CN114081953A - Prodrug dendrimer nano-carrier and preparation method and application thereof - Google Patents

Prodrug dendrimer nano-carrier and preparation method and application thereof Download PDF

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CN114081953A
CN114081953A CN202111217352.9A CN202111217352A CN114081953A CN 114081953 A CN114081953 A CN 114081953A CN 202111217352 A CN202111217352 A CN 202111217352A CN 114081953 A CN114081953 A CN 114081953A
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颜廷胜
刘忠华
许淼
胡岚馨
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Northeast Agricultural University
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Abstract

A prodrug dendrimer nano-carrier and a preparation method and application thereof belong to the field of nano-drug carrier materials, and the nano-carrier is prepared by a step-by-step condensation method, hydrophobic self-assembly and crosslinking reaction. The system has multifunctional targeting molecular ligands, and the targeting ligands can be used as targeting elements to improve the active targeting capability of the carrier and can also be used as size conversion elements to improve the penetration capability of the drug tumor. The drug delivery system can change local microenvironment of the tumor through primary drug release, thereby triggering secondary drug release and realizing cascade treatment of the tumor. Aiming at multiple biological barriers and complex dynamic microenvironments in the drug delivery process, the invention adopts the methods of multiple targets, size conversion and drug graded release, and is expected to realize accurate and efficient image-guided tumor cascade amplification treatment.

Description

Prodrug dendrimer nano-carrier and preparation method and application thereof
Technical Field
The invention belongs to the field of nano-drug carrier materials, and particularly relates to a prodrug dendrimer nano-carrier as well as a preparation method and application thereof.
Background
Limited tumor penetration and ineffective cellular internalization are important factors limiting tumor drug therapy. Small size nanoparticles have a greater chance of overcoming the interstitial transport barrier and diffusing deep into tumor tissue. However, they have difficulty in achieving satisfactory drug delivery due to the extravasation phenomenon of tumor vessels and poor pharmacokinetic profile. Particles with too small a particle size are likely to be cleared by renal excretion, and large-sized nanoparticles, while bypassing renal clearance, are generally weak in their tumor penetration capacity. Size-convertible Drug Delivery Systems (DDS) can be used to solve the above problems, and research groups have reported that "trojan horse" nanoparticles, which are double size/charge-convertible, can maintain a large size in the blood circulation to improve stability; after reaching the tumor part, the nano-particle can be rapidly decomposed into ultra-small nano-particles, and the tumor penetration capability of the nano-preparation is effectively improved. Multiple studies show that the DDS with the naked boric acid group can be combined with sialic acid excessively expressed on the surface of brain tumor cells, and the combination and the effective internalization of the brain tumor cells are improved. However, the cascade activation mechanism of these vectors needs to be perfected to fully develop their potential in tumor therapy.
Cascade amplification therapy can be used to synergize the therapeutic effect between different agents to achieve complementary therapeutic effects. Possible mechanisms for combining these approaches include: regulating ROS stress; secondly, inhibiting a repair mechanism of DNA damage induced by radioactive rays; and relieving tumor hypoxia. The use of pegylated hollow tantalum oxide (H-TaOx) nanoshells to encapsulate the anti-cancer drug 7-ethyl-10-hydroxycamptothecin (SN-38) has been investigated for chemical/radiation cascade treatment of tumors. SN-38 can induce not only apoptosis of tumor cells by inhibiting topoisomerase I, but also cell cycle arrest and force tumor cells into the radiation sensitive phase. By combining the energy deposition capability of Ta atoms and the radiosensitization effect of SN-38, the nano platform can obviously improve the efficacy of subsequent radiotherapy. The sequential interaction between PDT and chemotherapy, in addition to direct destruction of tumor cells, the ROS produced can also destroy key proteins such as P-glycoprotein (P-gp) associated with drug resistance development.
Target-specific release and activation are key to the success of cascade amplification therapy, and the abnormal metabolism of tumors creates a specific microenvironment that provides the possibility for the release and activation of drugs. However, the microenvironment is constantly changed during the tumor development process, and the novel DDS not only needs to adapt to the tumor microenvironment, but also needs to enhance the controllability of drug release and cascade activation by regulating the physiological state of the tumor.
Disclosure of Invention
The invention provides a prodrug dendrimer nano-carrier and a preparation method and application thereof aiming at the defects in the background technology, and the nano-carrier has the characteristics of high drug loading capacity, multiple targeting, variable size, good biocompatibility and the like; also has the performance of size conversion and drug graded release, and is expected to realize accurate and efficient brain tumor cascade treatment guided by images.
The prodrug dendrimer diagnosis and treatment platform is constructed aiming at multiple physiological barriers and complex dynamic microenvironments in the tumor drug delivery process, and can be applied to the visual cascade amplification treatment of various tumors.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a prodrug dendrimer nanocarrier, the prodrug dendrimer nanocarrier having the following structural formula:
Figure BDA0003311261970000021
a preparation method of the prodrug dendrimer nano-carrier specifically comprises the following steps: the nano-carrier is prepared from an anti-tumor prodrug dendrimer modified by a bifunctional ligand by a self-assembly method; the antineoplastic prodrug dendrimer is formed by covalently bonding a basic dendritic block polymer and a borated modified diagnosis and treatment reagent through a phosphate ester bond.
Specifically, the method comprises the following steps:
the method comprises the following steps: synthesis of polyethylene glycol-lysine base block polymer Lys by using N, N' -diisopropylcarbodiimide and 1-hydroxybenzotriazole systemm-PEG-LysnWherein m is 1-20, n is 1-20, and the molecular weight of PEG is 1-20 KDa;
step two: coupling Lysm-PEG-LysnOne end of the polymer is connected with 3, 4-dihydroxy benzoic acid cathechol to obtain cathechol2m-Lysm-PEG-Lysn-Fmoc dendrimer, wherein m is 1-20;
step three: reacting anticancer drug or prodrug molecule containing boric acid group with Catechol2m-Lysm-PEG-Lysn-Fmoc reaction in dichloromethane solution, wherein the molar ratio of anticancer drug or prodrug molecule to block polymer is 2 m-4 m: 1, obtaining an amphiphilic prodrug dendrimer PD based on a boronic ester linkage2m-Catechol2m-Lysm-PEG-Lysn-Fmoc；
Step four: modifying the bifunctional ligand, specifically, reacting the compound containing the boric acid group with PD through an amido bond2m-Catechol2m-Lysm-PEG-LysnCoupling Lys tail end of Fmoc to obtain bifunctional ligand modified antitumor prodrug dendrimer PD2m-PEG-Lysn-BA2nWherein m is 1-20, n is 1-20; reacting a compound containing an ortho-dihydroxy group with PD through an amide bond2m-Catechol2m-Lysm-PEG-LysnCoupling Lys tail end of Fmoc to obtain bifunctional ligand modified antitumor prodrug dendrimer PD2m-PEG-Lysn-DH2nWherein m is 1-20, n is 1-20; dialyzing the obtained two prodrug dendrimers, and freeze-drying;
step five: will PD2m-PEG-Lysn-BA2nAnd PD2m-PEG-Lysn-DH2nMixing and dissolving in a polar solvent, and preparing the borate crosslinking integrated nano-carrier by utilizing solvent volatilization or reprecipitation.
An application of the prodrug dendrimer nano-carrier in tumor cascade therapy.
Compared with the prior art, the invention has the beneficial effects that:
(1) the drug delivery system has a multifunctional targeting molecule ligand. The targeting ligands can be used as targeting elements to improve the active targeting capability of a carrier system; on the other hand, they can be used as elements for size conversion of the carrier system. Under the physiological condition of normal tissues, a stable cross-linking state is maintained, and the stability in blood circulation is improved; when they reach the tumor tissue, the sensitive bonds are broken under the stimulation of local microenvironment, and the carrier releases the ultra-small nano particles to improve the infiltration capacity of the tumor.
(2) Functionalization of carrier prodrug structural molecules. The polymer forming the main component of the carrier contains prodrug active ingredients, and the prodrug active ingredients are used as diagnostic and therapeutic agents and play roles in imaging and inhibiting tumor growth after the prodrug is activated; in the self-assembly process, the polymer can be used as a hydrophobic core to maintain the stable state of the carrier.
(3) The drug delivery system can change local microenvironment of the tumor through primary drug release, thereby triggering secondary drug release and realizing cascade treatment of the tumor.
Drawings
FIG. 1 is a schematic diagram of the process for preparing prodrug dendrimer nanocarriers;
FIG. 2 is a particle size distribution diagram of DOX prodrug dendrimer nanocarriers;
FIG. 3 is a transmission electron micrograph of DOX prodrug dendrimer nanocarriers.
Detailed Description
The technical solution of the present invention is further described below with reference to the embodiments and the drawings, but the present invention is not limited thereto, and any modification or equivalent replacement of the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention should be covered by the protection scope of the present invention.
The prodrug dendrimer nano carrier is prepared by a step-by-step condensation method, hydrophobic self-assembly and crosslinking reaction. The system has multifunctional targeting molecular ligands, and the targeting ligands can be used as targeting elements to improve the active targeting capability of the carrier and can also be used as size conversion elements to improve the penetration capability of the drug tumor. The drug delivery system can change local microenvironment of the tumor through primary drug release, thereby triggering secondary drug release and realizing cascade treatment of the tumor. Aiming at multiple biological barriers and complex dynamic microenvironments in the drug delivery process, the invention adopts the methods of multiple targets, size conversion and drug graded release, and is expected to realize accurate and efficient image-guided tumor cascade amplification treatment.
The first embodiment is as follows: the present embodiment describes a prodrug dendrimer nanocarrier, wherein the structural formula of the prodrug dendrimer nanocarrier is as follows:
Figure BDA0003311261970000041
the second embodiment is as follows: a method for preparing a prodrug dendrimer nanocarrier according to the first embodiment, the method comprising: the nano-carrier is prepared from an anti-tumor prodrug dendrimer modified by a bifunctional ligand by a self-assembly method; the antineoplastic prodrug dendrimer is formed by covalently bonding a basic dendritic block polymer and a borated modified diagnosis and treatment reagent through a phosphate ester bond.
The third concrete implementation mode: the method for preparing a prodrug dendrimer nanocarrier according to the second embodiment comprises the following steps:
the method comprises the following steps: using N, N' -diisopropylcarbodiimide and 1-hydroxybenzotriazole (DI)C/HOBt) system, synthesis of polyethylene glycol-lysine base block polymer Lysm-PEG-LysnWherein m is 1-20, n is 1-20, and the molecular weight of PEG is 1-20 KDa;
step two: coupling Lysm-PEG-LysnOne end of the polymer is connected with 3, 4-dihydroxy benzoic acid cathechol to obtain cathechol2m-Lysm-PEG-Lysn-Fmoc dendrimer, wherein m is 1-20;
step three: reacting anticancer drug or prodrug molecule containing boric acid group with Catechol2m-Lysm-PEG-Lysn-Fmoc reaction in dichloromethane solution, wherein the molar ratio of anticancer drug or prodrug molecule to block polymer is 2 m-4 m: 1, obtaining an amphiphilic prodrug dendrimer PD based on a boronic ester linkage2m-Catechol2m-Lysm-PEG-LysnFmoc (abbreviated PD)2m-PEG-Lysn-Fmoc)；
Step four: modifying the bifunctional ligand, specifically, reacting the compound containing the boric acid group with PD through an amido bond2m-Catechol2m-Lysm-PEG-LysnCoupling Lys tail end of Fmoc to obtain bifunctional ligand modified antitumor prodrug dendrimer PD2m-PEG-Lysn-BA2n(abbreviated as PD)2m-PEG-BA2n) Wherein m is 1-20, n is 1-20; reacting a compound containing an ortho-dihydroxy group with PD through an amide bond2m-Catechol2m-Lysm-PEG-LysnCoupling Lys tail end of Fmoc to obtain bifunctional ligand modified antitumor prodrug dendrimer PD2m-PEG-Lysn-DH2n(abbreviated as PD)2m-PEG-DH2n) Wherein m is 1-20, n is 1-20; dialyzing the obtained two prodrug dendrimers, and freeze-drying;
step five: will PD2m-PEG-Lysn-BA2nAnd PD2m-PEG-Lysn-DH2nMixing and dissolving in a polar solvent, and preparing the borate crosslinking integrated nano-carrier by utilizing solvent volatilization or reprecipitation.
Wherein the solvent volatilization method specifically comprises the following steps: the mixed solution dissolved in the polar solvent was transferred to a round-bottom flask. The solvent was evaporated under vacuum to form a thin film. Thereafter, 1-5 mL of Phosphate Buffered Saline (PBS) buffer was added to rehydrate the film, followed by 3 minutes of sonication. After self-assembly in PBS, boronic ester linkages are formed between BA and DH of adjacent terminal dendrimers, resulting in the formation of crosslinked nanoparticles.
The reprecipitation method specifically comprises: and (3) sucking a certain amount of mixed solution by using a micro-injector, slowly dripping the mixed solution into the PBS buffer solution, and continuously stirring for 2-8 hours. The obtained nanoparticles were dialyzed and then freeze-dried.
The fourth concrete implementation mode: the preparation method of the prodrug dendrimer nano-carrier in the third embodiment comprises the following steps: coupling of (Fmoc) Lys (Boc) -OH to NH Using N, N' -diisopropylcarbodiimide and 1-hydroxybenzotriazole (DIC/HOBt) as coupling reagents2-PEG-NH2Adding cold ether to precipitate the pegylated molecule, and then washing twice with cold ether; treating with Dimethylformamide (DMF) solution containing 5-50% (v/v) 4-methylpiperidine to remove Fmoc group, and washing with cold ether for 3 times; vacuum drying the white powder, performing 1-3 times (Fmoc) Lys (Boc) -OH coupling and 3-10 times (Fmoc) Lys (Fmoc) -OH coupling, respectively, to produce Fmoc-Lys of dendrimer end-capped with Fmoc groupm-PEG-Lysn-Fmoc, wherein m is 1-20, n is 1-20, and the molecular weight of PEG is 1-20 KDa.
The fifth concrete implementation mode: in the third step of the preparation method of the prodrug dendrimer nanocarrier according to the third embodiment, the anticancer drug R containing a boronic acid group includes but is not limited to one of bortezomib, boronic acid-modified doxorubicin, or boronic acid-modified pheophorbide a.
The sixth specific implementation mode: the preparation method of the prodrug dendrimer nano-carrier in the third specific embodiment comprises the fourth step, wherein the bifunctional ligand has tumor targeting and cross-linking self-assembly performance. The compound containing boric acid groups is one or more of 2-carboxyphenylboronic acid, 3-carboxyphenylboronic acid, 4-carboxyphenylboronic acid or 3-carboxy-5-nitrophenylboronic acid; the compound containing the o-dihydroxy group is one or more of 3, 4-dihydroxy benzoic acid, maltobionic acid or sialic acid.
The seventh embodiment: in the fifth step, the polar solvent is one or more of dimethylformamide, methanol, ethanol, acetone, isopropanol, pyridine, n-butanol, or tetrahydrofuran; the PD2m-PEG-Lysn-BA2nAnd PD2m-PEG-Lysn-DH2nThe mass ratio of (1): 0.1 to 10.
The specific implementation mode is eight: an application of the prodrug dendrimer nano-carrier in tumor cascade therapy.
The specific implementation method nine: the prodrug dendrimer nano carrier respectively encapsulates hydrophilic and hydrophobic reagents in a super-small nanoparticle hydrophobic core and a cross-linked cavity by a layered encapsulation method or a one-pot method.
The detailed implementation mode is ten: the prodrug dendrimer nanocarrier according to embodiment nine is used in tumor cascade therapy, wherein the hydrophilic agent is one of indocyanine green (ICG), Cabazitaxel (CBA) or doxorubicin hydrochloride (DOX · HCl), cy7.5, DiD or gadopentetic acid; the hydrophobic agent is one of Methotrexate (MTX), Camptothecin (CPT), beta-lapachone, Vincristine (VCR) or Paclitaxel (PTX).
The specific method for encapsulating the hydrophilic and hydrophobic reagent comprises the following steps: dissolving a hydrophilic reagent A in ultrapure water at room temperature, wherein the concentration range is 0.1-10 mg/mL; then PD is2m-PEG-BA2nAnd PD2m-PEG-DH2nAccording to the following steps: 0.1 to 10 (wherein the mass of the hydrophilic agent A does not exceed PD)2m-PEG-BA2nAnd PD2m-PEG-DH2n50 percent of the total mass of the two components) are mixed and dissolved in the solution; carrying out ultrasonic treatment for 1-10 minutes, transferring the mixture into a round-bottom flask, and evaporating water in vacuum to form a thin film alpha; go toDissolving a hydrophobic reagent B in anhydrous chloroform, wherein the concentration range is 0.1-10 mg/mL; uniformly dispersing the film alpha into anhydrous chloroform dissolved with a hydrophobic reagent B (wherein the mass of the hydrophobic reagent B is not more than 40% of the mass of the film alpha), and performing vacuum evaporation to form a film beta; then, adding 1-5 mL of Phosphate Buffered Saline (PBS) buffer solution to rehydrate the film, and carrying out ultrasonic treatment for 3-8 minutes; transferring the drug-loaded nanoparticle solution into a centrifugal filter tube (molecular weight cut-off (MWCO): 3-5 kDa), and carrying out centrifugal filtration at 6000-10000 rpm to remove the unloaded free reagent.
Example 1:
preparation of Bortezomib (BTZ) prodrug dendrimer nanocarrier (figure 1)
(1) The preparation concentration is 0.25mMNH2-PEG2000-NH2The solution (2) was added with 4 times (molar ratio) of N, N' -diisopropylcarbodiimide and 1-hydroxybenzotriazole (DIC/HOBt) coupling reagent and 4 times (molar ratio) of (Fmoc) Lys (Boc) -OH to conduct coupling reaction for 120 minutes. After the reaction was complete, cold ether was added to precipitate the pegylated molecule, which was then washed twice with cold ether. The Fmoc group was removed by treatment with 10% (v/v) 4-methylpiperidine in Dimethylformamide (DMF) and washed again with cold ether 3 times. The white powder was dried in vacuo and subjected to 3 (Fmoc) Lys (Boc) -OH couplings and 1 (Fmoc) Lys (Fmoc) -OH couplings, respectively, to yield a dendrimer terminated with Fmoc group (Fmoc-Lys)8-PEG2000-Lys8-Fmoc)。
(2) Fmoc-Lys8-PEG2000-Lys8-Fmoc wherein 3, 4-dihydroxybenzoic acid (Catechol) is attached at one terminus to obtain Catechol16-Lys8-PEG2000-Lys8-Fmoc dendritic block polymers.
(3) Mixing bortezomib with Catechol16-Lys8-PEG2000-Lys8Fmoc reaction in dichloromethane solution (Bortezomib with Catechol)16-Lys8-PEG2000-Lys8Fmoc molar ratio 32:1) to obtain amphiphilic prodrug dendrimer based on boronate ester linkage (BTZ)16-PEG2000-Lys8-Fmoc)。
(4) 4-carboxyphenylboronic acid is reacted with BTZ through an amide bond16-PEG2000-Lys8Lys-terminal coupling of Fmoc to obtain BTZ16-PEG2000-CPA16(4-Carboxyphenylboronic acid with BTZ16-PEG2000-Lys8-Fmoc molar ratio 20: 1) and dialyzing to remove unreacted reagents, and freeze-drying.
(5) Reacting 3, 4-dihydroxy benzoic acid with BTZ through amido bond16-PEG2000-Lys8Lys-terminal coupling of Fmoc to obtain BTZ16-PEG2000-DDA16(3, 4-Dihydroxybenzoic acid and BTZ16-PEG2000-Lys8-Fmoc molar ratio 20: 1) and dialyzing to remove unreacted reagents, and freeze-drying.
(6) Mixing BTZ16-PEG2000-CPA16And BTZ16-PEG2000-DDA16According to the mass ratio of 1: 1 mix dissolved in DCM and transferred to a round bottom flask. The solvent was evaporated under vacuum to form a thin film. Thereafter, 5mL of Phosphate Buffered Saline (PBS) buffer was added to rehydrate the film, followed by sonication for 3 minutes. After self-assembly in PBS, crosslinked nanoparticles were formed. The cross-linked nanoparticles prepared by the embodiment have narrow particle size distribution, and the average particle size is 150 +/-20 nm. The nanoparticles were dispersed in DMEM medium containing 10% Fetal Bovine Serum (FBS) and incubated for 72h at 37 ℃ without significant change in particle size. The nano-particles synthesized by the method have good biocompatibility, and do not show obvious toxic effect on HUVEC cells in the concentration range lower than 1mg/mL in vitro. IC of nanoparticles on K-562 cells50The value was 2.5. mu.g/mL (BTZ equivalent).
Example 2:
preparation of boric acid modified Adriamycin (DOX) prodrug dendrimer nanocarrier (FIGS. 2 and 3)
This example is different from example 1 in that bortezomib in step (3) of example 1 described above was replaced with boric acid-modified doxorubicin. Boric acid modified adriamycin and cathechol16-Lys8-PEG-Lys8Of Fmoc reactionThe molar ratio is 28: 1.
The boric acid modified adriamycin prodrug dendrimer nanoparticle prepared by the embodiment has the average particle size of 100-130 nm and is in a spherical or ellipsoidal aggregation state. The nanoparticles were dispersed in PBS and incubated for 28 days at 37 ℃ without significant change in particle size. The nanoparticles have good biocompatibility, and do not show obvious toxic effect on HUVEC cells in a concentration range lower than 1 mg/mL. The IC50 value of nanoparticles to HepG2 cells was 2.8. mu.g/mL (DOX equivalent). The Mean Residence Time (MRT) value of DOX in vivo in the boronic acid-modified DOX prodrug dendrimer nanocarrier was nearly 10-fold longer than free DOX. The elimination rate constant (Kel) value decreased to 1/10, demonstrating that the vehicle was effective in prolonging the residence time of the drug in the blood circulation.
Example 3:
CPT encapsulation by bortezomib prodrug dendrimer nanocarriers
Under the condition of room temperature, BTZ is mixed16-PEG2000-CPA16And BTZ16-PEG2000-DDA16According to the mass ratio of 1: 1 mix dissolved in DCM and transferred to a round bottom flask. Evaporating the solvent under vacuum to form a thin film α; CPT was dissolved in anhydrous chloroform at a concentration of 5 mg/mL. The film alpha is uniformly dispersed into anhydrous chloroform dissolved with a hydrophobic reagent B, and vacuum evaporation is carried out to form a film beta. Thereafter, 5mL of Phosphate Buffered Saline (PBS) buffer was added to rehydrate the film, and sonication was performed for 8 minutes. The drug-loaded nanoparticle solution was transferred to a centrifugal filter tube (molecular weight cut-off (MWCO): 3kDa) and centrifuged at 8000rpm to remove the free reagent not loaded. The drug loading rate of the nano particles prepared by the embodiment on CPT can reach more than 30%. At H2O2In PBS (phosphate buffer solution) with the concentration of 0.01mM, the release amount of the cross-linked nano particles to CPT is kept extremely low within 48 h; at H2O2The amount of ICG48h released from the crosslinked nanoparticles was 75.3% in PBS at a concentration of 1.00 mM.
Example 4:
encapsulation of indocyanine green (ICG) by bortezomib prodrug dendrimer nanocarriers
ICG was dissolved in ultrapure water at room temperature to a concentration of 1 mg/mL. Then BTZ is added16-PEG2000-CPA16And BTZ16-PEG2000-DDA16According to the mass ratio of 2:1 mix and dissolve in the above solution and transfer to round bottom flask. The solvent was evaporated under vacuum to form a thin film. 5mL of Phosphate Buffered Saline (PBS) buffer was added to rehydrate the film and sonication was performed for 8 minutes. The drug-loaded nanoparticle solution was transferred to a centrifugal filter tube (molecular weight cut-off (MWCO): 2kDa) and centrifuged at 8000rpm to remove the free reagent not loaded. The drug loading of the nanoparticles prepared by the embodiment on ICG can reach more than 35%. At H2O2In PBS (phosphate buffer solution) with the concentration of 0.01mM, the release amount of the cross-linked nano particles to ICG is kept extremely low within 48 h; at H2O2The amount of ICG48h released by the crosslinked nanoparticles was 89.3% in PBS at a concentration of 1.00 mM.
Example 5:
co-encapsulation of DOX & HCl and PTX by bortezomib prodrug dendrimer nanocarriers
DOX & HCl was dissolved in ultrapure water at room temperature to a concentration of 2 mg/mL. Then BTZ is added16-PEG2000-CPA16And BTZ16-PEG2000-DDA16According to the mass ratio of 9: 1 mixing and dissolving in the solution. Ultrasonic treatment is carried out for 5 minutes, the mixture is transferred into a round-bottom flask, and water is evaporated in vacuum to form a thin film alpha; PTX was further dissolved in anhydrous chloroform in a concentration range of 1 mg/mL. The thin film α was uniformly dispersed in anhydrous chloroform in which PTX was dissolved, and evaporated in vacuo to form a thin film β. Thereafter, 5mL of Phosphate Buffered Saline (PBS) buffer was added to rehydrate the film, and sonication was performed for 5 minutes. The drug-loaded nanoparticle solution was transferred to a centrifugal filtration tube (molecular weight cut-off (MWCO): 5kDa) and centrifuged at 10000rpm to remove the free reagent that was not loaded. The drug loading of the nanoparticles prepared in the embodiment on DOX & HCl and PTX respectively reaches more than 20% and 25%. At H2O2In Simulated Body Fluid (SBF) at a concentration of 0.01mM, only 12.7% DOX and 13.6% PTX were released upon incubation for 48 h. At 10mMH2O2Under stimulation, the bortezomib prodrug dendrimer nano-carrier can rapidly release the loaded drug, and after incubation for 48 hours, the release amount of DOX is 89.5%, and the release amount of PTX is 84.3%.

Claims (10)

1. A prodrug dendrimer nanocarrier, comprising: the structural formula of the prodrug dendrimer nanocarrier is as follows:
Figure FDA0003311261960000011
2. a method of preparing the prodrug dendrimer nanocarrier of claim 1, wherein: the method specifically comprises the following steps: the nano-carrier is prepared from an anti-tumor prodrug dendrimer modified by a bifunctional ligand by a self-assembly method; the antineoplastic prodrug dendrimer is formed by covalently bonding a basic dendritic block polymer and a borated modified diagnosis and treatment reagent through a phosphate ester bond.
3. The method of claim 2, wherein the prodrug dendrimer nanocarriers are selected from the group consisting of: the method comprises the following steps:
the method comprises the following steps: synthesis of polyethylene glycol-lysine base block polymer Lys by using N, N' -diisopropylcarbodiimide and 1-hydroxybenzotriazole systemm-PEG-LysnWherein m is 1-20, n is 1-20, and the molecular weight of PEG is 1-20 KDa;
step two: coupling Lysm-PEG-LysnOne end of the polymer is connected with 3, 4-dihydroxy benzoic acid cathechol to obtain cathechol2m-Lysm-PEG-Lysn-Fmoc dendrimer, wherein m is 1-20;
step three: reacting anticancer drug or prodrug molecule containing boric acid group with Catechol2m-Lysm-PEG-LysnFmoc reaction in dichloromethane solution, wherein anticancer drug or prodrug molecule is polymerized with blockThe molar ratio of the substances is 2 m-4 m: 1, obtaining an amphiphilic prodrug dendrimer PD based on a boronic ester linkage2m-Catechol2m-Lysm-PEG-Lysn-Fmoc；
Step four: modifying the bifunctional ligand, specifically, reacting the compound containing the boric acid group with PD through an amido bond2m-Catechol2m-Lysm-PEG-LysnCoupling Lys tail end of Fmoc to obtain bifunctional ligand modified antitumor prodrug dendrimer PD2m-PEG-Lysn-BA2nWherein m is 1-20, n is 1-20; reacting a compound containing an ortho-dihydroxy group with PD through an amide bond2m-Catechol2m-Lysm-PEG-LysnCoupling Lys tail end of Fmoc to obtain bifunctional ligand modified antitumor prodrug dendrimer PD2m-PEG-Lysn-DH2nWherein m is 1-20, n is 1-20; dialyzing the obtained two prodrug dendrimers, and freeze-drying;
step five: will PD2m-PEG-Lysn-BA2nAnd PD2m-PEG-Lysn-DH2nMixing and dissolving in a polar solvent, and preparing the borate crosslinking integrated nano-carrier by utilizing solvent volatilization or reprecipitation.
4. The method of claim 3, wherein the prodrug dendrimer nanocarriers are selected from the group consisting of: the first step is specifically as follows: coupling (Fmoc) Lys (Boc) -OH to NH using N, N' -diisopropylcarbodiimide and 1-hydroxybenzotriazole as coupling reagents2-PEG-NH2Adding cold ether to precipitate the pegylated molecule, and then washing twice with cold ether; treating with a dimethylformamide solution containing 5-50% (v/v) 4-methylpiperidine to remove Fmoc groups, and washing with cold ether for 3 times; vacuum drying the white powder, performing 1-3 times (Fmoc) Lys (Boc) -OH coupling and 3-10 times (Fmoc) Lys (Fmoc) -OH coupling, respectively, to produce Fmoc-Lys of dendrimer end-capped with Fmoc groupm-PEG-Lysn-Fmoc, wherein m is 1-20, n is 1-20, and the molecular weight of PEG is 1-20 KDa.
5. The method of claim 3, wherein the prodrug dendrimer nanocarriers are selected from the group consisting of: in the third step, the anti-cancer drug R containing a boric acid group comprises but is not limited to one of bortezomib, boric acid modified adriamycin or boric acid modified pheophorbide A.
6. The method of claim 3, wherein the prodrug dendrimer nanocarriers are selected from the group consisting of: in the fourth step, the compound containing a boric acid group is one or more of 2-carboxyphenylboronic acid, 3-carboxyphenylboronic acid, 4-carboxyphenylboronic acid or 3-carboxy-5-nitrophenylboronic acid; the compound containing the o-dihydroxy group is one or more of 3, 4-dihydroxy benzoic acid, maltobionic acid or sialic acid.
7. The method of claim 3, wherein the prodrug dendrimer nanocarriers are selected from the group consisting of: in the fifth step, the polar solvent is one or more of dimethylformamide, methanol, ethanol, acetone, isopropanol, pyridine, n-butanol or tetrahydrofuran; the PD2m-PEG-Lysn-BA2nAnd PD2m-PEG-Lysn-DH2nThe mass ratio of (1): 0.1 to 10.
8. Use of the prodrug dendrimer nanocarrier of any of claims 1 to 7 in tumor cascade therapy.
9. The use of the prodrug dendrimer nanocarrier of claim 8 in tumor cascade therapy, wherein: the prodrug dendrimer nano carrier respectively encapsulates hydrophilic and hydrophobic reagents in a super-small nanoparticle hydrophobic core and a cross-linked cavity by a layered encapsulation method or a one-pot method.
10. The use of a prodrug dendrimer nanocarrier of claim 9 in tumor cascade therapy, wherein: the hydrophilic agent is one of indocyanine green, cabazitaxel or doxorubicin hydrochloride, Cy7.5, DiD or gadopentetic acid; the hydrophobic reagent is one of methotrexate, camptothecin, beta-lapachone, vincristine or paclitaxel.
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