CN109503848A - A kind of nanoscale medicine delivery system of hepatoma-targeting and its preparation method and application - Google Patents
A kind of nanoscale medicine delivery system of hepatoma-targeting and its preparation method and application Download PDFInfo
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- CN109503848A CN109503848A CN201811299585.6A CN201811299585A CN109503848A CN 109503848 A CN109503848 A CN 109503848A CN 201811299585 A CN201811299585 A CN 201811299585A CN 109503848 A CN109503848 A CN 109503848A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
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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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses nanoscale medicine delivery systems of a kind of hepatoma-targeting and its preparation method and application；More particularly to a kind of preparation and application of hepatoma-targeting nanoparticle that the copolymer material load medicines resistant to liver cancer (camptothecine/10-hydroxycamptothecine) containing galactolipin, polyethylene glycol and PLGA is constituted.This delivery system is prepared by polymer material Gal-PEG-PLGA and medicines resistant to liver cancer (camptothecine/10-hydroxycamptothecine) by coprecipitation or dialysis.Material Gal-PEG-PLGA prepared by the present invention has hepatoma targeting character, biocompatibility and biodegradability, the preparation process of nanoparticle is simple, inside and outside targeting and activity rating, it was demonstrated that this delivery system can kill liver cancer cells by camptothecine/10-hydroxycamptothecine targeted delivery to liver cancer cells and effectively.
Description
Technical field
The present invention relates to nanoscale medicine delivery systems of a kind of hepatoma-targeting and its preparation method and application, belong to pharmaceutical technology neck
Domain.
Background technique
Onset of liver cancer concealment, invasion is high, growth is rapid, and Most patients have been advanced stages when medical, is not suitable for performing an operation,
It is one of the important means of common for selecting medicines resistant to liver cancer treatment liver cancer.Camptothecine (camptothecin, CPT) and 10- hydroxyl
Camptothecine (10-HCPT) is the inhibitor of topoisomerase I, and clinic shows that it is a variety of to liver cancer, gastric cancer and colon cancer etc. pernicious
Tumour has good therapeutic effect.However, due to the strong-hydrophobicity of camptothecine and 10-hydroxycamptothecine itself, stability difference and biology
The problems such as availability is low, and dosage is big when causing clinical use, toxic side effect is strong, accumulative without target area, to seriously limit
Its clinical application.
In addition, liver cancer tissue has irregular pulse guard system, interstitial fluid high pressure and the special cirrhosis pathology of liver cancer
The fibrosis sample extracellular matrix that feature generates constitutes the physiologic barrier of liver cancer complexity, cause medicines resistant to liver cancer be not easy to be penetrated into from
The farther away histocyte of blood vessel, and destruction of the non-selective killing of medicines resistant to liver cancer to normal hepatocytes born of the same parents, can also seriously affect
Therapeutic effect.For the curative effect for improving camptothecin therapy liver cancer, it need to further design the nanometer with liver cancer cells targeting and pass medicine
System is current urgent problem to be solved.
Summary of the invention
Purpose: in order to overcome the deficiencies in the prior art, for above-mentioned camptothecin medicines resistant to liver cancer hydrophobicity, surely
Drug these outstanding difficultys, the present invention such as is difficult to reach and mentions in the problems such as qualitative poor, without target tissue taxis and liver cancer treatment
For a kind of nanoscale medicine delivery system of hepatoma-targeting, the copolymer of specially a kind of tool galactolipin, polyethylene glycol and PLGA segment is carried
Medicines resistant to liver cancer can be targeted and be passed by the hepatoma-targeting nanoscale medicine delivery system that body load medicines resistant to liver cancer is constituted, this delivery system
It is sent to tumor cell of liver and effectively kills tumor cell of liver.
Technical solution: in order to solve the above technical problems, the technical solution adopted by the present invention are as follows:
A kind of polymer material, it is characterised in that: the polymer material Gal-PEG-PLGA is galactonic acid and PLGA
Two Amino End Groups of the PEG amino-terminated with both ends are connected respectively with amido bond, and chemical structural formula is as follows:
Wherein, m, n, x are positive integer.
Preferably, the amino-terminated PEG (NH in both ends2-PEG-NH2) molecular weight be 2000-5000Da, PLGA
Molecular weight be 5-100kDa.It is furthermore preferred that PLGA uses PLGA (50/50).
Further, the preparation method of the polymer material, comprising the following steps:
Step (1): it is appropriate to weigh galactonic acid, and anhydrous dimethyl sulphoxide dissolution sequentially adds DCC (dicyclohexyl carbon two
Imines), NHS (n-hydroxysuccinimide), stirred under nitrogen atmosphere react with activated carboxyl；Then it is amino-terminated that both ends are added
PEG (NH2-PEG-NH2), reaction generates Gal-PEG reaction solution；
Step (2): it is appropriate to weigh PLGA, anhydrous DMSO dissolution, sequentially adds DCC, NHS, nitrogen protection, be stirred to react with
Activated carboxyl；Then reaction solution is transferred in Gal-PEG reaction solution, is stirred to react to generate Gal-PEG-PLGA；
Filtering with microporous membrane removes precipitating after reaction, and filtrate is set in bag filter, is successively dialysed with DMSO, distilled water,
Remove unreacted reactant and solvent；Freeze-drying is after dialysis to get Gal-PEG-PLGA.
Preferably, in step (1), the DCC of addition and the molar ratio of galactonic acid are (1.2~2): 1；It is added
The molar ratio of NHS and galactonic acid is (1.2~2): 1；
In step (2), the molar ratio of the DCC and PLGA of addition are (1.2~2): 1；The molar ratio of the NHS and PLGA of addition
For (1.2~2): 1.
On the other hand, the present invention also provides a kind of hepatoma-targeting nanoparticles, it is characterised in that: the nanoparticle is polymer
Material Gal-PEG-PLGA and medicines resistant to liver cancer are prepared by coprecipitation or dialysis.
Preferably, the medicines resistant to liver cancer is camptothecine or 10-hydroxycamptothecine.
Further, the hepatoma-targeting nanoparticle, which is characterized in that the preparation method comprises the following steps: (1) nanoprecipitation method: claim
Gal-PEG-PLGA polymer material is taken to be dissolved in organic solvent；Separately weigh medicines resistant to liver cancer (camptothecine or 10- hydroxy-camptothecin
Alkali) it is dissolved with organic solvent, the two after mixing, is added slowly with stirring into 0.5~2% poly-vinyl alcohol solution, adds
Continue to be protected from light stirring certain time after complete up to nanoparticle suspension.
Further, the hepatoma-targeting nanoparticle, which is characterized in that the preparation method comprises the following steps: (2) dialysis: weighing
Gal-PEG-PLGA polymer material is dissolved in organic solvent；Separately weigh medicines resistant to liver cancer (camptothecine or 10-hydroxycamptothecine)
It is dissolved with organic solvent, the two after mixing, is transferred in bag filter, and dialysis removes organic solvent, after dialyzate freeze-drying
Up to nanoparticle, low temperature drying is saved, and the used time redissolves.
In above-mentioned preparation method, organic solvent is dimethyl sulfoxide, tetrahydrofuran or n,N-Dimethylformamide；Gal-
The ratio of PEG-PLGA polymer material and medicines resistant to liver cancer (camptothecine or 10-hydroxycamptothecine) is 10:1~1:1.
The present invention also provides application of the above-mentioned polymer material in preparation treatment liver-cancer medicine.
The present invention also provides application of the above-mentioned hepatoma-targeting nanoparticle in preparation treatment liver-cancer medicine.
The utility model has the advantages that the nanoscale medicine delivery system of hepatoma-targeting of the present invention, constructs galactolipin-polyethylene glycol-polylactic acid-hydroxyl
Acetate multipolymer (Gal-PEG-PLGA) bioabsorbable polymer material, PLGA is considered safe and non-toxic material by FDA in material, can
Camptothecine, 10-hydroxycamptothecine or other medicines resistant to liver cancer are wrapped up, outer layer hydrophilic material PEG can realize steady well in vivo
Qualitative and long circulating, galactolipin (Gal) can be in conjunction with the asialo-glycoprotein receptor on tumor cell of liver surface, active targeting
Delivering nanoparticle enters tumour cell, discharges medicines resistant to liver cancer, plays anti-tumor effect.Material Gal- prepared by the present invention
PEG-PLGA has hepatoma targeting character, biocompatibility and biodegradability, Gal-PEG-PLGA load camptothecine/10- hydroxyl
The hepatoma-targeting nanoparticle preparation process of base camptothecine is simple, and inside and outside targeting and activity experiment prove, this delivery system energy
Enough by camptothecine/10-hydroxycamptothecine targeted delivery to liver cancer cells and effectively kill liver cancer cells.
Detailed description of the invention
Fig. 1 is the characterization of Gal-PEG-PLGA polymer prepared by embodiment 1: the hydrogen spectrum of Gal-PEG-PLGA；
Fig. 2 is the partial size and current potential of 3 hepatoma-targeting nanoparticle of embodiment；
Fig. 3 is the release figure of the Gal-PEG-PLGA/CPT nanoparticle camptothecine of embodiment 4；
Fig. 4 is the Gal-PEG-PLGA/CPT nanoparticle extracorporeal suppression tumor cell cultivation effect figure of embodiment 5；
Fig. 5 is the Gal-PEG-PLGA/10-HCPT nanoparticle extracorporeal suppression tumor cell cultivation effect figure of embodiment 5；
Fig. 6 is the HepG2 cell-targeting intake Gal-PEG-PLGA/CPT nanoparticle of embodiment 6；
Fig. 7 is antineoplaston result in the Gal-PEG-PLGA/CPT nanoparticle body of embodiment 7；
Fig. 8 is Gal-PEG-PLGA/10- hydroxycamptothecin (Gal-PEG-PLGA/10-HCPT) nanoparticle of embodiment 8
Internal antineoplaston result.
Specific embodiment
With reference to the accompanying drawing and specific embodiment the invention will be further described, but the present invention is not limited to following implementations
Example.
Embodiment 1
The synthesis of material Gal-PEG-PLGA.It is appropriate to weigh galactonic acid, anhydrous dimethyl sulphoxide dissolution sequentially adds
DCC, NHS, stirred under nitrogen atmosphere react 12h with activated carboxyl；Then the amino-terminated PEG in both ends is added, reacts 12h with life
At Gal-PEG.It is appropriate to weigh PLGA, anhydrous DMSO dissolution sequentially adds DCC, NHS (the two and PLGA molar ratio be 1.2:1),
Reaction 12h activated carboxyl is stirred at room temperature in nitrogen protection；Then reaction solution is transferred in Gal-PEG reaction solution, is stirred at room temperature
12h is reacted to generate Gal-PEG-PLGA.Filtering with microporous membrane removes precipitating after reaction, and filtrate sets bag filter (Mw
In 8000-14000), is successively dialysed with DMSO, distilled water, remove unreacted reactant and solvent.It is lyophilized after dialysis, obtains product
Gal-PEG-PLGA。
Using1H NMR confirms structure.Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of Gal-PEG-PLGA, composes chemical shift according to hydrogen
, there is the characteristic peak (- CH2-CH2-) of PEG in 3.507ppm, the spy of PLGA occurs in 1-2ppm, 3.9-4.0ppm in analysis
Peak is levied, occurs the characteristic peak (- CH-) of Gal at 4.591ppm.Show the successful synthesis of material Gal-PEG-PLGA.
Embodiment 2
The preparation of nanoparticle:
Gal-PEG-PLGA carries camptothecine/10-hydroxycamptothecine nanoparticle: weighing Gal-PEG-PLGA polymer in proportion
Material 100mg is dissolved in 5mL organic solvent, separately weighs medicines resistant to liver cancer camptothecine or 10-hydroxycamptothecine 10-100mg 5-
The dissolution of 10mL organic solvent, the two are uniformly mixed.One of preparation method is to be slowly added into mixed liquor to contain under stiring
In 1% poly-vinyl alcohol solution, continue to be protected from light stirring certain time after adding to get nanoparticle suspension.Another preparation method is
Mixed liquor is transferred in bag filter (MW 1500Da), dialysis removes organic solvent, and dialyzate is lyophilized up to nanoparticle, low temperature
Kept dry, used time redissolve.
In the present embodiment, material used in Macroscopic single crystal has galactonic acid, and band amino-terminated polyethylene glycol in both ends (divides
Son amount is 2000-5000Da), PLGA (50/50, molecular weight 5-100kDa).
Embodiment 3
Gal-PEG-PLGA load camptothecine/10-hydroxycamptothecine nanoparticle characterization
The size and surface charge of nanoparticle are measured using dynamic light scattering.Proper amount of nano grain suspension is taken, it is suitable with distilled water
After degree dilution, nanoparticle partial size and Zeta potential are measured using NanoBrook 90Plus Zeta.As shown in Fig. 2, nanoparticle grain
Diameter about 140nm, Zeta electric potential about -20mV.
Camptothecine/10-hydroxycamptothecine nanoparticle encapsulation rate and load are carried using reverse dialysis measurement Gal-PEG-PLGA
Dose.The nanoparticle encapsulation rate of above method preparation is about 70%-85%, and drugloading rate is about 15%-40%.
Embodiment 4
The cumulative release of Gal-PEG-PLGA load camptothecine nanoparticle.
Precision pipettes camptothecine nanoparticle suspension solution that 5mL is prepared in bag filter, after both ends tighten, by bag filter
It is placed in the conical flask of the PBS dissolution medium containing 95mL pH=7.4, setting speed 100r/min, 37 DEG C of temperature, constant temperature vibration
It swings.Solution 4mL in conical flask is taken in 0.25,0.5,0.75,1,2,4,8,12,24,36,48h, and mends the release of same volume equality of temperature
Medium.Sample liquid surveys absorbance value after filtering with microporous membrane at 367nm, calculates camptothecine Cumulative release amount.
As shown in figure 3, free camptothecine discharges completely substantially in 4h, camptothecine exists in Gal-PEG-PLGA/CPT nanoparticle
4h releases 30.3%, there is phenomenon of burst release, it may be possible to caused by the camptothecine due to being adsorbed on nanoparticle surface discharges.48h is accumulative
Release 83.2%.Gal-PEG-PLGA/CPT nanoparticle has certain slow releasing function as the result is shown.
Embodiment 5
Cytotoxicity
The influence that Gal-PEG-PLGA and nanoparticle inhibit hepatoma cell proliferation is analyzed using MTS method.Growth conditions are good
Good HepG2 cell is with every hole 1 × 104Cell is added in 96 orifice plates, after being incubated overnight, is discarded culture medium, is separately added into phase
The sample solution answered, each sample at least 3 multiple holes, as a control group with normal cell, only plus culture medium is blank group.Culture
After for 24 hours, the MTS solution of 20 μ L is added in every hole, is protected from light 37 DEG C of shakings 4h, microplate reader 490nm and is detected absorbance value (A).As a result such as
Shown in Fig. 4, material Gal-PEG-PLGA does not have inhibiting effect to cell, illustrates with safety.Gal-PEG-PLGA carries camplotheca acuminata
Alkali nanoparticle significantly inhibits growth of tumour cell compared with free camptothecine, enhances the anti-tumor activity of CPT.As shown in figure 5,
Material Gal-PEG-PLGA does not have inhibiting effect to cell, illustrates with safety.Gal-PEG-PLGA carries 10-hydroxycamptothecine
Nanoparticle significantly inhibits growth of tumour cell compared with 10-hydroxycamptothecine, enhances the anti-tumor activity of 10-HCPT.
Embodiment 6
Liver cancer cells targeting is investigated
Using flow cytomery galactolipin to the targeting of 2 cell of HepG.It is prepared according to nanoparticle preparation method
Carry Coumarin-6 nanoparticle.2 cell of HepG of logarithmic growth phase, with every hole 1 × 105Cell inoculation is in 24 orifice plates, and 37 DEG C
After culture for 24 hours, culture medium is discarded, the nanoparticle solution of the load Coumarin-6 of 1mL is added, continues to cultivate 4h.Sample is discarded later
Product solution is cleaned 3 times with cold PBS, and every hole digests a moment with pancreatin, discards pancreatin, and the PBS that proper volume is added is blown and beaten into cell
Suspension after 300 mesh nylon net filters, carries out flow cytomery immediately.To detect galactolipin competitive binding, another group adds
Enter to carry first to use before Coumarin-6 nanoparticle solution the galactolipin culture cell 2h of 20mM, operation is same as above later.Every hole is repeated 3 times.
Data processing is carried out using FlowJo software (Tree Star Software, the U.S.).As a result see that Fig. 6, galactolipin are saturated in advance
2 cell of HepG (p < 0.05 *) is substantially reduced to the intake of nanoparticle, 2 cell of HepG normally cultivated to nanoparticle absorb
It is more.
Embodiment 7
Internal antitumor drug effect
The Heps cell of logarithmic growth phase, with 1.0 × 107A cell/mL concentration is inoculated in right side of mice armpit is subcutaneous
0.1mL.It is long to 100mm to mouse oxter tumor3When, being randomly divided into 3 groups, (physiological saline group, CPT group, Gal-PEG-PLGA carry happiness
Set alkali group), every group 6, tail vein injection administration is carried out respectively.It is administered and is calculated as the 0th day with first time, respectively at 0,3,6,9,12
Its administration (camptothecine 10mg/kg, every time 100 μ L).Every 3 days measurement diameter of tumor, and gross tumor volume is calculated, it draws tumour and generates
Volume-time curve figure.As shown in fig. 7, Gal-PEG-PLGA/CPT group can obviously inhibit compared with control group and camptothecine group
The growth of tumour.
Embodiment 8
Internal antitumor drug effect
The Heps cell of logarithmic growth phase, with 1.0 × 107A cell/mL concentration is inoculated in right side of mice armpit is subcutaneous
0.1mL.It is long to 100mm to mouse oxter tumor3When, it is randomly divided into 3 groups of (physiological saline groups, 10-hydroxycamptothecine group, Gal-
PEG-PLGA carries 10-hydroxycamptothecine group), every group 6, tail vein injection administration is carried out respectively.It is administered with first time and is calculated as the 0th
It, respectively at administration (10-hydroxycamptothecine 10mg/kg, every time 100 μ L) in 0,3,6,9,12 day.Every 3 days measurement diameter of tumor,
And gross tumor volume is calculated, it draws tumour and generates volume-time curve figure.As shown in figure 8, with control group and 10-hydroxycamptothecine
Group is compared, and Gal-PEG-PLGA/10- hydroxycamptothecin group can obviously inhibit the growth of tumour.
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 polymer material, it is characterised in that: the polymer material Gal-PEG-PLGA is galactonic acid and PLGA points
Not two Amino End Groups of the PEG amino-terminated with both ends are connected with amido bond, and chemical structural formula is as follows:
Wherein, m, n, x are positive integer, and the molecular weight of the amino-terminated PEG in both ends is 2000-5000Da, and the molecular weight of PLGA is
5-100kDa。
2. the preparation method of polymer material described in claim 1, comprising the following steps:
Step (1): it is appropriate to weigh galactonic acid, and anhydrous dimethyl sulphoxide dissolution sequentially adds DCC, NHS, stirs under nitrogen protection
Reaction is mixed with activated carboxyl；Then the amino-terminated PEG in both ends is added, reaction generates Gal-PEG reaction solution；
Step (2): it is appropriate to weigh PLGA, anhydrous DMSO dissolution, sequentially adds DCC, NHS, and nitrogen protection is stirred to react to activate
Carboxyl；Then reaction solution is transferred in Gal-PEG reaction solution, is stirred to react to generate Gal-PEG-PLGA.
3. the preparation method of polymer material according to claim 2, it is characterised in that:
In step (1), the DCC of addition and the molar ratio of galactonic acid are (1.2~2): 1；The NHS of addition and rubbing for galactonic acid
You are than being (1.2~2): 1；
In step (2), the molar ratio of the DCC and PLGA of addition are (1.2~2): 1；The molar ratio of the NHS and PLGA of addition is
(1.2~2): 1.
4. a kind of hepatoma-targeting nanoparticle, it is characterised in that: the nanoparticle is polymer material Gal-PEG-PLGA and anti-liver
Cancer drug is prepared by coprecipitation or dialysis.
5. hepatoma-targeting nanoparticle according to claim 4, it is characterised in that: the medicines resistant to liver cancer be camptothecine or
10-hydroxycamptothecine.
6. hepatoma-targeting nanoparticle according to claim 4, which is characterized in that preparation method uses nanoprecipitation method, tool
Body is as follows: weighing Gal-PEG-PLGA polymer material and is dissolved in organic solvent；It is molten separately to weigh medicines resistant to liver cancer organic solvent
Solution, the two after mixing, are added slowly with stirring into 0.5~2% poly-vinyl alcohol solution, continue to be protected from light stirring after adding
Certain time to obtain the final product.
7. hepatoma-targeting nanoparticle according to claim 4, which is characterized in that preparation method uses dialysis, specifically such as
Under: it weighs Gal-PEG-PLGA polymer material and is dissolved in organic solvent；It separately weighs medicines resistant to liver cancer to be dissolved with organic solvent, two
Person after mixing, is transferred in bag filter, and dialysis removes organic solvent, up to nanoparticle after dialyzate freeze-drying.
8. hepatoma-targeting nanoparticle according to claim 6 or 7, it is characterised in that: organic solvent is dimethyl sulfoxide, four
Hydrogen furans or N,N-dimethylformamide；And/or the ratio of Gal-PEG-PLGA polymer material and medicines resistant to liver cancer is 10:1
~1:1.
9. application of the polymer material described in claim 1 in preparation treatment liver-cancer medicine.
10. application of the described in any item hepatoma-targeting nanoparticles of claim 4-8 in preparation treatment liver-cancer medicine.
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