CN116832031A - Responsive drug-loaded polymer, iron death nanoparticle, and preparation method and application thereof - Google Patents

Responsive drug-loaded polymer, iron death nanoparticle, and preparation method and application thereof Download PDF

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CN116832031A
CN116832031A CN202210301003.3A CN202210301003A CN116832031A CN 116832031 A CN116832031 A CN 116832031A CN 202210301003 A CN202210301003 A CN 202210301003A CN 116832031 A CN116832031 A CN 116832031A
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responsive
formula
polymer
drug
iron death
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于海军
王颖婕
周惠玲
刘小英
江幸羽
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Shanghai Institute of Materia Medica of CAS
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Abstract

The invention relates to a responsive drug-loaded polymer, iron death nanoparticles, and a preparation method and application thereof. The iron death nanoparticle comprises the following components: responsive artemisinin ester polymers, responsive phenylborate polymers and small molecule tumor iron death induction drugs; wherein, in the iron death nanoparticle, the responsive artemisinin ester polymer and the responsive phenylboronate polymer form a nano carrier, and small molecule tumor iron death induction drugs are physically loaded in an ultrasonic mode. The nanoparticle can be loaded with different small molecular drugs for inducing tumor to generate iron death, is enriched at a tumor part through the EPR effect, has good tumor tissue accumulation and retention capacity, can rupture a responsive sensitive group, and promotes the release of the entrapped tumor therapeutic drugs.

Description

Responsive drug-loaded polymer, iron death nanoparticle, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a responsive drug-loaded polymer, iron death nanoparticles formed by using the same, a preparation method thereof and application thereof in tumor treatment.
Background
Iron death is a novel form of cell death distinct from apoptosis, necrosis, etc., and is mainly the production of lethal levels of lipid reactive oxygen species within cells. In recent years, researchers have found that various small molecule drugs can act on the iron death pathway, and that the inhibition of the amino acid exchange pathway or the inhibition of the lipid peroxidation repair pathway induces the fatal accumulation of lipid peroxidation in tumors, thereby playing an important role in iron death in tumors.
However, small molecular drugs have the defects of difficulty in preparing medicines, short half-life, inability to accurately reach target organs, easy metabolism during in vivo circulation, easy generation of drug resistance of tumors due to repeated administration of small doses, and non-negligible toxic and side effects on normal organs due to large-dose administration, so that the selection of a proper drug delivery carrier is very important to achieve the purpose of accurate tumor administration.
In view of this, the present invention has been made.
Disclosure of Invention
One of the purposes of the present invention is to provide a responsive drug-carrying polymer.
The second object of the present invention is to provide a method for preparing the responsive drug-carrying polymer.
The invention further aims at providing iron death nanoparticles prepared from the responsive drug-carrying polymer.
The fourth object of the present invention is to provide a method for preparing the iron death nanoparticle.
The fifth object of the present invention is to provide an application of the iron death nanoparticle.
In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:
the first aspect of the present invention provides a responsive drug-carrying polymer of formula I,
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is an integer of 10 to 145, for example 10, 12, 15, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, preferably an integer of 100 to 130, further preferably 113;
y is an integer from 20 to 80, for example 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, preferably an integer from 55 to 70, more preferably 60;
z is an integer from 5 to 40, for example 5, 10, 15, 20, 25, 30, 35, 40, preferably an integer from 10 to 20, further preferably 15;
R 1 each independently an acid-sensitive group that is responsive to pH;
R 2 selected from C6-C12 alkylthio, substituted or unsubstituted C6-C12 aryl, said substituted substituents being selected from C1-C6 alkyl, C1-C6 alkylthio;
x is-L-A or-O- (CH) 2 ) n -R 3 ；
L is a linking group linking the polymer backbone to A;
each a is independently a group derived from an artemisinin derivative (preferably dihydroartemisinin and artesunate);
n is an integer from 1 to 6, preferably 1;
R 3 each independently is a pair H 2 O 2 Responsive ROS-sensitive groups.
In one placeIn some embodiments, R 1 Selected from the following groups:
wherein, the liquid crystal display device comprises a liquid crystal display device,indicating the connection location.
Preferably, R 1 Is N, N-diisopropylamino.
In some embodiments, R 2 Selected from the group consisting of C8-C12 alkylthio, phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkylthio substituted phenyl.
R 2 May be a functional group derived from the following RAFT (reversible addition-fragmentation chain transfer, reversible Addition-Fragmentation Chain Transfer Polymerization) polymeric chain transfer agent:
during the polymerization reaction, the RAFT polymerization chain transfer agent can be opened to be connected with other groups, and R is formed after the polymerization reaction 2 Is a RAFT polymerization chain transfer agent fragment.
Preferably, R 2 Is dodecylthio.
In some embodiments, X is-L-A, L is selected from the group consisting of groups represented by formula i1, formula i2, formula i3, and formula i 4:
wherein M is 1 、M 2 Each independently selected from alkylene groups having 1 to 4 carbon atoms;
R 4 、R 5 each independently selected from carbonyl (-C (=o) -), imino (-NH-), -O-;
preferably, M 1 And M 2 The same applies.
Preferably, L is selected from the following groups:
further preferably, L is
In some embodiments, X is-L-A, with A having the structure:
the formula I forms a responsive artemisinin ester polymer.
In some embodiments, X is O- (CH) 2 ) n -R 3 ，R 3 Phenylboronate groups, which are sensitive to ROS, have the following structure:
wherein R is 4 Selected from H, C-C6 alkyl, halogen (Cl, br, F) or NH 2 Preferably, R 4 Is H;
the formula I forms a type of responsive phenylboronate polymers.
In some embodiments, the responsive drug-carrying polymer of formula I is selected from the group consisting of responsive drug-carrying polymers of formula I-1 and responsive drug-carrying polymers of formula I-2:
wherein x, y,z、R 1 、R 2 、R 3 The definition of L, A is the same as before.
The responsive drug-carrying polymer of the formula I-1 comprises a polymer skeleton, a connecting group L and a small molecule group A derived from an artemisinin derivative, wherein the polymer skeleton, the connecting group L and the small molecule group A are connected with each other through a covalent bond, namely one end of the polymer skeleton is connected with the artemisinin derivative group A through the connecting group L through a covalent bond, specifically one end of the polymer skeleton is connected with one end of the connecting group L through a polymethacryloyl group in the polymer skeleton through a covalent bond, and the artemisinin derivative group is connected with the other end of the connecting group L through a hydroxyl group in dihydroartemisinin or a carboxyl group in artesunate through a covalent bond.
The polymer backbone of the responsive drug-carrying polymer of formula I-1 comprises the following segments: methoxy, polyethylene glycol, amido, RAFT polymerization chain transfer agent containing acid sensitive group R 1 And (3) a polyethyl methacrylate and a polymethacrylyl group.
The polymethacryloyl groups in the polymer backbone have a plurality of methacryloyl groups (the number of z), i.e. the polymer backbone has a plurality of methacryloyl ends, each of which is attached to one linking group L, each linking group L being in turn attached to one group a (dihydroartemisinin or artesunate group), so that the polymer backbone can be attached to a plurality of-L-a.
The responsive drug-loaded polymer of formula I-2 comprises the following fragments: methoxy, polyethylene glycol, amido, RAFT polymerization chain transfer agent containing acid sensitive group R 1 Is poly (ethyl methacrylate) containing ROS sensitive group R 3 Each methacrylate on the polymer backbone with R 3 Covalently linked.
In a preferred embodiment, the responsive drug-carrying polymer of formula I-1 is selected from the following polymers:
in a preferred embodiment, the responsive drug-carrying polymer of formula I-2 is selected from the following polymers:
the second aspect of the invention provides a preparation method of a responsive drug-carrying polymer of formula I, comprising the following steps:
1) NH is added to 2 -PEG-OCH 3 Chain transfer agent polymerized with RAFTAmidation reaction to obtain CH 3 O-PEG-NH-CO-RAFT polymerization chain transfer agent +.>
2) The CH is subjected to 3 O-PEG-NH-CO-RAFT polymerization chain transfer agent, R 1 Substituted ethyl methacrylateAnd a precursor of methylpropylenated L +.>RAFT polymerization reaction is carried out to obtain the high molecular polymer 1
3) Reacting the high molecular polymer 1 with dihydroartemisinin or artesunate to obtain a responsive medicine carrying polymer shown in the formula I-1;
in some embodiments, L isThe precursor of L is->
The third aspect of the invention provides a method for preparing a responsive drug-loaded polymer of formula I-2, comprising the steps of:
1) NH is added to 2 -PEG-OCH 3 Chain transfer agent polymerized with RAFTAmidation reaction to obtain CH 3 O-PEG-NH-CO-RAFT polymerization chain transfer agent +.>
2) The CH is subjected to 3 O-PEG-NH-CO-RAFT polymerization chain transfer agent, R 1 Substituted ethyl methacrylateAnd ring-opened glycidyl methacrylate to carry out RAFT polymerization reaction to obtain a high molecular polymer 2
3) Mixing the high molecular polymer 2 with phenylboronic acidAnd reacting to obtain the responsive drug-carrying polymer shown in the formula I-2.
The fourth aspect of the invention provides an iron death nanoparticle, which is formed by self-assembling a response type drug-carrying polymer of a formula I and a small molecule tumor iron death induction drug, preferably by self-assembling a response type drug-carrying polymer of a formula I-1, a response type drug-carrying polymer of a formula I-2 and a small molecule tumor iron death induction drug, and further preferably by a mass ratio of the response type drug-carrying polymer of the formula I-1 to the response type drug-carrying polymer of the formula I-2 of 1:1. fig. 1 shows a schematic view of iron death nanoparticles, but the present invention is not limited thereto.
In some embodiments, the pH is 7.4 and the hydrodynamic diameter of the iron death nanoparticles is 40-150nm, preferably 40-60nm.
The small molecule tumor iron death inducing drugs are drugs that activate tumor cell iron death, including but not limited to one or more of sorafenib, sulfasalazine, erastin, imidazolone Erastin, DPI12, 13, 17, 18, 19, ml210, (1 s,3 r) -RSL-3, ml162, fin56, fino2, ferrotacides, octreotide, statin drugs (fluvastatin, simvastatin, lovastatin acid), sulfoximine, lapatinib, siramesine, artemisinin derivatives, and the like.
The iron death nanoparticle is a nano preparation which can respond to pH and ROS simultaneously, and comprises an acid sensitive group which can be protonated and a ROS responding broken phenylboronate group. At a neutral pH of 7.4, the nanoparticle is composed of an artemisinin ester polymer capable of acidic ionization in cells and a phenylboronate polymer with ROS and acid response, and the phenylboronate structure can provide pi-pi stacking to stably encapsulate the entrapped small molecule drug in the core of the hydrophobic nanoparticle. The PEG shell outside the nanoparticle is beneficial to long circulation of the nanoparticle in a living body, and after the nanoparticle is ingested by cells through an EPR effect, the lysosome (pH=5.4-6.2) in the cells triggers dynamic covalent bond cleavage of PDPA and PBE through acid and ROS and releases entrapped drugs through hydrophobic core protons, so that the PEG shell is beneficial to enrichment of small molecular drugs in tumors, thereby improving the drug concentration of a target part and effectively causing iron death of the tumors.
The fifth aspect of the present invention provides a method for preparing the iron death nanoparticle, comprising the steps of:
dissolving a responsive drug-carrying polymer of the formula I and a small molecule tumor iron death induction drug in an organic phase, dispersing in water, and obtaining iron death nanoparticles by ultrafiltration or dialysis of the obtained solution;
preferably, the responsive drug-carrying polymer of formula I-1, the responsive drug-carrying polymer of formula I-2 and the small molecule tumor iron death inducing drug are dissolved in an organic solvent and then dispersed in water, and the obtained solution is subjected to ultrafiltration or dialysis to obtain the iron death nanoparticles.
In some embodiments, the water is deionized water and the organic solvent is any one of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide.
The ultrafiltration process can be carried out by adopting an ultrafiltration tube centrifugal ultrafiltration or ultrafiltration machine ultrafiltration mode, the molecular weight cut-off of an ultrafiltration tube or an ultrafiltration membrane bag used in the process can be 1.5KD, 3KD, 5KD and 10KD, and one of the ultrafiltration tube, the ultrafiltration membrane bag and the ultrafiltration membrane bag is reasonably selected.
The cut-off molecular weight of the dialysis bag in the dialysis process can be 800, 1000, 3500 and 14000, and one of the cut-off molecular weight and the cut-off molecular weight is reasonably selected. The solvent used for dialysis was deionized water.
In a sixth aspect, the present invention provides the use of an iron-death nanoparticle as described above for the manufacture of a medicament for the prevention or treatment of a malignancy, preferably selected from breast cancer, cervical cancer, liver cancer, gastric cancer, ductal pancreatic cancer, ovarian cancer, colon cancer, prostate cancer, head and neck cancer or melanoma.
The technical scheme of the invention has at least the following technical effects:
in order to relieve poor targeting property, short half-life and toxic and side effects on other normal organs of a small molecular drug, the embodiment of the invention provides an iron death nanoparticle with double responses of acid and ROS and a preparation method thereof, and the preparation method of the iron death nanoparticle enhances the endocytosis of tumor cells to the nanoparticle by virtue of the EPR effect of the tumor cells, increases the uptake of the drug by the cells, and further improves the drug concentration of tumor sites; meanwhile, under the action of the nanoparticles, the half-life period of the medicine in the organism is effectively prolonged, and the tissue distribution of the medicine is obviously improved. The iron death nanoparticle of the embodiment of the invention is formed by self-assembling two responsive polymers. According to the responsive polymer provided by the embodiment of the invention, the PEG macromolecular skeleton, the pH sensitive and ROS sensitive groups and the dihydroartemisinin are covalently connected with the connecting groups through the RAFT polymer, so that long circulation of nanoparticles in vivo and controllable release of the drug at a tumor position can be realized. The invention firstly combines carboxyl and CH of chain transfer agent CTA of RAFT reaction 3 O-PEG-NH 2 Amino reaction of (C), and RAFT polymerization reaction of the obtained product to connect R-containing 1 And R is 3 Ethyl methacrylate, methylpropenyl phenylborate or dihydroartemisinin with a linking group. Because of the multiple response function, the nanoparticle can be increased to release the entrapped small molecule drug under the specific tumor condition. In addition to the iron death nanoparticlesThe load quantity of the micromolecular medicaments can be flexibly controlled by adjusting the polymerization synthesis method and adjusting the proportion of the two polymers, and the exposure concentration of the medicaments at the target position is further improved, so that the medicament effect is improved and the risk of medicament resistance is reduced.
According to the iron death nanoparticle obtained by self-assembly of the response type dihydroartemisinin polymer and the response type phenylboronate polymer, the PEG shell of the iron death nanoparticle is beneficial to long circulation of the nanoparticle in a living body, the iron death nanoparticle is taken up by tumor cells through an EPR effect, the tissue distribution condition of the iron death nanoparticle in the living body is improved, an iron death inducer is effectively and selectively delivered to a tumor part, and efficient accumulation and retention of the iron death inducer in the tumor tissue are realized; the entrapped small molecule tumor iron death inducer is released through responding to acid and high ROS in tumors, so that the probability of iron death of tumor cells is improved, the tumor immune microenvironment is improved, the tumor immune treatment effect is improved, and the growth proliferation and transfer recurrence processes of tumors are inhibited. The method can reduce toxic and side effects on other organs while enhancing the treatment effect, and lays a foundation for the clinical effective delivery of tumor treatment medicines.
The iron death nanoparticle can be loaded with various small molecule tumor therapeutic drugs, has good biocompatibility, can be effectively absorbed by tumors through the EPR effect of tumor tissues, and has good tumor tissue accumulation and penetration capacity. After the nanoparticle is efficiently ingested by tumor cells, an activatable response bond of the nanoparticle is broken to release the entrapped small molecular medicine, so that tumor tissue selectivity of the small molecular medicine and the ingestion capacity of the tumor cells on the small molecular medicine are improved, and toxic and side effects of the small molecular medicine on normal tissues and organs are reduced while the efficient tumor tissue killing effect is realized.
Drawings
FIG. 1 shows a schematic of an iron death nanoparticle of the present invention;
FIG. 2 shows a nuclear magnetic resonance image of PEG-CTA prepared in example 1 of the present invention;
FIG. 3 shows a nuclear magnetic resonance diagram of a responsive artesunate polymer prepared in example 2 of the present invention;
FIG. 4 shows a nuclear magnetic pattern of a responsive phenylboronate polymer prepared in example 3 of the present invention;
FIG. 5 shows a particle size distribution diagram of iron death nanoparticles prepared in example 4 of the present invention;
FIG. 6 shows the entrapment of iron death agonist RSL-3 by the iron death nanoparticles prepared in example 4 of the present invention;
FIG. 7 shows iron death nanoparticles prepared in example 4 of the present invention at different pH and H 2 O 2 Hydrodynamic particle size and transmission electron microscopy under the conditions, wherein, left 1 is pH=7.4, left 2 is H 2 O 2 =10 mM, left 3 ph=5.4, right 1 ph=5.4+10 mM H 2 O 2 The scale mark is 100 nm.
FIG. 8 shows the cumulative release profile of RSL-3 in an in vitro simulated tumor cell physiological microenvironment for iron death nanoparticles prepared in example 4 of the present invention;
FIG. 9 shows the uptake capacity of iron death nanoparticles prepared in example 4 of the present invention in Panc02 pancreatic cancer cells;
FIG. 10 shows cytotoxicity assays after 24h of co-incubation of iron death nanoparticles prepared in example 4 of the present invention with Panc02 cells at different concentrations;
FIG. 11 shows the tumor inhibition of PBS solution, iron death nanoparticles prepared in example 4 of the present invention in female Balb/c nude mice, wherein the circles represent PBS and the squares represent iron death nanoparticles;
fig. 12 shows the effect of PBS solution, iron death nanoparticles prepared in example 4 of the present invention on the body weight of female Balb/c nude mice, wherein the circles represent PBS and the squares represent iron death nanoparticles.
FIG. 13 shows the tumor inhibition of PBS solution, iron death nanoparticles prepared in example 4 of the present invention in C57/BL6 immune healthy mice, wherein the coordinates are circles for PBS and triangles for iron death nanoparticles;
FIG. 14 shows the weight effect of PBS solution, iron death nanoparticles prepared in example 4 of the present invention on the body weight of C57/BL6 immune-sound mice, wherein the circles indicate PBS and the triangles indicate iron death nanoparticles.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention is further illustrated by the following examples, which are provided for illustrative purposes only and are not to be construed as limiting the scope of the invention as claimed.
CH used in the examples 3 O-PEG 113 -NH 2 (PEG-NH 2 Mn=5000 Da) from key Kai technology (China), diisopropylaminoethyl methacrylate (DPA), hydroxyethyl methacrylate (HEMA), 4-cyano-4- [ [ (dodecylthio) thioketomethyl]Thio group]Valeric acid (CTA) was purchased from sigma aldrich (china), artesunate (ARS), phenylboronic acid, glycidyl Methacrylate (GMA) was purchased from aladine (Shanghai), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 4-Dimethylaminopyridine (DMAP), tetrahydrofuran, N-Dimethylformamide (DMF), diisopropylethylamine (DIEA) dimethyl sulfoxide (DMSO), 2- (7-azabenzotriazol) -N, N' -tetramethylurea Hexafluorophosphate (HATU), azobisisobutyronitrile (AIBN) were purchased from Shanghai belgium technologies, and dihydroartemisinin was purchased from calibre biotechnology. The remaining reagents and solvents were purchased from the national drug group (Shanghai) chemical reagent Co., ltd unless otherwise specified.
Panc02 pancreatic cancer cells were purchased from the national institute of sciences Shanghai cell bank, and the cell culture medium was purchased from Dai Lian Biotechnology Co., ltd, and fetal bovine serum was purchased from Gibco company.
The hydrodynamic particle size of the iron death nanoparticles was measured by a malvern laser particle sizer (ZEN 3690, malven, USA); morphology investigation of nanoparticles was done by 120kV transmission electron microscopy (Talos L120C, FEI, USA). Electronic balances (quinmix 224-1,Sartorius Germany); rotary evaporator (B-40, buchi, switzerland); constant temperature magnetic stirrer (DF-101S, shanghai pre-treatment instruments Co., ltd.); nuclear magnetic resonance spectroscopy (mercuryplus 400, varian, usa); the release of RSL-3 was done by a Waters 2695 high performance liquid chromatograph (Waters e2695 chromatograph pump, xbridge C18 5 μm19 x 250mm chromatographic column, waters 2998 UV detector). Flow assay data were measured by BD FACS Fortessa flow cytometer. Unless otherwise indicated, the equipment and testing methods used are those conventional in the art.
Example 1: PEG-CTA synthesis
By reacting 4-cyano-4- [ (dodecylsulfanylthiocarbonyl) sulfanyl]Pentanoic acid (228.6 mg,0.6 mmol) was dissolved in 10.0mL of anhydrous N, N-Dimethylformamide (DMF), and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 608mg,1.2 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 2.9mg,0.015 mmol) was added thereto, and after activating carboxyl groups for 2 hours under ice bath, PEG-NH was added dropwise 2 (1.5 g,0.3 mmol) of N, N-dimethylformamide was reacted at room temperature for 24 hours. After the reaction is finished, removing impurities by a dialysis method, and freeze-drying to obtain a polymer CH 3 O-PEG 113 CTA (1.2 g) (abbreviated as PEG-CTA) in 80% yield.
FIG. 2 shows a nuclear magnetic resonance image of the prepared PEG-CTA.
Example 2: synthesis of responsive artesunate polymer
PEG-CTA (200 mg,0.019 mmol), diisopropylaminoethyl methacrylate (DPA, 256.8mg,2.6 mmol), hydroxyethyl methacrylate (HEMA, 48.1mg,0.7 mmol) and azobisisobutyronitrile (AIBN, 0.5mg, 0.003mmol) were dissolved in 2.0ml DMF and reacted at 70℃for 24h after three freeze-thaw cycles to remove oxygen. After the reaction, the impurities were removed by dialysis, and the resulting mixture was freeze-dried to give a PEG-b-P (DPA-r-HEMA) (b represents a block, r represents a graft, and P represents a polymer) diblock copolymer (381.4 mg) in a yield of 74.8%.
Artesunate (ARS, 115.2mg,0.03 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 170mg,0.09 mmol), 4-dimethylaminopyridine (DMAP, 109.8mg,0.09 mmol), N-diisopropylethylamine (DIEA, 116.1mg,0.06 mmol) were dissolved in 5ml DMF, and after activating the carboxyl groups on an ice bath for 1.5h, PEG-b-P (DPA-r-HEMA) (200 mg,0.01 mmol) dissolved in DMF was added dropwise and reacted for 24h. After the reaction, the impurities are removed by a dialysis method, and the freeze-drying is carried out to obtain the responsive artesunate polymer (222 mg) with the yield of 71.2%. Gel Permeation Chromatography (GPC) test: mn=14923, mw=17761, mw/mn=1.190.
FIG. 3 shows the nuclear magnetic pattern of the prepared responsive artesunate polymer.
Example 3: synthesis of responsive phenylboronate polymer
PEG-CTA (100 mg,0.019 mmol), diisopropylaminoethyl methacrylate (DPA, 162.1mg,0.76 mmol), glycerol methacrylate (GMA, 91.3mg,0.57 mmol) and azobisisobutyronitrile (AIBN, 0.5mg, 0.003mmol) were dissolved in 2.0ml DMF and reacted at 70℃for 24h after three freeze-thaw cycles to remove oxygen. After the reaction, the impurities were removed by dialysis, and the resulting PEG-b-P (DPA-r-GMA) diblock copolymer (222.6 mg) was obtained by freeze-drying in a yield of 62.3%.
PEG-b-P (DPA-r-GMA) (100 mg, 0.003mmol) and phenylboronic acid (67.6 mg,0.55 mmol) were dissolved in 10ml toluene and refluxed at 120℃for 24h. After the reaction, impurities were removed by dialysis, and the reaction mixture was freeze-dried to give a responsive phenylboronate polymer (112.4 mg) in a yield of 67.6%. Gel Permeation Chromatography (GPC) test: mn=10939, mw=13001, mw/mn=1.251.
FIG. 4 shows a nuclear magnetic pattern of the prepared responsive phenylboronate polymer.
Example 4: preparation of iron death nanoparticles
1mg of the responsive artesunate polymer of example 2, 1mg of the responsive phenylboronate polymer of example 3 and 0.018mg of (1S, 3R) -RSL-3 were dissolved in 50. Mu.l of dimethyl sulfoxide solvent, and the solution was slowly dropped into 1.0mL of deionized water under the action of ultrasound (power 80W,3 min). Subsequently, the obtained solution was subjected to centrifugal ultrafiltration in an ultrafiltration tube to obtain iron death nanoparticles (designated as PDBA@RSL-3, wherein P represents a polymer, D represents diisopropylaminoethyl methacrylate, B represents phenylboronic acid, and A represents dihydroartemisinin).
Control nanoparticles: 2mg of the responsive artesunate polymer of example 2 and 0.018mg of (1S, 3R) -RSL-3 were dissolved in 50. Mu.l of dimethyl sulfoxide solvent, and the solution was slowly dropped into 1.0mL of deionized water under ultrasound (power 80W,3 min). Subsequently, the obtained solution was subjected to centrifugal ultrafiltration in an ultrafiltration tube, and thus nanoparticles (denoted as pda@rsl-3 in which P represents a polymer, D represents diisopropylaminoethyl methacrylate, and a represents dihydroartemisinin) were obtained as a control which contained no phenylboronate in response to ROS.
Example 5: particle size and PDI of iron death nanoparticles
The particle sizes of PDBA@RSL-3 nanoparticles and PDA@RSL-3 nanoparticles prepared in example 4 were measured by a Markov particle sizer in a solution of pH 7.4 under the following conditions: the temperature was 25℃and the results were shown in FIG. 5, three times, 15 cycles each. The result shows that the particle size of PDA@RSL-3 is 119.7+/-0.6, the PDI is 0.196+/-1.4, the particle size of PDBA@RSL-3 nano particles is 48.8+/-1.1, and the PDI is 0.14+/-0.01, so that the phenylboronic acid structure in the PDBA@RSL-3 has better compression and entrapment effects on the RSL-3.
Example 6: evaluation of the encapsulation Effect of iron death nanoparticles on RSL-3
PDBA@RSL-3 nanoparticles and PDA@RSL-3 nanoparticles prepared in example 4 were dispersed in dialysis bags (14,000 Da), dialyzed in deionized water for 24 hours, nanoparticle solution in the dialysis bags was centrifuged by ultrafiltration, methanol (1:9, v/v) was added, and after 2 hours, the inclusion of RSL-3 was detected by an ultraviolet spectrophotometer.
As shown in FIG. 6, PDBA nanoparticles with phenylboronates can encapsulate more RSL-3.
Example 7 acid and ROS response test of iron death nanoparticles
The pdba@rsl-3 iron death nanoparticles prepared in example 4 were dissolved at ph=7.4, ph=5.4, 10mM H, respectively 2 O 2 Containing 10mM H 2 O 2 The nanoparticle hydrodynamic radius was determined at different time points using a dynamic light scattering instrument, treated with a buffer solution having ph=5.4.
As a result, FIG. 7 shows (squares of coordinates indicate that 10mM H was contained in the simulated environment) 2 O 2 The circle of the coordinate point represents the pH=5.4 in the simulated environment, the diamond of the coordinate point represents the pH=7.4 in the simulated environment, and the triangle of the coordinate point represents the simulated environment and simultaneously contains 10mM H 2 O 2 And ph=5.4) at a concentration of 10mM H 2 O 2 The iron death nanoparticle particle diameter and PDI become gradually larger with time in the condition of buffer solution of ph=5.4.
Will be at ph=7.4, ph=5.4, 10mM H, respectively 2 O 2 Containing 10mM H 2 O 2 An iron death nanoparticle solution (1 mg/mL) treated for 24 hours with a buffer solution having ph=5.4 was dropped onto a carbon film support copper mesh for transmission electron microscopy, after 2 minutes, excess droplets were sucked out with filter paper, stained with a 0.1% uranium acetate solution for 30 seconds, and after excess staining solution was removed, baked with an incandescent lamp. And observing the prepared copper mesh by using a transmission electron microscope, and taking the morphological characteristics of the nanoparticles into consideration.
The results are shown in fig. 7 at ph=5.4 and 10mM H 2 O 2 The nanoparticles in (a) showed only swelling, but were in the presence of 10mM H 2 O 2 The iron death nanoparticles having response under the condition of the buffer solution of ph=5.4 are dissociated to take an amorphous state, and the nanoparticles at ph=7.4 have a round and uniform shape. Indicating that the nanoparticle has stability under neutral conditions at ph=7.4 when full of ph=5.4 and ROS bars simultaneouslyIn the case of a piece, the nanoparticle will dissociate.
Example 8: release of RSL-3 in iron death nanoparticles
PDBA@RSL-3 iron death nanoparticles prepared in example 4 were dispersed in dialysis bags (14,000 Da) and the following buffer solutions were prepared: 1) Buffer solution at ph=7.4, 2) containing 10mM H 2 O 2 Ph=7.4 buffer solution, 3) ph=5.4 buffer solution, 4) 10mM H containing 2 O 2 In a buffer solution with ph=5.4, samples were taken at 0, 2, 4, 8, 12, 24h, respectively, at 37 ℃ on a constant temperature shaker, and the cumulative release of RSL-3 was calculated using a high performance liquid chromatograph.
As a result, FIG. 8 shows (squares of coordinates indicate that 10mM H was contained in the simulated environment) 2 O 2 The circle of the coordinate point represents the pH=5.4 in the simulated environment, the diamond of the coordinate point represents the pH=7.4 in the simulated environment, and the triangle of the coordinate point represents the simulated environment and simultaneously contains 10mM H 2 O 2 And ph=5.4), the results indicate that the constructed iron death nanoparticles can rapidly release RSL-3 under conditions that meet both ph=5.4 and ROS.
Example 9: determination of ability of tumor cells to ingest iron-death nanoparticles with phenylboronates
Panc02 cells were cultured according to 5X 10 4 Is seeded in 24-well plates and after 24h, is used when the cells are in the logarithmic phase of growth. The two PDBA@RSL-3 nanoparticles and the PDA@RSL-3 nanoparticles prepared in example 4 were incubated with cells for 0, 4, 8 and 12 hours, washed 3 times with PBS after the end of uptake, and then the uptake thereof (the presence of fluorescent dye DiL (cell membrane red fluorescent probe) molecules in the nanoparticles prepared herein was detected using a flow cytometer), and the fluorescence intensity of intracellular DiL was detected.
The test results are shown in fig. 9, the uptake of the pdba@rsl-3 iron death nanoparticles containing phenylboronic acid by tumor cells is significantly improved and time-dependent, and the uptake of the pdba@rsl-3 iron death nanoparticles containing phenylboronic acid ester is higher than that of the pda@rsl-3 iron death nanoparticles containing no phenylboronic acid ester, which shows that the iron death nanoparticles containing phenylboronic acid ester can be effectively accumulated and dissociated at tumor sites to release the entrapped drug.
Example 10: cytotoxicity assay of iron death nanoparticles
Panc02 cells were cultured according to 6X 10 3 After 24 hours, PDBA@RSL-3 iron death nanoparticles prepared in example 4 were incubated with cells at a concentration (0.625. Mu.g/mL, 1. Mu.g/mL, 1.25. Mu.g/mL, 2. Mu.g/mL, 2.5. Mu.g/mL, 5. Mu.g/mL) for 24 hours, the dosing medium was removed, a medium containing 10% CCK8 was added, incubated for 30 minutes, absorbance was measured at 450nm with an enzyme-labeled instrument, and cytotoxicity of the nanoparticles was calculated.
The test result is shown in fig. 10, and the pdba@rsl-3 iron death nanoparticles show concentration-dependent cytotoxicity to Panc02 pancreatic cancer cells, which indicates that the nanoparticles can release entrapped drugs after being taken up by the cells, so that the drug concentration in tumor cells is increased and the anti-tumor cytotoxicity is enhanced.
Example 11: evaluation of tumor growth inhibition effect of iron death nanoparticles
Establishing a tumor-bearing mouse model: after feeding purchased female Balb/C nude mice and C57/BL6 mice for one week, panc02 pancreatic cancer cells (500 ten thousand/mouse) were subcutaneously planted. The observed tumor volume was about 100mm 3 After that, it was randomly divided into 2 groups of 5 mice each, and the PBS buffer and PDBA@RSL-3 iron death nanoparticles were injected into the tail vein every three days, 3 times. The tumor volume and the body weight of the mice were measured every other day and the tumor volume of the mice was calculated as follows (L is the longest diameter, W is the shortest diameter in millimeters):
V＝L×W×W/2；
the test results are shown in fig. 11-14, the iron death nanoparticles can effectively inhibit tumor growth with an inhibition rate of about 65%, and the body weight of mice has no differential change, which indicates that the nanoparticles have no obvious toxic or side effect.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (10)

1. A responsive drug-carrying polymer shown in formula I,
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is an integer of 10 to 145, preferably an integer of 100 to 130, further preferably 113;
y is an integer of 20 to 80, preferably an integer of 55 to 70, further preferably 60;
z is an integer of 5 to 40, preferably an integer of 10 to 20, further preferably 15;
R 1 each independently an acid-sensitive group that is responsive to pH;
R 2 selected from C6-C12 alkylthio, substituted or unsubstituted C6-C12 aryl, said substituted substituents being selected from C1-C6 alkyl, C1-C6 alkylthio;
x is-L-A or-O- (CH) 2 ) n -R 3 ；
L is a linking group linking the polymer backbone to A;
each a is independently a group derived from an artemisinin derivative;
n is an integer from 1 to 6, preferably 1;
R 3 each independently is a pair H 2 O 2 Responsive ROS-sensitive groups.
2. The responsive drug-loaded polymer of claim 1, wherein,
R 1 selected from the following groups:
representing the connection location;
preferably, R 1 Is N, N-diisopropylamino.
3. The responsive drug-loaded polymer of claim 1, wherein,
R 2 selected from the group consisting of C8-C12 alkylthio, phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkylthio substituted phenyl;
preferably, R 2 Is dodecylthio.
4. The responsive drug-loaded polymer of claim 1, wherein,
x is-L-A, L is selected from the group consisting of the groups represented by formula i1, formula i2, formula i3 and formula i 4:
wherein M is 1 、M 2 Each independently selected from alkylene groups having 1 to 4 carbon atoms;
R 4 、R 5 each independently selected from carbonyl, imino, -O-;
preferably, M 1 And M 2 The same;
preferably, L is selected from the following groups:
further preferably, L is
5. The responsive drug-loaded polymer of claim 4, wherein,
x is-L-A, A has the following structure:
6. the responsive drug-loaded polymer of claim 1, wherein,
x is O- (CH) 2 ) n -R 3 ，R 3 The structure of (2) is as follows:
wherein R is 4 Selected from H, C C6 alkyl, halogen or NH 2 Preferably, R 4 H.
7. The responsive drug-loaded polymer of any one of claims 1-6, wherein the responsive drug-loaded polymer of formula I is selected from the group consisting of a responsive drug-loaded polymer of formula I-1 and a responsive drug-loaded polymer of formula I-2:
therein, x, y, z, R 1 、R 2 、R 3 L, A are defined in the corresponding claims;
preferably, the responsive drug-carrying polymer of formula I-1 is selected from the following polymers:
preferably, the responsive drug-carrying polymer of formula I-2 is selected from the following polymers:
8. an iron death nanoparticle self-assembled from the responsive drug-loaded polymer of any one of claims 1-7 and a small molecule tumor iron death-inducing drug, preferably from the responsive drug-loaded polymer of formula I-1, the responsive drug-loaded polymer of formula I-2 and the small molecule tumor iron death-inducing drug, further preferably from the responsive drug-loaded polymer of formula I-1, the responsive drug-loaded polymer of formula I-2 in a mass ratio of 1:1, a step of;
preferably, the hydrodynamic radius of the iron death nanoparticles is 40-150nm, more preferably 40-60nm.
9. The method for preparing iron death nanoparticles according to claim 8, comprising the steps of:
dissolving a responsive drug-carrying polymer of the formula I and a small molecule tumor iron death induction drug in an organic phase, dispersing in water, and obtaining iron death nanoparticles by ultrafiltration or dialysis of the obtained solution;
preferably, the responsive drug-carrying polymer of formula I-1, the responsive drug-carrying polymer of formula I-2 and the small molecule tumor iron death inducing drug are dissolved in an organic solvent and then dispersed in water, and the obtained solution is subjected to ultrafiltration or dialysis to obtain the iron death nanoparticles.
10. Use of the iron-death nanoparticle according to claim 8 for the manufacture of a medicament for preventing or treating a malignancy, preferably selected from breast cancer, cervical cancer, liver cancer, gastric cancer, pancreatic ductal carcinoma, ovarian cancer, colon cancer, prostate cancer, head and neck cancer or melanoma.
CN202210301003.3A 2022-03-24 2022-03-24 Responsive drug-loaded polymer, iron death nanoparticle, and preparation method and application thereof Pending CN116832031A (en)

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