CN114533891B - Targeted traceless release drug conjugate and preparation method and application thereof - Google Patents
Targeted traceless release drug conjugate and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a targeted traceless release drug conjugate, a preparation method and application thereof, wherein the targeted traceless release drug conjugate has a structural formula shown in a formula I:wherein R is 1 The amino group of a lysine side chain selected from RGD peptide, cyclic RGD peptide, RGDyK cyclic peptide, RGD peptide derivative or cyclic RGD peptide derivative forms an amido bond in a structural formula shown in a formula I for coupling; r 2 is-CH 3 、‑CH 2 OC(CH 3 ) 3 、‑CH 2 OH;R 3 is-CH 3 、‑CH 2 OC(CH 3 ) 3 ;A ‑ Is CF 3 CO 2 ‑ 、Cl ‑ 、CH 3 COO ‑ . The drug conjugate of the invention adopts the specific linker, and the self-elimination reaction of the cracked specific linker to the aminobenzyl releases the active drug without trace, thereby reducing the toxicity of the drug and enhancing the treatment effect.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a targeted traceless release medicine conjugate as well as a preparation method and application thereof.
Background
Coibamide A (Coibamide A, CA) is a marine natural product separated from the marine cyanobacteria Leptolyngbya sp of Panama in 2008 McPhail et al. The cyclic lipopeptide is rich in a plurality of N-methylated amino acids, has low nanomolar cell growth inhibitory activity on a plurality of cancer cells, and is an anticancer lead compound with potential advantages. In the previous studies, the present inventors completed the total synthesis of CA for the first time by a solid phase synthesis method, and modified the structure of CA. Through the structure-activity relationship research, the inventor finds a CA analogue, [ MeAla3-MeAla6] -coibamide (1 a), which has equivalent antiproliferative activity and relatively simple structure with CA. The specific structure is as follows:
however, in subsequent studies, the present inventors found that 1mg/kg of 1a injected intravenously into animals resulted in greater toxicity and side effects. Based on the defects of poor water solubility, high toxicity and the like of the kobaypeptide A and the analogue 1a thereof, the inventor carries out further modification to obtain an enzyme digestion response compound RGD-VC-CA (patent: CN201711320821.3, publication number is CN 109908363A), the patent uses a kobaypeptide A analogue to connect with a targeting group through a Linker (Linker) which responds to cathepsin B and releases without trace, and realizes the release at a tumor part, thereby obtaining a certain effect. However, the release efficiency of the enzyme digestion response compound is low, and the tumor inhibition activity needs to be improved. How to further reduce the toxicity of the copaiba peptide A and the analogues thereof and improve the treatment efficiency is an urgent problem to be solved in the research process.
Disclosure of Invention
In order to solve the problems, the invention further modifies the kobazaki-peptide A and the analogue thereof to obtain a compound with better drug release performance and higher treatment efficiency under the condition of a tumor microenvironment.
One aspect of the present invention provides a targeted traceless release drug conjugate having a structural formula shown in formula I:
wherein R is 1 The amino group of a lysine side chain selected from RGD peptide, cyclic RGD peptide, RGDyK cyclic peptide, RGD peptide derivative or cyclic RGD peptide derivative forms an amido bond in a structural formula shown in a formula I for coupling;
R 2 is-CH 3 、-CH 2 OC(CH 3 ) 3 、-CH 2 OH;
R 3 is-CH 3 、-CH 2 O C(CH 3 ) 3 ;
A - Is CF 3 CO 2 - 、Cl - 、CH 3 COO - 。
In one embodiment of the invention, R 1 Preferably an RGDyK cyclic peptide.
In one embodiment of the invention, R 2 is-CH 3 ,R 3 is-CH 3 。
In a specific embodiment of the invention, the targeted traceless release drug conjugate has the following structural formula:
in another aspect, the present invention provides an intermediate for preparing a targeted traceless release drug conjugate, said intermediate having the following structure:/>
in another aspect, the invention provides the use of the above intermediate in the preparation of traceless release drug conjugate compounds.
In one embodiment of the present invention, the traceless release drug conjugate compound has a targeting moiety conjugated to one end of the intermediate and an active drug molecule conjugated to the other end.
Another aspect of the present invention provides a method for preparing a targeted traceless release drug conjugate, which specifically comprises the following steps:
1) Coupling a linker to the kobaypeptide a and kobaypeptide a analogs;
2) Coupling the conjugate obtained in the step 1) with a targeting group; obtaining a targeted traceless release drug conjugate;
The structure of the kobupeptide A analogue isWherein R is 2 is-CH 3 、-CH 2 OC(CH 3 ) 3 、-CH 2 OH;R 3 is-CH 3 、-CH 2 O C(CH 3 ) 3 ;
The structure of the targeting group isWherein R1 is selected from RGD peptide, RGD cyclopeptide, RGDyK cyclopeptide, RGD peptide derivative or cyclic RGD peptide derivative, and the lysine side chain amino group of the RGD peptide, RGD cyclopeptide, RGDyK cyclopeptide, RGD peptide derivative or cyclic RGD peptide derivative forms an amido bond in the targeting group.
In one embodiment of the invention, R 1 Preferably an RGDyK cyclic peptide;
In a particular embodiment of the invention, R 2 is-CH 3 ,R 3 is-CH 3 。
In a specific embodiment of the invention, the reaction conditions of step 1) are activation of the linker compound with thionyl chloride, followed by reaction with a kobaypeptide A analog under conditions of tetrabutylammonium iodide and N, N-diisopropylethylamine.
In the specific embodiment of the invention, the reaction condition of the step 2) is that the product obtained in the step 1) reacts with the targeting group under the condition of sodium ascorbate and copper sulfate.
In a specific embodiment of the present invention, the preparation method of the linker in step 1) is:
the compoundActivating under the conditions of triphosgene and pyridine, and then reacting with p-aminobenzyl alcohol under the alkaline condition to obtain the linker.
In particular embodiments of the invention, compoundsThe preparation method comprises the following steps: bis (2-hydroxyethyl) disulfide is reacted with methanesulfonyl chloride under basic conditions, followed by addition of NaN 3 And (4) further reacting.
In another aspect, the invention provides a use of the targeted traceless release drug conjugate in preparation of a drug for treating tumors.
In particular embodiments of the invention, the tumor is selected from one or more of colon cancer, rectal cancer, brain tumor (preferably glioblastoma), lung cancer (preferably non-small cell lung cancer), epidermal squamous carcinoma, bladder cancer, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, colorectal cancer, renal cell carcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-hodgkin's lymphoma, liver cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, glioma, and nasopharyngeal carcinoma; more preferably, the hyperproliferative disease is breast cancer, non-small cell lung cancer.
English abbreviation comparison table in the invention:
advantageous effects
1. The targeted traceless release drug conjugate with stimulation responsiveness is designed by using the cyclic RGD with targeting effect and easy synthesis and modification to replace an expensive and difficult-to-synthesize antibody as a targeting molecule.
2. The drug conjugate is formed without any modification of the active group, and the active group is released tracelessly based on the self elimination of the aminobenzyl group when the linker is specifically cut by the reducing agent, so that the toxicity of the active drug is reduced, and the treatment effect is enhanced.
3. The drug conjugate has novel joint structure, can realize traceless release, and has high release speed and complete release.
Drawings
FIG. 1: process for preparation of compound 5 1 H NMR spectrum.
FIG. 2: process for preparation of Compound 6 1 H NMR spectrum.
FIG. 3: process for preparation of Compound 6 13 C NMR spectrum.
FIG. 4: HRMS profile of compound 7.
FIG. 5 is a schematic view of: HRMS map of RGD-SS-CA (2).
FIG. 6: HPLC analysis of RGD-SS-CA (2). Wherein the results of retention time at 220nm and the like are as follows
FIG. 7 is a schematic view of: schematic structural diagram and release mechanism of RGD-SS-CA (2) and RGD-VC-CA (3).
FIG. 8: in contrast to RGD-VC-CA (3), the in vitro release of RGD-SS-CA (2) was studied.
FIG. 9: the results of example 3 show the analysis of the antiproliferative activity of RGD-SS-CA (2) on tumor cells, in comparison with RGD-VC-CA (3). Wherein, A is a curve of drug concentration-cell survival rate aiming at BT549 cells, compounds RGD-SS-CA (2) and RGD-VC-CA (3), B is a curve of drug concentration-cell survival rate aiming at A549 cells, compounds RGD-SS-CA (2) and RGD-VC-CA (3), and C is a curve of drug concentration-cell survival rate aiming at A549 cells and comparing with compound 1a, RGD-SS-CA (2) and RGD-VC-CA (3) are respectively under the action of release agent.
FIG. 10: evaluation of antitumor Activity of RGD-SS-CA (2) in vivo. (A) Mean body weight of mice in the RGD-SS-CA (2) group (n = 7), the RGD-VC-CA (3) group and the control group (n = 7). (B) Tumor volume in mice of the group of drugs (n = 7) and control (n = 7). (C) sacrifice of mice, mass of tumor detached. (D) photograph of the tumor after the exfoliation.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, specific embodiments thereof are described in detail below, but the present invention is not to be construed as being limited to the implementable range thereof. Reagents and equipment used in the examples of the present invention are commercially available unless otherwise specified.
Example 1 Synthesis of RGD-SS-CA (2)
And 2, synthesizing a compound 6. Triphosgene (BTC, 196mg, 0.66mmol) was dissolved in anhydrous dichloromethane (DCM, 2 mL), and a solution of compound 5 (359mg, 2mmol) and pyridine (42. Mu.L, 3 mmol) in DCM was added under ice-bath stirring for 30min. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in 2mL of anhydrous DCM, followed by addition of p-aminobenzyl alcohol (368.8mg, 3mmol) and triethylamine (416. Mu.L, 3 mmol) in DCM/THF (3mL, 1), and stirring at room temperature for 30min. The reaction was diluted with DCM (20 mL), washed twice with 1M HCl (2X 10 mL), and the organic phase was collected over anhydrous Na 2 SO 4 And (5) drying. The solvent was removed by concentration under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 2) to give compound 6 (225mg, 34%) as a yellow oil. 1 H NMR(400MHz,CDCl 3 ) δ 2.35 (s, 1H), 2.85-2.89 (t, J =6.8hz, 2h), 2.95-3.0 (t, J =4.8hz, 2h), 3.57-3.62 (t, J =6.8hz, 2h), 4.39-4.61 (t, J =4.8hz, 2h), 4.60 (s, 2H), 7.13 (s, 1H), 7.26-7.29 (d, J =8.4hz, 2h), 7.34-7.36 (d, J =8.0hz, 2h) ppm (fig. 2). 13 C NMR(100MHz,CDCl 3 ) Δ 37.6,37.8,50.0,62.7,64.8,118.8,128.3,136.2,137.1,153.0ppm (FIG. 3).
And 3, synthesizing a compound 7. Compound 6 (108mg, 0.329mmol) is dissolved in dry DCM (2 mL), and a solution of thionyl chloride in DCM (1 mol/L, 362. Mu.L, 0.362 mmol) is added dropwise over the ice bath, stirred for 30min under the ice bath, and allowed to warm to room temperature for further stirring for 30min. The reaction was concentrated under reduced pressure and the residue was dissolved in 10mL DCM and taken up with saturated NaHCO 3 The solution was washed once. Collecting the organic phase, and adding anhydrous Na 2 SO 4 . The solvent was removed by concentration under reduced pressure, and the residue was dissolved in 2mL of DCM, followed by addition of 1a (30mg, 0.024mmol), tetrabutylammonium iodide (60mg, 0.169mol) and N, N-diisopropylethylamine (10. Mu.L, 0.057 mmol). The reaction mixture was stirred at rt for 5h and finally purified by HPLC. After lyophilization, compound 7 (15mg, 39%) was obtained as a white powder. HRMS (ESI) m/z, calcd.for C 75 H 112 N 14 O 16 S 2 [M] + 1537.8521, found 1537.8517 (FIG. 4).
And 4, synthesizing RGD-SS-CA (2). Compound 7 (28mg, 0.018mmol) was dissolved in 1.5mL of THF, an aqueous solution (1.4 mL) of cyclic RGD (8) (15mg, 0.022mmol) was added, followed by sodium ascorbate (1.76M aqueous solution, 50. Mu.L) and CuSO 4 ·5H 2 O (0.26M aqueous solution, 50. Mu.L). The reaction mixture was stirred at room temperature overnight and purified by HPLC to give RGD-SS-CA as a white solid after lyophilization (12mg, 30%). HRMS (ESI) m/z: calcd. For C 107 H 167 N 23 O 25 S 2 [M+H] 2+ 1119.0967, found 1119.09595 (FIG. 5).
EXAMPLE 2 in vitro drug Release study
RGD-SS-CA was dissolved in 10% DMF in PBS buffer (50. Mu.M, 500. Mu.L, pH = 7.4), dithiothreitol (DTT) was added to the solution to a final concentration of 250. Mu.M, incubated at 37 ℃ and 50. Mu.L of the sample was taken out at 30, 60 and 90min, respectively, for HPLC analysis.
In vitro drug release studies of RGD-VC-CA (3) were performed in the same manner. RGD-VC-CA was dissolved in 10% DMF in PBS buffer (50. Mu.M, 500. Mu.L, pH = 7.4), cathepsin B was added to the solution to a final concentration of 250. Mu.M, the solution was incubated at 37 ℃ and 50. Mu.L of the sample was taken out at 4, 12 and 24 hours, respectively, for HPLC analysis.
Compared with the enzyme digestion response compound RGD-VC-CA (3), the in vitro release result of RGD-SS-CA shows (figure 8), in the presence of a reducing agent DTT, RGD-SS-CA can rapidly and seamlessly release 1a, and in 90min, RGD-SS-CA can be completely cut by DTT to realize 100% release. The enzyme-responsive cleavage of RGD-VC-CA (3) is relatively slow, and it can be seen from FIG. 8 that the enzyme-responsive cleavage still cannot be completely released, but only can be released by 50% within 24 hours, and the reaction is incomplete.
According to the embodiment, the joint designed by the invention not only can realize traceless release, but also can be quickly released at a specific site, and the release is complete. The release rate and the release degree are far better than those of the existing conjugate.
EXAMPLE 3 in vitro anti-proliferative Activity
3000 to 4000 human non-small cell lung carcinoma a549 was inoculated into 96-well plates. Inoculation 2After 4h, the medium was removed, new medium was added, and then new medium containing RGD-SS-CA complex at different concentrations was added to the cells, using blank solvent as control. Cells at 5% CO 2 Incubate at 37 ℃ in an incubator. After 48h, CCK8 reagent was added and incubation continued for 1h. The absorption at 450nm was then measured with a full wavelength reader (Thermol Multiskan GO). Each experiment was independently repeated three times. The values of a in the table below are obtained.
3000 to 4000 human non-small cell lung carcinoma a549 was inoculated into 96-well plates. After 24h of inoculation, the medium was removed, fresh medium was added, 1mM GSH-OEt was added first and the cells were incubated in 5% CO 2 The cells were incubated at 37 ℃ in an incubator. Then adding RGD-SS-CA conjugate and co-culturing the cells for 48h, adding CCK8 reagent and continuing culturing for 1h. The absorption at 450nm was then measured with a full wavelength reader (Thermol Multiskan GO). Each experiment was independently repeated three times. The values of b in the table below are obtained.
3000 to 4000 human non-small cell lung carcinoma a549 was inoculated into 96-well plates. After 24h of inoculation, the medium was removed, new medium was added, and then new medium containing RGD-VC-CA conjugates at different concentrations was added to the cells, using the blank solvent as a control. Cells at 5% CO 2 The cells were incubated at 37 ℃ in an incubator. After 48h, CCK8 reagent was added and incubation continued for 1h. The absorption at 450nm was then measured with a full wavelength reader (Thermol Multiskan GO). Each experiment was independently repeated three times. The values of c in the table below are obtained.
3000 to 4000 individuals of non-small cell lung carcinoma a549 were inoculated into 96-well plates. After 24h of inoculation, the medium was removed, fresh medium was added, cathepsin B was added first and the cells were incubated in 5% CO 2 Incubate at 37 ℃ in an incubator. Then adding RGD-VC-CA conjugate and co-culturing with cells for 48h, adding CCK8 reagent, and continuing culturing for 1h. The absorption at 450nm was then measured with a full wavelength reader (thermo Multiskan GO). Each experiment was independently repeated three times. The d values in Table 1 below were obtained
3000 to 4000 human breast cancer cells BT549 were seeded in 96-well plates. After 24h of inoculation, the medium was removed, new medium was added and new cultures containing RGD-SS-CA conjugates at different concentrations were incubatedMedium was added to the cells and blank solvent was used as control. Cells at 5% CO 2 Incubate at 37 ℃ in an incubator. After 48h, CCK8 reagent was added and incubation continued for 1h. The absorption at 450nm was then measured with a full wavelength reader (thermo Multiskan GO). Each experiment was independently repeated three times.
The growth inhibition rate calculation formula is as follows: growth inhibition rate (%) = [ 1-absorbance of complex sample/absorbance of control sample]*100 percent. semi-Inhibitory Concentration (IC) 50 ) Defined as the concentration of drug at which the complex inhibits cell growth by 50% compared to control cells.
This example simulates the situation where the compound does not reach the tumor site by not adding a cleavage agent, and the results can be used to demonstrate the toxicity of the compound to cells, where IC 50 Larger values indicate lower cytotoxicity. Adding cracking agent GSH-OEt and cathepsin B for simulating tumor part, hydrolyzing GSH-OEt into GSH under the action of intracellular esterase, specifically cutting disulfide bond joint by GSH, eliminating 1,6 of aminobenzyl, and releasing 1a without trace, so that IC 50 The value dropped rapidly, achieving almost the same IC as the 1a compound 50 The values indicate that RGD-SS-CA can be well released in tumor cells and recover the high-efficiency antitumor activity of 1 a.
The activity of RGD-VC-CA is greatly reduced compared with RGD-SS-CA and 1a, which indicates that the release efficiency of RGD-VC-CA (3) in cells is poor, and the activity of 1a cannot be completely recovered. Meanwhile, the cathepsin B in the tumor cells is in lysosomes, RGD-VC-CA is not easy to enter the lysosomes, so that the lysis is not easy to realize, and the speed of enzymolysis is far lower than that of the disulfide bond lysis. Therefore, RGD-VC-CA (3) is much less effective than RGD-SS-CA (2) in antitumor effect.
TABLE 1 IC of RGD-SS-CA (2), RGD-VC-CA (3) and 1a on BT549 and A549 cells 50 Value of
GSH-OEt, b-value denotes GSH-OEt, cd IC 50 Values are the three mean values, SD is the standard deviation of the mean.
Cell growth inhibition analysis shows that (figure 9, table 1), RGD-SS-CA compound can effectively inhibit the growth of tumor cells BT549 and A549, IC 50 The toxicity was reduced by 16 times and 12 times compared with the original drug 1a in 310.7 + -74.6 nM and 251.48 + -95.5 nM, respectively. IC of RGD-SS-CA under external stimulation of GSH-OEt 50 Recovering to 20.58 + -7.3, inhibiting activity and 1a (IC) 50 =19.2 ± 8.6 nM) was maintained at the same level, which indicates that RGD-SS-CA has an excitatory release property in response to a tumor microenvironment and exhibits a tumor suppressive activity comparable to that of the original drug. The release effect is far better than that of a similar conjugate RGD-VC-CA. This result is also consistent with the in vitro drug release results in example 2. Although not wishing to be bound by theory, it is possible that the RGD-VC-CA cannot form effective release due to too harsh release conditions of RGD-VC-CA, thereby leading to IC of RGD-VC-CA 50 The results after addition of the releasing agent were all too high to achieve a high antitumor effect. Moreover, as can be seen from C in fig. 9, the anti-tumor effect of the compound of the present invention under the action of the releasing agent is almost completely consistent with that of the original drug 1a, which indicates that the compound of the present invention perfectly realizes the effective release of the active drug.
Example 4 evaluation of antitumor Activity in vivo
Balb/c male nude mice of 6 weeks old were used to establish tumor transplantation models. Collecting 1X 10 7 A549 cells, washed twice with cold PBS, suspended in fresh serum-free, high-glucose DMEM, and injected subcutaneously into the right forelimb of each mouse. When the tumor volume reaches 50mm 3 (LxW × 1/2W), the rats were randomly divided into 3 groups of 7 rats. RGD-SS-CA (2) at 5mg/kg was dispersed in 100. Mu.L of 10-% DMSO/PBS, and injected every two days through the tail vein for 10 times in total to obtain the RGD-SS-CA group. RGD-VC-CA (3) at 5mg/kg was dispersed in 100. Mu.L of 10% DMSO/PBS, and injected every two days through the tail vein for 10 injections, which was the RGD-VC-CA group. Equal volume of 10% DMSO/PBS was used as a control. The body weight and tumor volume of the mice were measured before each injection. After 10 injections, mice were sacrificed, tumors were stripped and weighed. All animal complianceThe use rules of the animal administration and use committee of Shenzhen advanced technology research institute of national academy of sciences. All data are presented as mean ± standard deviation. Statistical analysis was performed by GraphPad Prism 5.0 software using the method of ANOVA to assess differences between groups. * P<0.05 was considered to have a significant difference.
In vivo animal experiments show (figure 10) that the intravenous injection of 5mg/kg RGD-VC-CA (2 injections every two days) already causes the body weight of the mice to drop sharply, and finally the mice die. The group did not complete 10 injections. The RGD-SS-CA group and the control group have no obvious weight change when 5mg/kg of RGD-SS-CA is intravenously injected every two days (10 times in total); the tumor volume of the drug group is slowly increased, while the tumor volume of the control group is in a steady-state increasing trend; after the experiment is finished, the mice are killed, the stripped tumor tissues are weighed, and the average mass of the RGD-SS-CA group tumors is 4 times smaller than that of the control group, which shows that the RGD-SS-CA can effectively inhibit the growth of the tumors and has small toxic and side effects.
Claims (12)
1. A targeted traceless release drug conjugate having the structural formula shown in formula I:
wherein R is 1 The amino group of a lysine side chain of the RGD peptide forms an amido bond in a structural formula shown in a formula I for coupling;
R 2 is-CH 3 、-CH 2 OC(CH 3 ) 3 、-CH 2 OH;
R 3 is-CH 3 、-CH 2 O C(CH 3 ) 3 ;
A - Is CF 3 CO 2 - 、Cl - 、CH 3 COO-。
2. The targeted traceless release drug conjugate of claim 1, wherein the RGD peptide is selected from the group consisting of cyclic RGD peptide, RGDyK cyclic peptide.
4. The targeted traceless release drug conjugate of claim 1, wherein R is 2 is-CH 3 And R is 3 is-CH 3 (ii) a Or R 2 is-CH 2 OH and R 3 is-CH 2 OC(CH) 3 (ii) a Or R 2 is-CH 2 OC(CH) 3 And R is 3 is-CH 3 。
6. The process for the preparation of a targeted traceless release drug conjugate according to any of claims 1 to 5, comprising the steps of:
1) Coupling a linker to a chrysanthemumide a or a chrysanthemumide a analog;
2) Coupling the conjugate obtained in the step 1) with a targeting group; obtaining a targeted traceless release drug conjugate;
The structure of the kobupeptide A analogue isWherein R is 2 is-CH 3 、-CH 2 OC(CH 3 ) 3 、-CH 2 OH;R 3 is-CH 3 、-CH 2 O C(CH 3 ) 3 ;
7. The method for preparing a targeted traceless release drug conjugate according to claim 6, wherein the RGD peptide is selected from a cyclic RGD peptide and an RGDyK cyclic peptide.
8. The method of claim 6, wherein the step 1) comprises activating the linker compound with thionyl chloride, and reacting with a kobupeptide A or a kobupeptide A analog under the conditions of tetrabutylammonium iodide and N, N-diisopropylethylamine.
9. The method of claim 6, wherein the reaction conditions of step 2) are such that the product of step 1) reacts with the targeting group under conditions of sodium ascorbate and copper sulfate.
10. Use of the targeted traceless release drug conjugate of any of claims 1-5 in the preparation of a medicament for the treatment of a tumor.
11. The use according to claim 10, wherein the tumor is selected from one or more of colon cancer, rectal cancer, brain tumor, glioblastoma, lung cancer, epidermal squamous carcinoma, bladder cancer, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, colorectal cancer, renal cell carcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-hodgkin's lymphoma, liver cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, and nasopharyngeal cancer.
12. The use of claim 11, wherein the lung cancer is non-small cell lung cancer and the glioblastoma is glioma.
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CN109908363A (en) * | 2017-12-12 | 2019-06-21 | 深圳先进技术研究院 | It is a kind of to target seamless release drug conjugate and the preparation method and application thereof |
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CN107596380A (en) * | 2017-09-03 | 2018-01-19 | 河南师范大学 | Reduction-sensitive camptothecine prodrug based on polyethylene glycol makrolon and its preparation method and application |
CN109908363A (en) * | 2017-12-12 | 2019-06-21 | 深圳先进技术研究院 | It is a kind of to target seamless release drug conjugate and the preparation method and application thereof |
CN111944140A (en) * | 2020-08-28 | 2020-11-17 | 南开大学 | Polymeric prodrug micelle with reduction responsiveness and preparation method and application thereof |
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