CN111484501A - Hydroxycamptothecin linoleate micromolecule prodrug and construction of self-assembled nanoparticles thereof - Google Patents
Hydroxycamptothecin linoleate micromolecule prodrug and construction of self-assembled nanoparticles thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and relates to a hydroxycamptothecin linoleate micromolecule prodrug and construction of self-assembled nanoparticles thereof. Meanwhile, the shape representation of the prodrug self-assembly nanoparticles and the in-vivo and in-vitro anti-tumor effects are inspected by taking the hydroxycamptothecine solution as a control. More choices are provided for designing camptothecin drug nano-preparations with high drug-loading rate, a new strategy is provided for developing a high-efficiency low-toxicity drug delivery system, the clinical service life of first-line chemotherapeutic drugs is prolonged, and the urgent need of high-end cancer chemotherapeutic preparations in clinic is met.
Description
Technical Field
The invention belongs to the field of new auxiliary materials and new dosage forms of medicinal preparations, and comprises construction of a hydroxycamptothecin linoleate micromolecule prodrug and self-assembled nanoparticles thereof, and application of the prodrug in medicament delivery.
Background
Cancer threatens the health of all people, and according to the World Health Organization (WHO), more than 800 million people die of cancer every year worldwide. Chemotherapy is an important approach in cancer treatment, especially for tumors that cannot be surgically removed and metastasized for dissemination. Camptothecin drugs can exert good antitumor drugs by inhibiting DNA topoisomerase I. In the research on camptothecin and derivatives thereof, it is found that the anti-tumor activity of camptothecin can be greatly enhanced by hydroxylating the 10-position of camptothecin, so that 10-hydroxycamptothecin (called hydroxycamptothecin for short) and 7-ethyl-10-hydroxycamptothecin become the first choice of camptothecin anti-cancer drugs. However, the effective delivery of camptothecin drugs is not easy due to their poor water solubility and ester solubility and strong urinary toxicity. Although camptothecin drugs have potential application to various solid tumors, the development of camptothecin drug formulations is not completed once.
With the development of nanotechnology, the development of camptothecin drugs by the same lines at home and abroad still starts with the traditional nanometer preparation. However, the conventional nano-formulation still has some problems such as low drug loading, leakage and stability in systemic circulation, etc. Therefore, a new idea is needed for developing camptothecin medicaments with high drug loading and good stability. The small molecule prodrug self-assembly nano-drug delivery system is used as a drug carrier and can release an active parent drug, shows the advantages of ultrahigh drug loading and low auxiliary material related toxicity, and has become a hotspot of chemotherapy drug delivery research in recent years. However, the paclitaxel-docosahexaenoic acid prodrug enters the clinical stage III, the clinical result of the stage III is not ideal, and the parent drug is difficult to release from the prodrug rapidly, so the paclitaxel-docosahexaenoic acid prodrug has no obvious advantage in inhibiting the growth of melanoma compared with the first-line anticancer drug dacarbazine.
And the disulfide bond with redox sensitivity is introduced between fatty acid and chemotherapeutic drugs, and the constructed disulfide bond bridged small molecule prodrug can efficiently release the parent drug by utilizing the highly expressed redox environment in the tumor microenvironment. Therefore, the development of the redox-sensitive hydroxycamptothecin prodrug aims to solve the problems of low solubility of camptothecin drugs and difficulty in developing preparations and improve the drug properties of the camptothecin drugs. The platform has certain universality, can also be applied to the development of other camptothecin and derivatives thereof pharmaceutical preparations, reverses the current situation that the clinical application of camptothecin medicaments is limited, and prolongs the clinical life of the camptothecin medicaments.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a hydroxycamptothecin linoleate prodrug with redox double sensitivity, as shown in table 1, and the self-assembled nano preparation has extremely high drug loading rate before and after different degrees of PEGylation. The prodrug is used for self-assembled nanoparticles, and can realize the effects of high drug loading, good stability and low toxic and side effects, thereby improving the antitumor activity.
The invention aims to design and synthesize a high drug-loading rate and redox-sensitive hydroxycamptothecin linoleate prodrug, prepare prodrug self-assembly nanoparticles, research the preparation characteristics and the form of the prodrug self-assembly nanoparticles and the influence of in vivo and in vitro pharmacodynamics compared with a solution, probe the superiority of the redox-sensitive prodrug, provide a new strategy and more choices for developing an intelligent tumor microenvironment response type drug delivery system, and meet the urgent need of high-efficiency chemotherapy preparations in clinic.
The invention realizes the aim through the following technical scheme:
the invention relates to a prodrug of hydroxycamptothecin linoleate (HCPT-SS-L A) with redox double sensitivity, which is synthesized by connecting hydroxycamptothecin serving as a mimic drug with 2,2' -dithiodiethanol, and has the structural formula:
further, the invention provides a method for synthesizing the hydroxycamptothecin linoleate prodrug, which comprises the following steps: firstly, linoleic acid and 2,2' -dithiodiethanol are esterified to obtain an intermediate product. Then the intermediate product is made into carbonic ester with one molecule of hydroxycamptothecin to obtain the final product.
Specifically, the invention provides a synthesis method of an intermediate product for forming ester by linoleic acid and 2,2' -dithiodiethanol, which comprises the following steps:
adding linoleic acid into toluene solution dissolved with p-toluenesulfonic acid and 2,2' -dithiodiethanol, and reacting in a system of N2Heating to 110 ℃ under protection, detecting the reaction completion by T L C, and then using saturated NaHCO3Extracting with anhydrous Na2SO4Removing excessive water, and separating by column chromatography to obtain the intermediate product.
The invention provides a method for synthesizing a hydroxycamptothecin linoleate micromolecule prodrug, which comprises the following steps:
the intermediate was dissolved in dichloromethane, DIPEA and p-nitrophenyl chloroformate were added under ice-bath conditions and stirred at room temperature overnight. Decompressing and rotary evaporating to remove the solvent, redissolving the system by DMF, carrying out ice bath to 0 ℃, slowly adding hydroxycamptothecin solution dissolved in DMF, adding anhydrous triethylamine, reacting for 24 hours at room temperature, and separating and purifying the obtained product by a preparation liquid phase after extraction treatment.
The linoleic acid in the invention can be replaced by oleic acid, stearic acid, trans-oleic acid, α -linolenic acid, gamma-linolenic acid, docosahexaenoic acid and arachidonic acid.
The invention also provides the hydroxycamptothecin linoleate micromolecule prodrug self-assembly nanoparticles and a preparation method thereof.
The small molecule prodrug nanoparticles can be non-PEG prodrug nanoparticles and PEG modified prodrug nanoparticles.
The hydroxycamptothecin can be replaced by other anticancer drugs containing active hydroxyl or amino, such as camptothecin compounds, nucleoside compounds, anthracycline compounds or taxane compounds.
The preparation method of the hydroxycamptothecin linoleate micromolecule prodrug self-assembly nanoparticles provided by the invention comprises the following steps:
dissolving a certain amount of hydroxycamptothecin linoleate micromolecule prodrug singly or in a mixture with a PEG modifier into a proper amount of tetrahydrofuran, slowly dripping the tetrahydrofuran solution into water under stirring, and spontaneously forming uniform nanoparticles by the prodrug. Finally, removing tetrahydrofuran in the preparation by adopting a reduced pressure rotary evaporation method to obtain the nano colloidal solution without any organic solvent.
The PEG modifier is TPGS, DSPE-PEG, P L GA-PEG, PE-PEG and the like, the preferable PEG modifier is TPGS, the molecular weight of the PEG is 1000-5000, specifically 1000, 2000 and 5000, the preferable PEG molecular weight is 2000, the weight ratio of the micromolecular prodrug to the PEG modifier is 92: 8-70: 30, and under the condition of the range, the hydroxycamptothecin can exert the best anti-tumor effect.
(1) The preparation method of the non-PEG small molecule prodrug self-assembly nanoparticle comprises the following steps: dissolving a certain amount of prodrug into a proper amount of tetrahydrofuran, slowly dripping the tetrahydrofuran solution into water under stirring, and spontaneously forming uniform nanoparticles by the prodrug. Removing tetrahydrofuran in the preparation by reduced pressure rotary evaporation method to obtain nano colloidal solution without any organic solvent.
(2) Dissolving a certain amount of PEG modifier (TPGS, DSPE-PEG, P L GA-PEG or PE-PEG) and prodrug into proper amount of tetrahydrofuran, stirring, slowly dripping the tetrahydrofuran solution into water, and spontaneously forming uniform nanoparticles from the prodrug.
The invention investigates the optimal prescription and the representation of the hydroxycamptothecin linoleate prodrug and the antitumor activity of the prodrug self-assembled nanoparticles.
The result shows that the prodrug can be self-assembled into nanoparticles if not PEGylated, HCPT-SS-L A can also form stable nanoparticles with the particle size of about 160nm when PEGylated nanoparticles are obviously reduced, the particle size of about 140nm when 8% PEGylated nanoparticles are PEGylated, the particle size of about 135nm when 20% PEGylated nanoparticles are about 135nm, the nanoparticle colloid stability of 20% PEGylated nanoparticles is better, and compared with the traditional nanometer preparation, the colloid stability of non-PEGylated and 8% PEGylated nanoparticles is poorer.
The hydroxycamptothecin linoleate micromolecule prodrug or the pharmaceutical composition thereof or the micromolecule prodrug self-assembly nanoparticles thereof can be used for preparing a tumor microenvironment intelligent response type drug delivery system. And can be used for injection, oral administration or topical administration.
The invention has the following beneficial effects: (1) the redox double-sensitive small molecule prodrug bridged by the disulfide bond is designed and synthesized, and the synthesis method is simple and easy to implement; (2) the uniform small-molecule prodrug self-assembly nanoparticles are prepared, the preparation method is simple and easy to implement, the stability is good, and the efficient entrapment of the hydroxycamptothecin is realized; (3) the morphological representation of the disulfide bond bridged prodrug self-assembled nanoparticles is investigated, and the in vivo and in vitro anti-tumor effects are achieved. The advantages of disulfide bond bridged micromolecule self-assembled prodrug are displayed, a new strategy and more choices are provided for developing an intelligent response type tumor microenvironment drug delivery system, and the urgent need of high-efficiency low-toxicity chemotherapy preparations in clinic is met.
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FIG. 1 shows the preparation of hydroxycamptothecin linoleate (HCPT-SS-L A) according to example 1 of the present invention1HNMR spectrogram.
FIG. 2 is a mass spectrum of hydroxycamptothecin linoleate (HCPT-SS-L A) according to example 1 of the present invention.
Fig. 3 is a transmission electron microscope image of PEG-unmodified small molecule prodrug self-assembled nanoparticles of example 2 of the present invention.
Fig. 4 is a transmission electron microscope image of 8% PEG-modified small molecule prodrug self-assembled nanoparticles of example 2 of the present invention.
Fig. 5 is a transmission electron microscope image of 20% PEG-modified small molecule prodrug self-assembled nanoparticles of example 2 of the present invention.
FIG. 6 is a transmission electron microscope image of hydroxycamptothecin nanocrystal of the invention in example 2.
Fig. 7 is a cytotoxicity diagram of PEG-modified small molecule prodrug self-assembled nanoparticles of example 3 of the invention.
Fig. 8 is a graph of the change in tumor volume of a mouse in an in vivo anti-tumor experiment of PEG-modified small molecule prodrug self-assembled nanoparticles of example 4 of the present invention.
Fig. 9 is a mouse tumor burden graph of the PEG-modified small molecule prodrug self-assembled nanoparticle of embodiment 4 of the present invention in an in vivo anti-tumor experiment.
Fig. 10 is a graph of the change in body weight of a mouse in an in vivo anti-tumor experiment of the PEG-modified small molecule prodrug self-assembled nanoparticle of example 4 of the present invention.
Fig. 11 is a mouse tumor comparison graph of the PEG-modified small molecule prodrug self-assembly nanoparticle of example 4 of the present invention in an in vivo anti-tumor experiment.
Fig. 12 is a safety experiment chart of PEG-modified small molecule prodrug self-assembled nanoparticles of example 4 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
EXAMPLE 1 Synthesis of hydroxycamptothecin linoleate Small molecule prodrug (HCPT-SS-L A)
Adding linoleic acid into toluene solution dissolved with p-toluenesulfonic acid and 2,2' -dithiodiethanol, and reacting in a system of N2Heating to 110 ℃ under protection, detecting the reaction completion by T L C, and then using saturated NaHCO3Extracting with anhydrous Na2SO4Removing excessive water, and performing column chromatographyThe intermediate product is obtained by separation. The intermediate was dissolved in dichloromethane, DIPEA and p-nitrophenyl chloroformate were added under ice-bath conditions and stirred at room temperature overnight. Decompressing and rotary evaporating to remove the solvent, redissolving the system by DMF, carrying out ice bath to 0 ℃, slowly adding hydroxycamptothecin solution dissolved in DMF, adding anhydrous triethylamine, reacting for 24 hours at room temperature, and separating and purifying the obtained product by a preparation liquid phase after extraction treatment.
Mass spectrometry and NMR spectroscopy were used to determine the structure of the prodrug of example 1, and the results are shown in FIG. 1. The solvent selected for nuclear magnetic resonance is CDCl3The results of the spectrum analysis were as follows:
1H NMR(400MHz,CDCl3)8.36(s,1H,Ar-H),8.26(d,J＝9.3Hz,1H,Ar-H),7.79(d,J＝2.6Hz,1H,Ar-H),7.69–7.64(m,1H,Ar-H),5.75(d,J＝16.4Hz,1H,Py-H),5.43–5.27(m,4H,-CH＝CH-),4.58(d,J＝6.6Hz,1H,-OH),4.37(q,J＝6.5Hz,2H,Py-C 2H-O-C＝O-),3.77(s,2H,Py-N-C 2H-),3.08(t,J＝6.5Hz,2H,-C 2H-O-C＝O-O-),2.98(t,J＝6.6Hz,2H,-C＝O- 2CH-),2.95–2.86(m,4H,-C 2H-SS-C 2H-),2.76(s,2H,-CH＝CH-C 2H-CH＝CH-),2.32(t,J＝7.8Hz,2H,-C 2H-C＝O-O-),2.03(s,4H,-CH＝CH-C 2H-),1.63(s,2H),1.30(s,18H,-C 2H-),1.05(t,J＝7.4Hz,3H,-CH2-C 3H),0.94–0.83(m,3H,-(CH2)4-C 3H).MS(ESI)m/z for HCPT-SS-LA[M+H]+＝807.33263,[M-H]-＝805.31754.
example 2: preparation of small molecule prodrug self-assembled nanoparticles
TPGS is weighed to precision2kProper amount (8% is 0.35mg, 20% is 1mg, 30% is 1.7mg) and prodrug 4mg, dissolving the tetrahydrofuran with 1m L tetrahydrofuran, slowly dripping the tetrahydrofuran solution into 4m L deionized water under stirring to spontaneously form uniform nanoparticles (HCPT-SS-L A nanoparticles, HCPT-SS-L A/8% PEG nanoparticles, HCPT-SS-L A/20% PEG nanoparticles, HCPT-SS-L A/30% PEG nanoparticles), and performing reduced pressure rotary evaporation at 35 deg.CRemoving organic solvent from the nanometer preparation.
TABLE 1 drug loading of hydroxycamptothecin linoleate prodrugs
The prodrug self-assembly nanoparticles can be prepared by the prescription in the table 1, but the particle sizes of 30% of PEG nanoparticles in different batches are not reproducible and fluctuate near 130-160nm, while the particle sizes of 8% of PEG nanoparticles and 20% of PEG nanoparticles in different batches are almost not different, so that TPGS possibly modified on the surface of 30% of PEG nanoparticles is supposed to be saturated, part of TPGS is self-assembled into micelles in a system, and the drug loading factor is considered at the same time, so that the 30% PEG prescription is eliminated in subsequent researches.
As shown in Table 2, the particle size of the nanoparticles is 135-165nm, the particle size distribution of the nanoparticles after PEGylation is less than 0.2, the surface charge is about-20 mV, and the drug loading is more than 35%. The particle size and morphology of the small molecule prodrug self-assembled nanoparticles prepared in example 2 and the hydroxycamptothecin nanocrystals prepared by the same method are determined by a transmission electron microscope, and the result is shown in fig. 2, and a transmission electron microscope picture shows that the drug-loaded nanoparticles are uniform spheres with the particle size of 120-100 nm.
TABLE 2 particle size, particle size distribution, surface charge, and drug loading of small molecule prodrug self-assembled nanoparticles
Example 3: cytotoxicity of PEG-modified small-molecule prodrug self-assembled nanoparticles
The cytotoxicity of PEG modified small molecule prodrug self-assembly nanoparticles on mouse breast cancer (4T1) cells is examined by adopting an MTT method, the cells in a good state are digested, the culture solution is diluted to 1000cells/m L cell density, 200 mu L of cell suspension is added into each hole of a 96-hole plate after the cells are uniformly blown, the cells are placed in an incubator for incubation for 24 hours to adhere to the cells, hydroxycamptothecin or the prodrug prepared in example 2 is added after the cells adhere to the cells, 1640 culture solution is used for preparation and dilution of the drug solution and the nanoparticle preparation in the experiment, 1640 filtration is carried out in a sterile manner by a 1640 filter membrane with 0.22 mu m, 200 mu L of tested solution is added into each hole, 3 parallel holes are formed in each concentration, the control group is not added with liquid medicine to be tested, 200 mu L of culture solution is singly added, the cells are placed in the incubator and incubated together with the cells, the 96 is taken out after the medicine is added for 48 hours, 35 mu L mu of 5mg/m MTT solution is added into each hole, the plate is placed in the incubator, the incubator is thrown, the 96 is fully covered on the 96-hole, the residual liquid is sucked on the 96-hole of the DMSO-hole plate, and the DMSO-adjusting the DMSO-hole is added, the absorbance-0.26-0.20 mu-0..
The cytotoxicity of the prodrug nanoparticles is lower than that of HCPT-SS-L A/8% PEG nanoparticles, and the cytotoxicity of the prodrug nanoparticles is lower than that of HCPT-SS-L A/20% PEG nanoparticles, because the HCPT-SS-L A/20% PEG nanoparticles is better than that of the former, the prodrug can exist in tumor cells for a longer time, as shown in Table 3, the advantages of the HCPT-SS-L A/20% PEG nanoparticles are more obvious after 72-hour incubation, the cytotoxicity of the nanoparticles is better ensured, the colloidal stability of the nanoparticles is ensured firstly, and therefore 20% of PEG modification can provide a nano preparation with stronger anti-tumor capacity than 8% of PEG modification under the same administration dosage.
TABLE 3 semi-Inhibitory Concentration (IC) of hydroxycamptothecin and prodrug nanoparticles on mouse breast cancer (4T1) cells50)
Example 4: in-vivo anti-tumor experiment of PEG (polyethylene glycol) -modified small-molecule prodrug self-assembled nanoparticles
The anti-tumor activity of the PEG modified small molecule prodrug self-assembly nanoparticles on a 4T1 ectopic tumor model is investigated. 4T1 cell suspension (5X 10)6cells/50 μ L) was inoculated into female Balb/c right dorsal subcutaneous injection to construct a 4T1 ectopic tumor model when the tumor volume grew to 100m3On the left and right sides, tumor-bearing mice were randomly grouped, five mice in each group were given physiological saline, hydroxycamptothecin solution and PEG-modified small molecule prodrug self-assembly nanoparticles prepared in example 2, respectively. The preparation is administered 1 time every 1 day and 4 times continuously, and the dosage is 2.5mg/kg calculated according to hydroxycamptothecin. After the administration, the survival state of the mice was observed every day, the body weight was weighed, and the tumor volume was measured. Two days after the last dose, tumor-bearing mice were sacrificed, organs and tumors were harvested and further evaluated for analysis. Major organs (heart, liver, spleen, lung, kidney) and tumor tissues were collected and fixed with formalin for H&And E, dyeing.
However, as the HCPT-SS-L A/20% PEG nanoparticles have better colloidal stability, longer blood circulation and effective drug release, the anti-tumor activity of the HCPT-SS-L A/20% PEG nanoparticles is stronger than that of the HCPT-SS-L A/8% PEG nanoparticles, the body weight of mice treated by the nanoparticles is maintained at a stable level and does not show obvious body function damage, which shows that the toxicity of hydroxycamptothecin is reduced because the HCPT-SS-L A nanoparticles selectively release the drug in tumor cells.
Claims (10)
1. The hydroxycamptothecin linoleate micromolecule prodrug is characterized in that hydroxycamptothecin is used as a mimic drug and is connected through 2,2' -dithiodiethanol to synthesize the prodrug, and the structure of the prodrug is as follows:
2. the hydroxycamptothecin linoleate small molecule prodrug of claim 1, wherein linoleic acid can be replaced with oleic acid, stearic acid, trans-oleic acid, α -linolenic acid, gamma-linolenic acid, docosahexaenoic acid, arachidonic acid.
3. The hydroxycamptothecin linoleate small molecule prodrug of claim 1, wherein the hydroxycamptothecin can be replaced by other anticancer drugs containing active hydroxyl or amino groups, preferably camptothecin, nucleoside, anthracycline or taxane compounds.
4. The method of claim 1, wherein the ester of linoleic acid with 2,2' -dithiodiethanol is formed as an intermediate, and the intermediate is then formed into a carbonate with a molecule of hydroxycamptothecin to form the final product.
5. The method of claim 3, wherein the method comprises the steps of:
adding linoleic acid into toluene solution dissolved with p-toluenesulfonic acid and 2,2' -dithiodiethanol, and reacting in a system of N2Heating to 110 deg.C under protection, detecting reaction with T L C, and detecting with saturated NaHCO3Extracting with anhydrous Na2SO4Removing excessive water, and separating by column chromatography to obtain intermediate product; dissolving the intermediate product in dichloromethane, adding DIPEA and p-nitrophenylchloroformate under ice bath condition, stirring at room temperature overnight, removing solvent by reduced pressure rotary evaporation, redissolving the system with DMF, ice-cooling to 0 deg.C, and slowly coolingAdding hydroxycamptothecin solution dissolved in DMF, adding anhydrous triethylamine, reacting at room temperature for 24 hr, and separating and purifying the product by liquid phase separation.
6. A pharmaceutical composition comprising the hydroxycamptothecin linoleate small molecule prodrug of any one of claims 1-3 and a pharmaceutically acceptable carrier or excipient.
7. The self-assembled nanoparticle of the hydroxycamptothecin linoleate micromolecule prodrug is characterized by comprising the following preparation processes:
dissolving a certain amount of mixture of the hydroxycamptothecin linoleate micromolecule prodrug and the PEG modifier into a proper amount of tetrahydrofuran, slowly dripping the tetrahydrofuran solution into water under stirring, spontaneously forming uniform nanoparticles by the prodrug, and finally removing the tetrahydrofuran in the preparation by adopting a rotary evaporation method to obtain the nano colloidal solution without any organic solvent.
8. The docetaxel dimer small molecule prodrug self-assembled nanoparticle as claimed in claim 7, wherein the PEG is TPGS, DSPE-PEG, P L GA-PEG, PE-PEG and DSPE-PEG-AA, and the ratio of the small molecule prodrug to the PEG modifier is 92: 8-70: 30.
9. Use of a small molecule prodrug of hydroxycamptothecin linoleate according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 6 or small molecule prodrug self-assembled nanoparticles according to any one of claims 7 to 8 for the preparation of a drug delivery system.
10. Use of the hydroxycamptothecin linoleate small molecule prodrug of any one of claims 1 to 3, the pharmaceutical composition of claim 6 or the small molecule prodrug self-assembled nanoparticles of any one of claims 7 to 8 in preparation of an anti-tumor drug.
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