CN115227672B - Solid lipid nanoparticle for promoting tumor vascular normalization and preparation and application thereof - Google Patents
Solid lipid nanoparticle for promoting tumor vascular normalization and preparation and application thereof Download PDFInfo
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Abstract
The invention discloses a solid lipid nanoparticle for promoting tumor vascular normalization, and preparation and application thereof. The solid lipid nanoparticle is coated with an anti-angiogenesis inhibitor, and adopts various lipids such as glyceryl monostearate, lecithin, triolein and the like as lipid materials, and the solid lipid nanoparticle is prepared by a solvent diffusion method. Based on the effect of temporary blood vessel normalization of tumors caused by the initial effect of low-dose anti-angiogenesis drugs and the characteristics of entrapment and slow release of the drugs by the lipid nano-carriers, the invention prepares the lipid nano-particles which can keep the anti-angiogenesis agents at tumor sites for a long time with low concentration, prolongs the window period of the vascular normalization effect, realizes the remodeling of tumor vascular systems and provides a new strategy for anti-tumor treatment research.
Description
Technical Field
The invention belongs to the field of pharmacy, relates to a solid lipid nanoparticle for promoting the normalization of tumor blood vessels, and preparation and application thereof, and relates to an anti-angiogenesis medicament and application of the lipid nanoparticle in vascular normalization research and anti-tumor treatment.
Background
Malignant tumors, i.e. cancers, are currently one of the major diseases affecting human health. In recent years, intensive studies on tumor tissues have found that the tissue environment in which tumor cells are located, i.e., tumor microenvironment, has an important influence on the growth and development of tumors. The abnormal vascular system of the tumor is one of the reasons for hypoxia, low pH and high mesenchymal pressure of the tumor microenvironment, and further promotes the malignant metastasis of the tumor, inhibits the infiltration of immune cells and promotes the resistance of the tumor to chemotherapy and radiotherapy. Early studies on tumor vasculature focused on directly inhibiting tumor angiogenesis by inhibiting the formation of new blood vessels, destroying existing blood vessels, inhibiting the intratumoral transport of oxygen and nutrients, and destroying tumors in "starvation therapy". However, the actual research results show that the anti-angiogenesis therapy has insufficient curative effect, mainly because of more angiogenesis-related signal paths, the existing research is dedicated to the development of multi-target inhibitors, but the activation of compensatory approaches is still difficult to avoid, so that tumor tissues generate drug resistance; meanwhile, research shows that excessive dosage of anti-angiogenesis block can cause excessive pruning of tumor blood vessels, excessive damage of tumor vascular systems leads to aggravation of leakage, and instead promotes overflow and escape of tumor cells through inter-vascular gaps, leading to worsening metastasis of tumors. The problems of insufficient curative effect, drug resistance, promotion of tumor exacerbation and metastasis and the like limit the development of the traditional anti-angiogenesis therapy.
With the intensive development of research related to the tumor angiogenesis process, the scholars find that: the low dose of angiogenesis inhibitor can reduce the size and tortuosity of blood vessels at the initial stage of action, induce endothelial cells to turn to mature phenotype, actively recruit pericytes and normalize basement membrane, thereby inducing tumor blood vessels to temporarily change to a more mature and complete phenotype, i.e. promoting blood vessel normalization in a short time. However, the low-dose anti-angiogenic agent has short onset time and narrow vascular normalization window period, and cannot have significant influence on tumor tissues; and a longer, more stable vascular normalization window phase helps to provide a stable, sustained delivery pathway for subsequent therapies, thereby further improving adjunctive therapeutic efficiency; in addition, long-term vascular normalization may lead to remodelling of the tumor microenvironment, thereby affecting tumor growth. Therefore, how to realize long-term and stable anti-angiogenesis effect becomes a new search direction of related research.
The solid lipid nanoparticle is prepared from natural or synthetic lipid materials such as triglyceride, composite glyceride and the like, and the particle size is between 50 and 1000 nm. The solid lipid nanoparticle has good biocompatibility; as a drug carrier, can prolong the half-life of the drug and promote the long-term circulation of the drug in vivo; the hydrophobic lipid core in the structure can wrap the insoluble medicine; the hydrophilic-hydrophobic structure can avoid recognition and elimination of reticuloendothelial system. The solid lipid nanoparticle is used as a nano carrier to load an anti-angiogenesis drug, so that the carrier can be delivered to a tumor vascular system by utilizing the requirement of tumor cells on lipid, and the retention and enrichment of tumor tissues are realized; then the slow release effect of the carrier on the medicine is utilized to control the angiogenesis intervention effect of the anti-angiogenesis agent for a long time and low concentration in tumor tissues, thus realizing the long-term tumor vascular normalization. Various researches show that the normalization of tumor tissue blood vessels reduces tissue mesenchymal pressure, increases perfusion, oxygenation, immune cell infiltration and drug delivery, and improves tumor microenvironment. In addition, the preparation process of the lipid nanoparticle is relatively simple, has stable structure and is easy for large-scale production.
Disclosure of Invention
The first object of the invention is to provide a solid lipid nanoparticle for promoting the normalization of tumor blood vessels, which takes an anti-angiogenesis drug as a core, and one or more lipid materials are coated on the surface of the nanoparticle, so that the nanoparticle has the function of drug slow release, can prolong the window period of the normalization of the blood vessels, and can realize the normalization of the tumor blood vessels. The tumor-promoting vascular normalization solid lipid nanoparticle is prepared by a solvent diffusion method, the core is a lipophilic small molecule tyrosine kinase inhibitor for inhibiting angiogenesis, the weight of lipid coated on the surface of the nanoparticle is 4-20 times of that of the loaded drug, and the particle size is 100-800 nm.
The second object of the present invention is to provide a method for preparing the solid lipid nanoparticle for promoting normalization of tumor blood vessels, which comprises two preparation methods:
the method one is a one-step method, and is realized by the following steps:
(1) Dissolving a lipid material and an anti-angiogenesis inhibitor in an organic solvent to obtain an organic phase;
(2) And (3) injecting the organic phase obtained in the step (2) into an aqueous phase under the heating condition, and obtaining the tumor vessel normalization promoting solid lipid nanoparticle through stirring, centrifuging and freeze drying.
The second method is a two-step method, which is realized by the following steps:
(1) Dissolving a lipid material in an organic solvent to obtain an organic phase;
(2) Injecting the organic phase obtained in the step (1) into water under the heating condition, stirring, probe ultrasonic treatment, rotary evaporation, water bath ultrasonic dispersion and freeze drying to obtain solid lipid powder;
(3) Redispersing the solid lipid powder obtained in the step (2) in water to obtain a water phase;
(4) Dissolving a fat-soluble anti-angiogenesis inhibitor in an organic solvent to obtain an organic phase;
(5) And (3) injecting the organic phase obtained in the step (4) into an aqueous phase under the heating condition, and obtaining the solid lipid nanoparticle for promoting the normalization of tumor blood vessels through stirring, centrifuging and freeze drying.
As preferable: the lipid material is one of glyceryl monostearate, lecithin, stearic acid or triolein. The organic solvent is one of dimethyl sulfoxide, methanol, N-dimethylformamide or ethanol. The anti-angiogenesis inhibitor is a fat-soluble anti-angiogenesis tyrosine kinase inhibitor, and is selected from vandetanib, sunitinib or sorafenib. The weight percentage of the anti-angiogenesis inhibitor and the lipid material is 5% -25%. When lecithin and triolein are selected as lipid materials for combination, the optimal mass ratio of the anti-angiogenesis inhibitor to the lecithin to the triolein is 6:22.5:7.5, at this time, the loading of the anti-angiogenesis inhibitor in the obtained lipid nanoparticle reached 16% (mass percent).
The particle size of the tumor-promoting vascular normalization solid lipid nanoparticle obtained by the method is 100-800 nm.
The third purpose of the invention is to provide the application of the solid lipid nanoparticle for promoting the normalization of tumor blood vessels in the preparation of anti-tumor drugs. The solid lipid nanoparticle loaded anti-angiogenesis inhibitor realizes the pharmacodynamic effect of promoting the normalization of tumor blood vessels in vivo. Experiments prove that the solid lipid nanoparticle prepared by the step scheme promotes the down regulation of the expression level of angiogenesis-related protein of human umbilical vein endothelial cells and the up regulation of the expression level of vascular normalization-related protein. In addition, the solid lipid nanoparticle provided by the invention can promote the increase of the coverage rate of perivascular cells of tumor tissues in a model mouse body and improve the structure and function of tumor blood vessels.
In most solid tumors there is a large number of abnormal vasculature due to angiogenesis, which is one of the causes of malignant metastasis of tumors. Therefore, the treatment strategy for promoting the normalization of tumor blood vessels has higher universality and can be applied to the treatment of various solid tumors. Compared with the prior art, the solid lipid nanoparticle for promoting the normalization of tumor blood vessels is applied to the research of the normalization of tumor blood vessels, the slow release function of the solid lipid nanoparticle is innovatively utilized, and the problems that the time for inducing the normalization of blood vessels by a small-molecule anti-angiogenesis drug is short, the efficiency is low and the excessive damage of blood vessels is easy to cause tumor metastasis are solved by loading an anti-angiogenesis agent; in-vivo and in-vitro experiments show that the tumor vessel normalization promoting solid lipid nanoparticle can prolong the window period of tumor vessel normalization and realize the stabilization and normalization effect, thereby further improving the tumor microenvironment, effectively inhibiting the growth and the metastasis of tumors and being expected to become a new strategy for anti-tumor treatment.
Drawings
Fig. 1A is a transmission electron microscope image of the tumor angiogenesis inhibitor-loaded lipid nanoparticle prepared in example 1, and fig. 1B is a particle size analysis image of the solid lipid nanoparticle standing at room temperature for 0h, 24h, 48h, showing that the solid lipid nanoparticle prepared in example 1 has better stability.
FIG. 2 is a time release profile of lipid nanoparticle encapsulated vandetanib in example 2.
FIG. 3 shows the Western blot detection results of the expression of VEGFR1 and VEGFR2, which are related to the angiogenesis and normalization of the cells loaded with lipid nanoparticles of Vandanix, by using human umbilical vein endothelial cells as model cells in example 3; fig. 3A is an Image result obtained by performing chemiluminescence and exposure on a protein band obtained by a Western blot experiment, fig. 3B is an Image J quantitative Western blot experiment analysis result of an expression level of a vascular normalization-related protein VEGFR1, and fig. 3C is an Image J quantitative Western blot experiment analysis result of an expression level of a vascular generation-related protein VEGFR 2. SLN-1 and SLN-2 are a plurality of lipid-coated solid lipid nanoparticles (lecithin-triolein nanoparticles) and a single lipid-coated solid lipid nanoparticle (glyceryl monostearate nanoparticles), respectively.
FIG. 4 is an immunofluorescence image of the vascular system in tumor tissue after pro-tumor vascular normalization of solid lipid nanoparticles in example 4. CD31 marks the blood vessel, characterizes the morphology of the blood vessel, and alpha smooth muscle actin (alpha-SMA) characterizes perivascular cell coverage. FIG. 4A is a representative image of immunofluorescence experiments taken with a confocal microscope; FIG. 4B shows the quantitative results of the CD31 positive expression region; FIG. 4C is a graph showing the quantitative results of the co-localized regions of CD31 and α -SMA.
Detailed Description
The invention is further described with reference to the drawings and examples.
Embodiment one: preparation of monoglyceride nanoparticle loaded with tumor angiogenesis inhibitor
48mg of glyceryl monostearate (monoglyceride) is dissolved in 2ml of ethanol, 4.8mg of vandetanib is dissolved in 1ml of ethanol, the two solutions are mixed to form an organic phase, the organic phase is added into the aqueous phase under the stirring condition of 400rpm at 60 ℃, the stirring is carried out for 5min, the ethanol is removed by dialysis for 24h, and the solid lipid nanoparticle is obtained by freeze drying.
Physicochemical properties of the tumor angiogenesis promoting normalized solid lipid nanoparticles prepared from monoglyceride and vandetanib in different proportions (w/w) are shown in Table 1. Example one shows that: the weight percentage of the anti-angiogenesis agent and the lipid is in the range of 5-25%, so that solid lipid nanoparticles can be formed.
TABLE 1 particle size, potential and encapsulation efficiency of tumor-promoting vascular normalization monoglyceride nanoparticles prepared from monoglyceride in different proportions
Embodiment two: preparation of composite lipid nanoparticle loaded with tumor angiogenesis inhibitor
Firstly, 102mg of lecithin and 34mg of triolein are weighed and dissolved in ethanol to form an organic phase, the organic phase is added into an aqueous phase under the stirring condition of 60 ℃ and 400rpm, a probe is used for ultrasonic preparation of microemulsion, after ethanol is removed by rotary evaporation, ultrasonic dispersion is carried out in a water bath for 30min, and then, solid lipid powder is obtained by freeze drying.
30mg of the solid lipid powder obtained above was weighed and redispersed in water, and sonicated in a water bath for 30min to obtain a water phase. Then 6mg of vandetanib is weighed and dissolved in dimethyl sulfoxide to obtain an organic phase; adding the organic phase into the water phase under stirring at 60deg.C and 400rpm, stirring for 30min, dialyzing for 24 hr to remove dimethyl sulfoxide, and lyophilizing to obtain solid lipid nanoparticle. The transmission electron microscope and the particle size measurement result of the prepared tumor-promoting vascular normalization lipid nanoparticle are shown in figure 1.
The second example shows that the preparation method of the invention can obtain solid composite lipid nano particles with complete structure and uniform particle size.
Embodiment III: in vitro drug release behavior study of lipid nanoparticles loaded with anti-angiogenic agents
A volume of aqueous lipid nanoparticle (SLN) dispersion was removed and placed in a dialysis bag (MWCO 3.5k Da) and placed in a release tube containing 25ml of release medium (pH 7.2 phosphate buffer). In vitro release was performed at 37℃with constant temperature shaking at 65rpm, samples were taken at specific time points (0.25 h, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h,24h and 48 h) while the entire release medium was replaced. The cumulative release amount and the cumulative release percentage of the drug were calculated by measuring the concentration of the drug in the sample by fluorescence spectrophotometry (ex=329 nm, em=372 nm, slit=10 nm, operating voltage=700V). The results are shown in FIG. 2. The lipid encapsulation achieves a slow release of the anti-angiogenic agent. The third embodiment shows that the solid lipid nanoparticle provided by the invention has the function of slowly releasing the anti-angiogenesis agent.
Embodiment four: in vitro pharmacodynamic investigation of lipid nanoparticles loaded with anti-angiogenic agents
Western blot was used to examine the effect of solid lipid nanoparticles on the expression of thrombopoietin in Human Umbilical Vein Endothelial Cells (HUVECs). First, according to 10 5 Cell Density of individual cells/mL cell fluid HUVECs were seeded onto 6 well cell plates at 37℃in 5% CO 2 The cells were cultured overnight in a cell incubator. Next, a high and low concentration drug solution and a lipid nanoparticle dispersion were prepared, the dilution medium was RPMI 1640 medium, and the required high and low drug concentrations were 4 and 16. Mu.g/mL, respectively. Then, 6-well cell plates were removed from the incubator, the culture medium was aspirated, each well was rinsed once with 500. Mu.L of phosphate buffer solution, the phosphate buffer solution was aspirated again, the corresponding liquid was added to each well, 3 duplicate wells were placed in parallel, and the wells were placed at 37℃and 5% CO 2 Culturing in a cell culture box for 48 hours. Then, 6-well cell plates were removed from the incubator, cells were lysed by adding RIPA lysate, and total protein numbers of all samples were quantified using BCA, followed by detection of angiogenesis-related protein VEGFR1, VEGFR2 protein expression in HUVEC cells using Western blot experiments, and quantitative analysis using Image J. As shown in FIG. 3, both the multiple lipid coated solid lipid nanoparticle (SLN-1) and the single lipid coated solid lipid nanoparticle (SLN-2) were effective in inhibiting HUVEC cell angiogenesis-related protein expression. The fourth embodiment shows that the tumor-promoting angiogenesis-normalized solid lipid nanoparticle provided by the invention can regulate the change of the expression level of angiogenesis-related proteins at the cell level and promote the angiogenesis-related eggsWhite expression, inhibiting angiogenesis-related protein expression, and has in vitro angiogenesis promoting effect.
Fifth embodiment: in vivo pharmacodynamic investigation of anti-angiogenic agent loaded lipid nanoparticles
Balb/c mice with 4T1 breast cancer as model animal, and the tumor grows to 100mm 3 The random average is divided into 4 groups: normal saline (Control), 3mg/kg of vandetanib prototype drug (V-1) per single administration, 3mg/kg of vandetanib prototype drug (V-4) per multiple administration, 30mg/kg of solid lipid nanoparticle (NP-H) per single administration, 3mg/kg of nanoparticle (NP-H) per single administration. The administration time of the single administration group was recorded as day 1, and the multiple administration groups were administered on days 1, 3, 5, and 7. On days 2, 4, 6, 8, 4 groups of mice were sacrificed using standard procedures and tumor samples were dissected. Using tissue Immunofluorescence (IF) technique, after frozen section treatment, using fluorescent dye to mark blood vessel related protein CD31 and alpha-SMA laser confocal microscope scanning record section staining result, using Image J software to analyze CD31 positive region to characterize micro blood vessel in tumor tissue, and co-localization region of CD31 and alpha-SMA to characterize pericyte coated complete mature blood vessel, as blood vessel normalization index, examining time-varying change after administration of tumor vascular system, evaluating time duration of tumor blood vessel normalization window period, and the result is shown in figure 4. The breast cancer is one of the common classical models of solid tumors, and has high reference value for the treatment research of the solid tumors. The fifth embodiment shows that the tumor vessel normalization promoting solid lipid nanoparticle prolongs the window period of tumor vessel normalization and has the function of promoting tumor vessel normalization in vivo.
Claims (4)
1. A process for preparing the solid nano-particles for promoting the normalization of tumor blood vessel features that the anti-angiogenesis inhibitor medicine is used as core, one or more lipid materials are coated on the surface of said core,
(1) Dissolving a lipid material in an organic solvent to obtain an organic phase;
(2) Injecting the organic phase obtained in the step (1) into water under the heating condition, stirring, probe ultrasonic treatment, rotary evaporation, water bath ultrasonic dispersion and freeze drying to obtain solid lipid powder;
(3) Redispersing the solid lipid powder obtained in the step (2) in water to obtain a water phase;
(4) Dissolving a fat-soluble anti-angiogenesis inhibitor in an organic solvent to obtain an organic phase; the anti-angiogenesis inhibitor is vandetanib, sunitinib or sorafenib;
(5) Injecting the organic phase obtained in the step (4) into an aqueous phase under the heating condition, and obtaining the solid lipid nanoparticle for promoting the normalization of tumor blood vessels through stirring, centrifugation and freeze drying;
the weight of the lipid material coated on the surface is 4-20 times of that of the loaded medicine, and the particle size is 100-800 nm.
2. The method for preparing solid lipid nanoparticles according to claim 1, wherein the lipid material is glyceryl monostearate, lecithin, stearic acid or glyceryl trioleate.
3. The method for preparing solid lipid nanoparticles according to claim 1, wherein the organic solvent is dimethyl sulfoxide, methanol, N-dimethylformamide or ethanol.
4. The use of the tumor angiogenesis promoting solid lipid nanoparticles prepared by the method of claim 1 in the preparation of anti-tumor therapeutic drugs, wherein the tumor is a solid tumor, and the tumor is a solid tumor with angiogenesis phenomena and abnormal vascular systems.
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