 新疆医科大学 | Photodynamic combined medicine composition and preparation method and application thereof |
| CN112618727A (en) * | 2021-01-08 | 2021-04-09 | 中国药科大学 | Preparation for enhancing photodynamic therapy of hypoxic tumor and preparation method and application thereof |
| CN112933229A (en) * | 2021-03-17 | 2021-06-11 | 山东大学 | Carrier-free self-assembly nanoparticle of IR820 and atovaquone and preparation method and application thereof |
| WO2021174868A1 (en) * | 2020-03-04 | 2021-09-10 | 苏州大学 | Chlorin nanometer photosensitizer, and preparation method therefor and application thereof |
| CN113384552A (en) * | 2021-05-14 | 2021-09-14 | 厦门大学 | Double-drug-loading nano preparation for neurodegenerative diseases and preparation method thereof |
| CN113797340A (en) * | 2020-06-12 | 2021-12-17 | 华东师范大学 | Anti-tumor double-medicine nano preparation and preparation method and application thereof |
| CN114191550A (en) * | 2022-01-11 | 2022-03-18 | 中国药科大学 | Oxygen-carrying nano photosensitive preparation and preparation method and application thereof |
| CN114796490A (en) * | 2022-04-14 | 2022-07-29 | 中国海洋大学 | Medicine-carrying multifunctional nanogel spray and preparation method and application thereof |
| CN115068615A (en) * | 2022-04-01 | 2022-09-20 | 南京鼓楼医院 | Open source throttling type reversal hypoxic anti-tumor pharmaceutical composition and application thereof |
| CN115414334A (en) * | 2022-08-17 | 2022-12-02 | 江苏省苏北人民医院 | Preparation method of bionic nano drug delivery system for synergistically enhancing photodynamic and photothermal therapy |
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