CN110179754A - With redox responsiveness and the multi-functional liposome of tissue infiltration can be enhanced - Google Patents
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Abstract
The invention discloses a kind of with redox responsiveness and the multi-functional liposome and its preparation method and application that can enhance tissue infiltration, the redox responsiveness DSPE-S-S- chemotherapeutics prodrug that the surface modification disulfide bond of the liposome mediates, phospholipid bilayer loads hydrophobic photosensitizer, and the hydrophilic medicament that can enhance tissue permeability is contained in intraliposomal aqueous phase.The oxidable reduction responsiveness of liposome prepared by the present invention discharges chemotherapeutics, and enhance liposome in the infiltration of tumor tissues and the infiltration of ambient oxygen, the pharmaceutical preparation of anti-breast cancer, anti-liver cancer and anti-, anti-lung cancer or anti-cervical cancer be can be used as oncotherapy, improve chemotherapy/photodynamic therapy synergistic antitumor effect.
Description
Technical field
The invention belongs to biomedical material technologies, and in particular to have redox responsiveness and can enhance tissue
The multi-functional liposome and its preparation method and application of infiltration.
Background technique
The oncotherapy of single-mode is generally unattainable satisfactory therapeutic effect, and multiple mode combiend therapeutic is available
Different mechanism of action realizes synergistic antitumor effect, improves curative effect.Photodynamic therapy (PDT) is a kind of emerging Noninvasive
Tumor therapeuticing method, principle are using photosensitizer under the excitation of appropriate wavelength light source, and converting oxygen molecule around to has carefully
Cellular toxicity singlet oxygen (1O2), to achieve the purpose that killing tumor cell.Chemotherapy is the main means for the treatment of malignant tumor
One of, by PDT in conjunction with chemotherapy, tumor killing effect can be significantly increased.Meanwhile enhancing the drug such as Losartan, glue of tissue permeability
Collagen, hyaluronic acid etc. in the degradable extracellular matrix such as protoenzyme, hyaluronidase enhance liposome in tumor tissues
Infiltration and surrounding oxygen molecule infiltration, improve oxygen concentration, enhancing chemotherapy/PDT synergistic antitumor effect.
Tumor microenvironment has the characteristics that weary oxygen, low ph value, high concentration reducing substances, high pressure, this to the growth of tumour with
Transfer plays a significant role.The redox response type liposome that disulfide bond (- S-S-) mediates can be swollen rich in glutathione
Disulfide bonds occur in oncocyte.The present invention combines the DSPE-S-S- chemotherapeutics prodrug with redox responsiveness, dredges
Aqueous photosensitive agent and the hydrophilic medicament that can enhance tissue permeability, building have redox responsiveness and can enhance tissue infiltration
Saturating multi-functional liposome is used for chemotherapy/PDT synergistic antitumor.
Summary of the invention
The purpose of the present invention is to provide a kind of with redox responsiveness and can enhance the multi-functional rouge of tissue infiltration
Plastid and its preparation method and application, the liposome can enhance the infiltration and surrounding oxygen of liposome in tumor tissues microenvironment
The infiltration of son improves oxygen concentration, and can realize that redox responsiveness discharges chemotherapeutics, enhancing chemotherapy/PDT synergistic effect.
To achieve the above object, the present invention adopts the following technical scheme:
A kind of with redox responsiveness and to enhance the multi-functional liposome of tissue infiltration, which contains
Redox responsiveness DSPE-S-S- chemotherapeutics prodrug, the cholesterol (Chol), hydrogenated soy phosphatidyl choline of disulfide bond mediation
(HSPC), 1,2- distearyl acid -3- phosphatidyl-ethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) and hydrophobic photosensitizer,
Middle DSPE-S-S- chemotherapeutics prodrug modification is in surface of liposome；Intraliposomal aqueous phase, which has contained, can enhance tissue permeability
Hydrophilic medicament.
HSPC、DSPE-PEG2000, DSPE-S-S- chemotherapeutics prodrug, Chol and hydrophobic photosensitizer molar ratio be
(45~65):6:(6~24):12:(6~12).The hydrophilic medicament and phosphatide of tissue permeability can be enhanced in intraliposomal aqueous phase
Mass ratio is 1:3 ~ 1:20.
The hydrophobic photosensitizer is any one in Ce6, porphine of bacterium, porphyrin and phthalocyanines.
The hydrophilic medicament for enhancing tissue permeability is Losartan, clostridiopetidase A, hyaluronidase, matrix metal egg
Any one in white enzyme.
The chemotherapeutics prodrug is platinum-like compounds, bearing taxanes, green onion cyclics, camptothecin chemical combination
Any one in object or vinca compound.
The preparation method of the multi-functional liposome that there is redox responsiveness and tissue infiltration can be enhanced, including with
Lower step:
(1) chemotherapeutics of sulfhydrylation and the DSPE of sulfhydrylation are linked by disulfide bond first, there is redox to ring for synthesis
The DSPE-S-S- chemotherapeutics prodrug of answering property；
(2) by HSPC, Chol, DSPE-PEG2000, DSPE-S-S- chemotherapeutics prodrug and hydrophobic photosensitizer be dissolved in chloroform/
In the mixed solution of methanol；Wherein the volume ratio of chloroform and methanol is 1:1；
(3) chloroform/methanol mixed solution is removed by rotary evaporation, obtains uniform thin-film material；
(4) after the elution of calcium acetate aqueous solution, sodium acetate aqueous solution or PBS solution, elution solution is obtained, addition can enhance tissue
Infiltrative hydrophilic medicament, then 5 ~ 20 min of cell crushing instrument ultrasound is used, ultrasonic power is 50 ~ 400 W；
(5) solution is after dialysing to get the multi-functional liposome for having redox responsiveness and can enhancing tissue infiltration.
It is described with redox responsiveness and the multi-functional liposome of tissue infiltration to be enhanced, be applied to anti-breast cancer,
The preparation of anti-liver cancer and anti-, anti-lung cancer or medicament for resisting cervical cancer carrier.
The present invention has the advantages that the multi-functional lipid that there is redox responsiveness and tissue infiltration can be enhanced of preparation
Collagen, hyaluronic acid etc. of the body in the degradable tumor extracellular matrix of tumor tissues enhance liposome in tumor tissues
Infiltration and surrounding oxygen molecule infiltration, improve oxygen concentration；After near-infrared laser irradiates, in the effect of photosensitizer and oxygen molecule
Under, play PDT effect.When liposome enters the tumour cell rich in glutathione, the DSPE-S-S- chemotherapeutic of surface modification
Object prodrug can discharge chemotherapeutics, enhancing chemotherapy/PDT synergistic antitumor effect because of disulfide bonds.
Detailed description of the invention
Fig. 1 is the multi-functional liposome for having redox responsiveness and can enhancing tissue infiltration prepared by embodiment 2
The result of oxidation-reduction quality response release cis-platinum.
Fig. 2 is the cellular uptake result of the multi-functional liposome of embodiment 2.
Fig. 3 is inhibiting tumor assay result of the multi-functional liposome to A549 tumor-bearing mice of embodiment 2.
Specific embodiment
In order to make content of the present invention easily facilitate understanding, With reference to embodiment to of the present invention
Technical solution is described further, but the present invention is not limited only to this.
Embodiment 1: the synthetic method of cis-platinum prodrug DSPE-S-S-Pt and DSPE-Pt
(1) aoxidize cis-platinum (Pt (IV)-OH): 200 mg cis-platinums are completely dissolved in 30% H of 7.0 mL2O2In, 50 DEG C are protected from light and stir
Mix 5 h；It is cooled to room temperature, precipitating is collected by centrifugation, and successively washed with ice water, ice ethyl alcohol, ice ether, is dried in vacuo；
(2) carboxylated cis-platinum (Pt (IV)-SA): 100 mg Pt (IV)-OH are dissolved completely in 8.3 mL DMSO, are added 0.03
G succinic anhydride, 45 DEG C of nitrogen protections are protected from light 24 h, are cooled to room temperature, and are centrifuged off precipitating, collect supernatant solution and freeze
Dry, product is successively washed and is dried in vacuo with acetone, ice ether；
(3) sulfhydrylation cis-platinum (Pt (IV)-SA-SH): 210 mg Pt (IV)-SA are dissolved completely in the mixing of 20 mL chloroform/methanols
0.523 mL DIPEA, 153 mg HOBT and 379 mg HBTU activated carboxyls are added in solution (chloroform: methanol=65:35), by
It is added dropwise to the mercaptoethylmaine (77 mg) for being dissolved in 1 mL chloroform/methanol mixed solution (chloroform: methanol=65:35) in advance, 40 DEG C
Nitrogen protection is protected from light 24 h, and rotary evaporation removes organic solvent, and ice ether is washed for several times and is dried in vacuo；
(4) redox responsiveness cis-platinum prodrug (DSPE-S-S-Pt): 79 mg DSPE are dissolved in 2.2 mL anhydrous chloroforms, add
Enter 90 55 DEG C of μ L triethylamines to stir evenly, and the 26.3 mg SPDP for being dissolved in 0.3 mL anhydrous chloroform are added, nitrogen protection is kept away
16.8 mg Pt (the IV)-SA-SH for being dissolved in 0.9 mL anhydrous chloroform, nitrogen protection reaction overnight, rotation is added in 5 h of light reaction
Evaporating organic solvent, acetonitrile dissolve and are centrifuged off precipitating, and 24 h of dialysis are simultaneously lyophilized；
(5) without disulfide bond cis-platinum prodrug (DSPE-Pt): 116 mg Pt (IV)-SA are dissolved in chloroform/methanol mixed solution (chlorine
It is imitative: methanol: water=65:35:8), 100 mg DSPE are added after 51.2 mg EDC and 30.6 mg NHS, 40 DEG C of 2 h of activation are added
12 h are reacted at room temperature, rotary evaporation removes organic solvent, and ultrapure water disperses again and is lyophilized after 48 h that dialyse.
A kind of embodiment 2: preparation side with redox responsiveness and multi-functional liposome that tissue infiltration can be enhanced
Method
(1) 19.6 mg, Chol 2.3 mg, DSPE-PEG of precision weighing HSPC2000 8.3 mg, cis-platinum prodrug (DSPE-S-S-
Pt) 3.6 mg of 7.3 mg and hydrophobic photosensitizer Ce6 is dissolved in 30 mL chloroform/methanol (V:V=1:1) mixed solutions；
(2) using rotary evaporation, rotary evaporation removes chloroform/methanol mixed solution under the conditions of 30 DEG C, 70 rpm, obtains one
The uniform thin-film material of layer；
(3) after the elution of 3.52 mL calcium acetate aqueous solutions (150 mM), with phosphatide and Losartan (Los) mass ratio for 10:1
Losartan is put into, 6 h are stirred at room temperature, then using cell crushing instrument in 300 W ultrasound, 10 min；
(4) liposome solutions have oxidation after containing the 10wt.% sucrose solution of 5 mM NaCl and ultrapure water dialysis to get described
Reduction responsiveness and the multi-functional liposome (Ce6-Lip-S-S-Pt/Los) that tissue infiltration can be enhanced.Meanwhile with no disulfide bond
Cis-platinum prodrug (DSPE-Pt) replace DSPE-S-S-Pt, preparation be free of disulfide bond cisplatin liposome (Ce6-Lip-Pt/Los)
For control.
A kind of embodiment 3: preparation side with redox responsiveness and multi-functional liposome that tissue infiltration can be enhanced
Method
(1) 21.6 mg, Chol 2.3 mg, DSPE-PEG of precision weighing HSPC20008.3 mg, cis-platinum prodrug (DSPE-S-
S-Pt) 3.6 mg of 7.9 mg and hydrophobic photosensitizer Ce6 is dissolved in chloroform/methanol (V:V=1:1) mixed solution of 30 mL；
(2) using rotary evaporation, rotary evaporation removes chloroform/methanol mixed solution under the conditions of 30 DEG C, 70 rpm, obtains one
The uniform thin-film material of layer；
It (3) is that 8:1 puts into chlorine sand with phosphatide and Los mass ratio after the elution of 3.79 mL calcium acetate aqueous solutions (150 mM)
It is smooth, 6 h are stirred at room temperature, then using cell crushing instrument in 350 W ultrasound, 5 min；
(4) liposome solutions have oxidation after containing the 10wt.% sucrose solution of 5 mM NaCl and ultrapure water dialysis to get described
Reduction responsiveness and the multi-functional liposome (Ce6-Lip-S-S-Pt/Los) that tissue infiltration can be enhanced.Meanwhile with no disulfide bond
Cis-platinum prodrug (DSPE-Pt) replace DSPE-S-S-Pt, preparation be free of disulfide bond cisplatin liposome (Ce6-Lip-Pt/Los)
For control.
Embodiment 4: a kind of cis-platinum with redox responsiveness and the multi-functional liposome that can enhance tissue infiltration is released
Put experiment
The multi-functional liposome for having redox response type and capable of enhancing tumor tissues infiltration prepared by 4 mL embodiments 2 is set
In bag filter, the PBS solution that 100 mL contain 20 mM dithiothreitol (DTT)s (DTT) is added, in 37 DEG C, 100 rpm/min conditions
Release；5 mL release liquids are taken out respectively at 0,10,30 min and 1,2,5,8,12,24 h, while supplementing the fresh release of 5 mL
Medium；The release liquid of taking-up detects the burst size of Pt using inductively-coupled plasma spectrometer, and calculates the cumulative release of Pt
Rate.
As shown in Figure 1, in the presence of with the DTT of Reduction of Disulfide effect, when discharging 24 h, the Ce6- with disulfide bond
The burst size of Pt is 56% in Lip-S-S-Pt/Los liposome, and the Ce6-Lip-Pt/Los liposome without disulfide bond is released
High-volume only 32%, this shows that the burst size of Pt in Ce6-Lip-S-S-Pt/Los is apparently higher than Ce6-Lip-Pt/Los, this is because
In DTT solution, the disulfide bond of Ce6-Lip-S-S-Pt/Los is broken, and causes the release of Pt to increase, it was demonstrated that Ce6-Lip-
S-S-Pt/Los has the ability of reduction responsiveness release Pt.
Embodiment 5: the cellular uptake experiment of the multi-functional liposome of embodiment 2
The A549 cell of logarithmic growth phase is diluted with 1640 culture mediums containing 10% fetal calf serum, with 1 × 106Cells/well
Density is inoculated in 6 well culture plates, and 37 DEG C of overnight incubations discard culture medium, and 2 mL are added in PBS washing under the conditions of being protected from light
Culture medium (Ce6 concentration is 10 μ g/mL) containing Ce6-Lip-Pt/Los, Ce6-Lip-S-S-Pt/Los and free Ce6 solution,
Culture medium is abandoned after cultivating 2 h, PBS is cleaned 2 times, and pancreatin digestion, PBS is resuspended, using flow cytometry analysis.
As a result as shown in Fig. 2, compared with free Ce6, the fluorescence intensity of liposome group is remarkably reinforced, this shows liposome pair
Ce6's contains the intake that can improve cell to Ce6.In addition, the red fluorescence of Ce6-Lip-S-S-Pt/Los is apparently higher than
Ce6-Lip-Pt/Los, this is because the DSPE-S-S-Pt in liposomal phospholipids discharges suitable in tumor microenvironment Reduction of Disulfide
Platinum, this may change liposomal phospholipids bilayer structure, increase the burst size of Ce6, promote intake of the cell to Ce6.
Embodiment 6: inhibiting tumor assay of the multi-functional liposome of embodiment 2 to A549 lotus knurl BALB/c mouse
The foundation of A549 lotus knurl BALB/c mouse model: the A549 cell of logarithmic growth phase is collected thin after PBS washing, digestion
Born of the same parents, being resuspended through 0.9% NaCl injection and being diluted to concentration is 1 × 108Cell/mL single cell suspension, in mouse right axillary skin
Lower injection 1 × 107A cell/only.Take tumour about 80-100 mm3The grouping of lotus knurl BALB/c mouse it is (physiological saline group, free
Ce6 group, Ce6-Lip-Pt/Los group and Ce6-Lip-S-S-Pt/Los group), 7.5 mg/kg tail vein of Ce6 dosage is pressed respectively
Drug administration by injection, physiological saline group inject 0.9% NaCl injection of equivalent.During experiment, gross tumor volume and mouse are measured daily
Weight.
As a result as shown in figure 3, in 14 d, physiological saline group has significant tumour growth, and liposome group is to tumour body
It is most strong that the inhibiting effect that product increases is significantly greater than free Ce6 group, especially Ce6-Lip-S-S-Pt/Los group inhibition level；Together
When, the mouse weight of physiological saline group, free Ce6 group and liposome group is without significant change.Illustrate Ce6-Lip-S-S-Pt/
Los has good internal tumor killing effect, hence it is evident that enhances chemotherapy/PDT synergistic antitumor effect, improves curative effect.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification, is all covered by the present invention.
Claims (8)
- With redox responsiveness and the multi-functional liposome of tissue infiltration can be enhanced 1. a kind of, it is characterised in that: the rouge Plastid phospholipid layer contain disulfide bond mediation redox responsiveness DSPE-S-S- chemotherapeutics prodrug, Chol, HSPC, DSPE-PEG2000And hydrophobic photosensitizer, wherein the modification of DSPE-S-S- chemotherapeutics prodrug is in surface of liposome, liposome Water phase has contained the hydrophilic medicament that can enhance tissue permeability.
- 2. the multi-functional liposome according to claim 1 that there is redox responsiveness and tissue infiltration can be enhanced, It is characterized in that: HSPC, DSPE-PEG2000, DSPE-S-S- chemotherapeutics prodrug, Chol and hydrophobic photosensitizer molar ratio be (45~65):6:(6~24):12:(6~12)；The hydrophilic medicament and phosphatide of tissue permeability can be enhanced in intraliposomal aqueous phase Mass ratio is 1:3 ~ 1:20.
- 3. the multi-functional liposome according to claim 1 that there is redox responsiveness and tissue infiltration can be enhanced, Be characterized in that: the hydrophobic photosensitizer is any one in Ce6, porphine of bacterium, porphyrin and phthalocyanines.
- 4. the multi-functional liposome according to claim 1 that there is redox responsiveness and tissue infiltration can be enhanced, Be characterized in that: the hydrophilic medicament for enhancing tissue permeability is Losartan, clostridiopetidase A, hyaluronidase, matrix metal Any one in protease.
- 5. the multi-functional liposome according to claim 1 that there is redox responsiveness and tissue infiltration can be enhanced, Be characterized in that: the chemotherapeutics prodrug is platinum-like compounds, bearing taxanes, green onion cyclics, camptothecin Close any one in object or vinca compound.
- 6. the multi-functional liposome according to claim 1 that there is redox responsiveness and tissue infiltration can be enhanced, Be characterized in that: the redox responsiveness DSPE-S-S- chemotherapeutics prodrug is by the chemotherapeutics and sulfhydrylation of sulfhydrylation DSPE be bonded by disulfide bond chain.
- 7. it is a kind of prepare as described in claim 1 ~ 6 any one with redox responsiveness and tissue infiltration being enhanced The method of multi-functional liposome, it is characterised in that: the following steps are included:(1) by HSPC, Chol, DSPE-PEG2000, DSPE-S-S- chemotherapeutics prodrug and hydrophobic photosensitizer be dissolved in chloroform/ In the mixed solution of methanol；Wherein the volume ratio of chloroform and methanol is 1:1；(2) chloroform/methanol mixed solution is removed by rotary evaporation, obtains uniform thin-film material；(3) after the elution of calcium acetate aqueous solution, sodium acetate aqueous solution or PBS solution, elution solution is obtained, addition can enhance tissue Infiltrative hydrophilic medicament, then 5 ~ 20 min of cell crushing instrument ultrasound is used, ultrasonic power is 50 ~ 400 W；(4) solution is after dialysing to get the multi-functional liposome for having redox responsiveness and can enhancing tissue infiltration.
- 8. a kind of described in any claim according to claim 1 ~ 6 with redox responsiveness and can enhance tissue infiltration Multi-functional liposome is preparing the application in anti-breast cancer, anti-liver cancer and anti-, anti-lung cancer or medicament for resisting cervical cancer.
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| CN115252558B (en) * | 2022-09-05 | 2024-03-08 | 华东理工大学 | Multi-drug liposome system taking phosphatidyl drug as framework, and preparation method and application thereof |
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