CN119345112B - A liposome hydrogel loaded with heat shock protein inhibitors and its preparation and application - Google Patents
A liposome hydrogel loaded with heat shock protein inhibitors and its preparation and applicationInfo
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- CN119345112B CN119345112B CN202411464434.7A CN202411464434A CN119345112B CN 119345112 B CN119345112 B CN 119345112B CN 202411464434 A CN202411464434 A CN 202411464434A CN 119345112 B CN119345112 B CN 119345112B
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Abstract
The invention provides liposome hydrogel carrying a heat shock protein inhibitor and a preparation method thereof, and aims to accurately treat HER2 high-expression breast cancer. The liposome surface is modified with HER2 antibody and light heating agent indocyanine green, trastuzumab is loaded inside, and heat shock protein inhibitor quercetin is embedded to enhance the treatment effect. The stable hydrogel drug delivery system is formed by simply mixing the liposome with the aqueous solution of poly DL-lactide-polyethylene glycol-poly DL-lactide, thereby protecting the drug and prolonging the stability thereof. The system realizes the targeted delivery and sustained release of the medicine, improves the treatment effect, reduces the side effect and provides an innovative and efficient solution for the breast cancer treatment.
Description
Technical Field
The invention relates to the technical field of nano biological medicines, in particular to liposome hydrogel loaded with a heat shock protein inhibitor and preparation and application thereof.
Background
In the field of breast cancer treatment, with a deep understanding of the biological properties of tumors, heat Shock Proteins (HSPs) are a key class of stress proteins, which increasingly play a role in tumorigenesis, development and drug resistance mechanisms. Overexpression of HSP not only enhances the viability of breast cancer cells, but also promotes invasiveness and drug resistance thereof, and therefore, development of specific inhibitors against HSP becomes a new strategy for improving the therapeutic effect of breast cancer. However, current research on small molecule inhibitors of breast cancer heat shock proteins is still in the primary stage, and despite its great potential, faces a number of technical challenges. In particular, how to design and synthesize a small molecule inhibitor capable of specifically inhibiting breast cancer-related HSP, while ensuring the stability and release controllability of the drug in vivo is a key issue of current research.
Hydrogel is one of the local drug release systems, and has been widely developed due to the advantages of concentrated drug release at tumor sites for a long period, low systemic drug toxicity, controlled drug release, and the like. However, the traditional hydrogel is limited to release of the drug under the action of passive diffusion of the drug and degradation of the hydrogel, and cannot meet the requirement of controllable release, so that the internal structure is changed due to the fact that the external stimulus is sensed, and the fixed-point, controllable and on-demand release of the drug is realized.
Disclosure of Invention
The invention aims to provide liposome hydrogel loaded with a heat shock protein inhibitor, and preparation and application thereof.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
a preparation scheme of liposome hydrogel loaded with heat shock protein inhibitor, comprising the following steps:
S1, dissolving Dipalmitin (DPPC), amphipathic lipid phospholipid polyethylene glycol maleimide (DSPE-PEG 5000 -Mal) and indocyanine green (ICG) in 15mL chloroform (CHCl 3) at room temperature, and removing organic solvent by rotary evaporation for 8h to form a liposome membrane. The product was transferred to 5mL of ultrapure water for ultrasonic hydration for 20 minutes to allow complete dissolution of the liposomes in water.
S2, adding Trastuzumab and heat shock protein inhibitor molecule quercetin (Qu) into the final product prepared in the step S1, performing ultrasonic treatment for 4 minutes by using a cell disruption instrument, then washing the obtained solution with ultra-filtration filter of 10kDa and 7500rpm by using ultra-filtration water, and repeating the ultra-filtration washing for a plurality of times to remove the unloaded Qu, trastuzumab and organic solvent, thereby preparing the pure DTQI@Lips.
And S3, rotating and incubating the DTQI@Lips prepared in the step S2 with a thiolated HER2 antibody PBS aqueous solution at room temperature for 8 hours, fully reacting Mal with-SH, and washing to remove unbound HER2 antibody to prepare the HDTQI@Lips.
And S4, uniformly mixing the HDTQI@lips prepared in the step S3 with a poly DL-lactide-polyethylene glycol-poly DL-lactide (PLEL) aqueous solution according to a certain mass ratio at room temperature to prepare the HDTQI@lips-gel hydrogel system.
Preferably, the mass ratio of DPPC, DSPE-PEG 5000 -Mal, ICG in step S1 is 3:1:2.
Preferably, trastuzumab to Qu mass ratio added in step S2 is 1:1.
Preferably, the concentration of the aqueous solution of the thiolated HER2 antibody PBS in step S3 is 0.5mg/mL.
Preferably, the dtqi@lips is reacted with the aqueous solution of thiolated HER2 antibody PBS in a molar ratio of 1:10 in step S3.
Preferably, the mass ratio between hdtqi@lips and PLEL (20 wt%) in step S4 is 1:10.
Compared with the prior art, the invention has the following beneficial effects:
The specific HER2 antibody is modified on the surface of the liposome in the hydrogel and is used for accurately identifying and targeting breast cancer cells with HER2 high expression. The liposome is internally loaded with trastuzumab serving as a therapeutic drug and ICG serving as a photothermal agent, and the photothermal effect of the trastuzumab can cause ablation of the liposome to trigger drug release. In addition, the liposome is also embedded with heat shock protein responsive molecule quercetin, so that heat resistance of tumor cells can be inhibited under the heat shock environment in the cells, heat sensitivity of the tumor cells can be promoted, and the drug treatment effect can be enhanced. In addition, the hydrogel and the internal liposome can form a stable drug delivery system only by simple mixing, and the hydrogel can be quickly converted into a solid gel structure from a flowing sol state at a physiological temperature of 37 ℃ due to good phase change (sol-gel) property, so that the internal liposome and the carried drug are effectively fixed and wrapped, and the stability and durability of the drug delivery system are ensured; in addition, the hydrogel matrix provides a good drug protection barrier, further prolongs the stability of the drug, realizes the targeted delivery and sustained release of the drug, improves the treatment effect and reduces the toxic and side effects.
Drawings
FIG. 1 shows the particle size and morphology results of HDTQII@lips nanoparticles.
Fig. 2 shows the result of controlled release of Trastuzumab triggered by near infrared hdtqi@lips nanoparticles, fig. 2a shows the cumulative release profile of Trastuzumab with or without continuous laser irradiation of hdtqi@lips nanoparticles, and fig. 2b shows the release profile of Trastuzumab with or without laser irradiation of hdtqi@lips nanoparticles.
FIG. 3 is a characterization result of the HDTQI@lips-Gels hydrogel, FIG. 3a is a rheological analysis of the HDTQI@lips-Gels hydrogel, and FIG. 3b is an SEM characterization result of the HDTQI@lips-Gels hydrogel, with a scale of 5 μm.
FIG. 4 is the water swelling performance results of the HDTQII@lips-Gels hydrogel system at pH=6.5.
FIG. 5 is a graph showing the results of the release of HDTQI@lips in a hydrogel carrier over time.
FIG. 6 shows the levels of BT474 cell HSP70 protein expression after treatment with different treatments, wherein group ①②③④⑤ was treated with PBS, qu, NIR-II, qu+NIR-II and HDTQI@lips-Gels+NIR-II, respectively.
FIG. 7 shows the result of a cytotoxicity test of HDTQI@lips-Gels hydrogel on tumor cells and normal cells.
Fig. 8 shows tumor volume changes over 14 days in mice treated with different treatments.
FIG. 9 shows H & E staining results of mouse tumor mass treated with different treatments.
Detailed Description
The invention is further described below with reference to examples.
Example 1 preparation method of HDTQI@lips-Gels hydrogel specifically comprises the following steps:
(1) 30mg of Dipalmitin (DPPC), 10mg of amphipathic lipo-phospholipid polyethylene glycol maleimide (DSPE-PEG 5000 -Mal) and 20mg of indocyanine green (ICG) were completely dissolved in 15mL of chloroform (CHCl 3), the organic solvent was removed, a liposome membrane was formed by rotary evaporation, and 5mL of ultrapure water was added for ultrasonic hydration for 20 minutes to completely dissolve the liposome in water. 10mg of Trastuzumab (Trastuzumab) and 10mg of heat shock protein responsive molecular quercetin (Qu) were added, sonicated with a cytobreaker for 4 minutes, and the resulting solution was washed with ultra-pure water using an ultra-filtration filter of 10kDa,7500rpm, and the unloaded Qu, trastuzumab and organic solvent were removed three times repeatedly to prepare DTQI@lips.
(2) And (3) rotating and incubating the DTQI@Lips prepared in the step (1) and a thiolated HER2 antibody PBS aqueous solution (0.5 mg/mL) for 8 hours at room temperature according to a reaction molar ratio of 1:10, so that Mal and-SH fully react, and washing to remove unbound HER2 antibody, thereby preparing the HDTQI@Lips.
(3) The preparation method comprises the steps of completely dissolving poly DL-lactide-polyethylene glycol-poly DL-lactide (PLEL) in ultrapure water, and uniformly mixing the HDTQI@lips and PLEL (20 wt%) in a mass ratio of 1:10 in a room temperature environment to prepare the HDTQI@lips-Gels hydrogel system.
EXAMPLE 2 particle size and morphology characterization of HDTQI@Lips nanoparticles
After the hdtqi@lips prepared in step (2) of example 1 was diluted 10 times with distilled water, the particle size was measured by a laser dynamic light scattering nanoparticle sizer. Meanwhile, after the HDTQI@lips is diluted by 35 times by distilled water, 20 mu L of the diluted HDTQI@lips is dripped on a transmission electron microscope copper mesh, a sample is carefully sucked by filter paper from one side of the copper mesh after 1h, and phosphomolybdic acid is added for dyeing for 3s, and then the transmission electron microscope scanning is carried out.
As can be seen from fig. 1, the hdtqi@lips nanoparticle exhibits a spherical shape with a size of about 100 nm.
Example 3 controlled Release of Trastuzumab by near-infrared triggering of HDTQI@Lips nanoparticles
1ML of the HDTQII@lips solution was placed in a dialysis bag (3500 Da) and the release of Trastuzumab in the HDTQII@lips was measured. The dialysis bag was immersed in 20mL of PBS (ph=7.4) and irradiated with NIR-II (1064 nm,1.0w cm -2, 5 min) laser every 20 minutes, 400 μl of release medium was removed and replaced with an equal volume of fresh PBS. Trastuzumab release was detected by High Performance Liquid Chromatography (HPLC) at 280nm and the cumulative percent release was calculated as E r(％)＝Ft/F100 X100%.
The hdtqi@lips nanoparticle has a photo-thermal effect due to ICG, and DPPC can be melted by heating, promoting the effective release of Trastuzumab from the ruptured liposomes. Under the continuous irradiation of laser, trastuzumab is released from the release process of the HDTQI@lips nanoparticles, and the cumulative release rate can reach 83% (figure 2 a), which shows that the HDTQI@lips has thermosensitive responsiveness. In addition, drug release of hdtqi@lips nanoparticles with/without laser irradiation was measured, switching infrared light on and off every 10 minutes. As a result, as shown in fig. 2b, the drug release rate of Trastuzumab under laser irradiation was 60%, whereas no release of Trastuzumab was detected without laser irradiation, which more fully demonstrates the thermosensitive responsiveness of hdtqi@lips.
EXAMPLE 4 SEM characterization experiments of the HDTQI@lips-Gels hydrogel System
The gel strength and gel time of the hydrogel prepared in example 1at 37℃were analyzed in a rheometer by opening Thermo Scientific the rheometer, preheating the instrument, setting an oscillation mode, setting the temperature at 37℃and adjusting the distance between the rheometer parallel plate and the rotor to 1nm, dropping 200. Mu.L of the HDTQI@lips-gel solution onto the rheometer parallel plate to avoid bubble generation, and recording the change of the storage modulus (G ') and the loss modulus (G') with time within 1 min.
The hdtqi@lips-Gels prepared in example 1 was suspended in 37 ℃ water bath until gel was formed, then the hydrogel system was frozen and broken in-196 ℃ liquid nitrogen, and the surface of the sample slice was coated with gold prior to scanning electron microscope imaging, and the morphology of the hdtqi@lips-Gels was observed by scanning electron microscope.
As shown in FIG. 3a, the initial spring modulus (G ') and viscous modulus (G') were very low and the values of G 'and G' were very variable, indicating that the gel had not yet formed at this time and the system was still in an aqueous state. Subsequently, G' is significantly greater than G "at 33s, and the latter curve trend gradually tends to stabilize, indicating that the hydrogels have good hydrogel phase transition (sol-gel) properties, which can be used for the preparation of injectable drug delivery vehicles. FIG. 3b is a scanning electron microscope image of the HDTQII@lips-Gels material prepared in example 1 of the present invention, and it can be seen that the material exhibits a typical hydrogel three-dimensional network structure under a scanning electron microscope, which fully proves that the HDTQII@lips-Gels with a desired structure is successfully prepared by the method described in example 1, the internal three-dimensional network structure is clearly visible, and a highly crosslinked state is shown to be a porous structure.
Example 5 swelling Properties of the HDTQI@lips-Gels hydrogel System
In order to study the swelling performance of the HDTQII@lips-Gels hydrogel system at different time points, 1mL of the HDTQII@lips-Gels hydrogel is placed in a 50mL centrifuge tube, the mass of the centrifuge tube is weighed to be W 0, the mass of the centrifuge tube and the mass of the hydrogel are weighed to be W 1, 30mL of PBS is added into the centrifuge tube, the hydrogel is completely immersed, the shaking is carried out under the condition of 37 ℃, the PBS in the centrifuge tube is removed through a leak hole with the diameter of 1mm in the middle of a bottle cap at regular intervals, the total mass of the centrifuge tube and the hydrogel is weighed to be W 2, and the swelling ratio is calculated according to a formula of (W 2-W0)/(W1-W0) multiplied by 100%.
The swelling properties of the hydrogel system were evaluated gravimetrically. As shown in fig. 4, the hdtqi@lips-Gels hydrogel system exhibited a strong water-swelling capacity and reached the maximum swelling value around 16h, when ph=6.5. The tumor acidic microenvironment provides ideal swelling conditions for the HDTQI@lips-gel hydrogel system, when the hydrogel system is implanted into tumor tissues, the internal DPPC can rapidly respond to the acidic environment to promote the swelling process of the hydrogel, and meanwhile, the time window also provides favorable conditions for the sustained and stable release of the internal medicine Trastuzumab and the heat shock protein inhibitor Qu.
Example 6 in vitro Release of HDTQII@lips-Gels hydrogel System HDTQII@lips
To study drug release from hydrogels, 5mL of PBS (ph=6.5) was slowly added to the prepared hdtqi@lips-Gels and incubated in a shaker at 37 ℃ at 100rpm, and 400 μl of release medium was removed and replaced with the same volume of fresh PBS over a predetermined period of time. Trastuzumab release was detected by High Performance Liquid Chromatography (HPLC) at 280nm and the cumulative percent release was calculated as E r(％)＝Ft/F100 X100%.
On the basis of example 4, which demonstrates that the hdtqi@lips-Gels hydrogel system prepared by the invention has good phase change performance under the condition of 37 ℃, the in vitro release of hdtqi@lips-Gels is studied in a simulated tumor acidic microenvironment (PBS, ph=6.5). As shown in FIG. 5, the HDTQI@lips can be slowly and continuously released from the hydrogel, so that the hydrogel can be relatively fast and then slow within 24 hours of initial release, and the cumulative release rate is about 78% after 96 hours, and the experimental results show that the hydrogel system can slowly release the HDTQI@lips and then release Trastuzumab from the liposome under NIR-II illumination, and the hydrogel system has continuous and stable drug release capability.
EXAMPLE 7 protein analysis of HSP70 in tumor cells after treatment with different therapeutic modalities
BT474 cells (1 x 10 5/well) were inoculated into six well plates for pre-incubation for 24h. The medium was then incubated with PBS, qu, NIR-II, qu+NIR-II and HDTQI@lips-Gels+NIR-II (10 nM) in place of for 24h. After the cultured cells were completed, the cells were washed with PBS for 2 times, total proteins were extracted by lysing the cells, and protein concentration was measured using a BCA kit. An equal amount of protein sample was subjected to 10% SDS-PAGE and transferred to PVDF membrane. PVDF membrane after successful transfer was blocked with 5% (w/v) skim milk powder (1 XTBE) in a room temperature shaker for 1h, washed 3 times with 1 XTBE containing 0.1% Tween-20, incubated at 4℃overnight, washed with 1 XTBE for unbound primary antibody, incubated at room temperature for 2h, washed again and developed with ECL.
Western blot analysis was used to detect HSP70 expression levels in BT474 cells under different treatments using GADPH as an internal control. As shown in fig. 6, the HSP70 expression level was significantly higher in the NIR-II treated group compared to the control group, and the HSP70 expression was significantly reduced after treatment with qu+nir-II, which suggests that Qu can effectively suppress the increase in HSP70 content caused by photo-heat, and reduce the heat resistance of tumor cells. It is worth noting that the expression level of HSP70 is reduced after the treatment of HDTQI@lips-Gels+NIR-II, which is almost no different from that of the treatment group of Qu+NIR-II, and the hdTQI@lips-Gels hydrogel system has no influence on the activity of the Qu, so that the preparation material can stably release the Qu in an in-vivo environment, effectively target and inhibit the expression of the HSP70, and further realize the accurate regulation of the response to the photo-thermal stress.
Example 8 cytotoxicity test of HDTQI@lips-Gels hydrogel System
After HER2 positive breast cancer cells BT474 and human normal breast cancer cells MCF-10A are cultured to the logarithmic phase, the cells are inoculated into a 96-well plate, and after adherence is carried out for 24 hours, the cells are respectively divided into 5 groups of PBS, trastuzumab, PLEL, qu +NIR-II, HDTQI@lips-gel+NIR-II, 10nM of the sample solution diluted with the complete culture medium with the same concentration is added into the wells, and the wells are incubated for 24 hours at 37 ℃. After the incubation was completed, 10. Mu.L of CCK8 solution was added to each well, and the mixture was incubated for 3 hours, and absorbance at 450nm was measured by using an ELISA reader.
As shown in fig. 7, the control group had negligible cell death, and most of the tumor cells were killed and also had killing ability for normal breast cells for Trastuzumab group due to broad-spectrum anticancer effect of Trastuzumab. For group PLEL, no cytotoxicity was generated for tumor cells and normal cells due to good biocompatibility of PLEL. For the group Qu+NIR-II, since Qu inhibits the heat resistance of tumor cells under the irradiation stimulation of near infrared, certain cytotoxicity is generated for the tumor cells, and meanwhile, obvious cytotoxicity is not shown for normal cells. Notably, for the hdtqi@lips-gel+nir-II group, the most potent cytotoxicity was shown to BT474 cells due to HER2 targeting compared to the other groups, while the same better biocompatibility was seen for normal cells, indicating the specificity and safety of the hdtqi@lips-gel+nir-II treatment.
EXAMPLE 9 in vivo anti-tumor Effect of HDTQI@lips-Gels liposome-hydrogel System
25 Healthy female Nude mice (BALB/c Nude) were selected, and BT474 cells were subcutaneously injected into the right forelimb region to prepare tumor-bearing mice. When the tumor volume was about 50mm 3, mice were randomly divided into 5 groups (n=5) (1) PBS, (2) NIR-II, (3) Qu+NIR-II (4) HDTQI@Lips+NIR-II, (5) HDTQI@Lips-Gels+NIR-II (500 μg/mL,100 μl) for the experiment. Drug injection was performed every two days, and after 30 minutes of injection, tumors were irradiated with a laser of 0.6W/cm 2 1064nm for 10 minutes. Tumors were removed from mice after 14 days of treatment and sacrificed. Tumor sections were stained with hematoxylin and eosin (H & E) to further evaluate the effect of treatment.
During the treatment period, tumor volumes of each group were recorded every 2 days as a function of time according to the formula width 2 x length x pi/6. As shown in fig. 8, tumor volumes of PBS control and NIR-II laser groups increased rapidly, indicating that NIR light irradiation alone had little effect on tumor inhibition. The rate of increase of the volume of the Qu+NIR-II group tumor is slowed down to a certain extent, which indicates that the Qu has a certain tumor inhibition effect. In addition, in the HDTQII@Lips+NIR-II treatment group, the tumor growth speed is reduced, firstly, the HER2 antibody on the surface of the liposome accurately recognizes and targets breast cancer cells with high HER2 expression, ICG is excited by irradiation of near infrared light to generate a photo-thermal effect, so that the liposome is broken, and an internally loaded medicine is released to play a role in treatment, meanwhile, qu can inhibit heat resistance generated by tumor cells due to photo-thermal treatment, and the tumor growth speed is reduced under the comprehensive effect. Because of the local intelligent release and slow release effects of the hydrogel, the growth speed of the HDTQI@lips-Gels+NIR-II group tumor is further slowed down, and on the basis of the treatment effect of the HDTQI@lips+NIR-II group tumor, the hydrogel outside the HDTQI@lips plays a good role in sustained and stable release of drugs, so that longer treatment is provided at tumor tissue sites, the treatment effect of the tumor is best, and as shown in the results of staining of FIG. 9H & E, compared with a control group, although the HDTQI@lips+NIR-II treatment group shows the tumor cell necrosis result, the HDTQI@lips-Gels+NIR-II group shows the most serious tumor cell necrosis and the most good treatment effect, and further shows that the treatment effect of the HDTQI@lips-Gels liposome hydrogel system integrates photothermal treatment, heat shock protein inhibition, tumor targeting and stable release.
The foregoing has outlined rather broadly the more detailed description of the invention, and the detailed description thereof that follows may be better understood as being in the sense of limiting the scope of the present invention. It will be understood by those skilled in the art that various modifications and equivalent substitutions may be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention, and it is intended to cover the scope of the claims of the present invention.
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