CN101590241B - Cisplatin nano-micelle prodrug and preparation method thereof - Google Patents
Cisplatin nano-micelle prodrug and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a cisplatin nano-micelle prodrug and a preparation method thereof in the technical field of nano medicaments. The cisplatin nano-micelle prodrug comprises the following compositions in percentage: 5 to 30 percent of cisplatin and 95 to 70 percent of macromolecular carrier modified by folic acid. The chemical structure of the cisplatin nano-micelle prodrug is as follows: wherein a and b are respectively integers more than or equral to 10 and less than or equal to 60; x is an integer more than or equal to 23 and less than or equal to 92; FA is the folic acid, and m=0, 1 or 2. The cisplatin nano-micelle prodrug is a cisplatin nano-micelle drug carrier system which has narrow particle size distribution, can perform long-acting circulation in blood,and has double targeting effects on lung cancer tissues and adjustable drug release rate so as to improve the water-solubility and the drug-loading rate of the cisplatin, and simultaneously reduce the toxic and side effects of the cisplatin to the utmost.
Description
Technical field
What the present invention relates to is medicine of a kind of technical field of pharmaceuticals and preparation method thereof, specifically is a kind of cisplatin nano-micelle prodrug and preparation method thereof.
Background technology
(cis dichloro two ammino platinum CDDP) are a kind of cell cycle nonspecific agent (CCNSA) to cisplatin, can combine with DNA to form cross-bond, thereby destroy the copy function of DNA and suppress cell division.Clinical practice proof cisplatin has that anticancer spectrum is wide, effect is strong, with multiple antitumor drug synergism is arranged and do not have characteristics such as crossing drug resistant, be one of medicine the most frequently used in the current combined chemotherapy, be widely used in ovarian cancer, cervical cancer, carcinoma of testis, breast carcinoma, esophageal carcinoma, nonsmall-cell lung cancer and gastric cancer etc.Yet, the water solublity that cisplatin is low, severe digestive tract reaction, bone marrow depression, acoustic nerve toxicity especially easily cause irreversible damage etc. to limit the further raising of its clinical efficacy to kidney.
Find through retrieval prior art, cisplatin is stated from the good α of biocompatibility by chemical bond, on β-poly-(altheine) amino acid derivativges carrier, also reduce (Lv Zhengrong, Yu Jiahui greatly improving its cellulotoxic side effect of water miscible while of cisplatin, Zhuo Renxi, Wang Xuli, Yang Fuhua, SCI, 19 (1998), 817-820; Wang Chengyun, Gong Yanbao, Liu Shunying, Luo Shufang, Huang advances, Yu Jiahui, SCI, 8 (2008) 1665-1670); Wu Zirong etc. find that the macromole cisplatin medicine can effectively reduce the toxicity of cisplatin, and improve its active anticancer (Haifeng Ye with gamma-polyglutamic acid-/cisplatin macromolecule Drug therapy human breast cancer in nude mice, Li Jin, Rongzhang Hu, Zhengfang Yi, Jing Li, YelinWu, Xuguang Xi, Zirong Wu, Biomaterials, 27 (2006), 5958-5965), but the drug loading of these two kinds of carriers is all very low, is no more than 10%.Kataoka etc. are assembled into nano-micelle with cisplatin and polyethylene glycol-glutamic acid (PEG-b-Glu) di-block copolymer, drug loading has obtained improving greatly, can reach about 30%, the cisplatin nano-micelle medicine is good to the therapeutic effect of nude mice solid tumor models, demonstrate good clinical application prospect (Nobuhiro Nishiyama, Souichiro Okazaki, Horacio Cabral, MasakiMiyamoto, Yukio Kato, Yuichi Sugiyama, Kazuto Ni shio, Yasuhiro Matsumura, and Kazunori Kataoka, Cancer Research, 63 (2003) 8977-8983; NobuhiroNishiyama, Masayuki Yokoyama, Takao Aoyagi, Teruo Okano, Yasuhisa Sakurai, and Kazunori Kataoka, Langmuir, but the micelle particle diameter influences the passive target effect below 30nm 15 (1999) 377-383).
Summary of the invention
The present invention is directed to the prior art above shortcomings, a kind of cisplatin nano-micelle prodrug and preparation method thereof is provided, utilize the principle of cisplatin induction graft copolymer macromolecule generation nanoscale molecule self assembly, assemble a class particle diameter 70-100nm and controlled, narrow diameter distribution, can long-acting circulation in blood, cancerous lung tissue is had cisplatin nano-micelle drug-loading system dual-target, that rate of releasing drug is adjustable, in the hope of improving the water solublity of cisplatin, improve its drug loading, lower its toxic and side effects simultaneously to greatest extent.
The present invention is achieved by the following technical solutions:
The cisplatin nano-micelle prodrug that the present invention relates to, its component and mass percent are: the macromolecule carrier 95～70% of cisplatin 5～30% and modified with folic acid, the chemical constitution of this cisplatin nano-micelle prodrug is as follows:
Wherein: a and b are respectively more than or equal to 10 and smaller or equal to 60 integer, and x is more than or equal to 23 and smaller or equal to 92 integer, FA is a folic acid, m=0,1 or 2.
Described complex ring is: 6,7,8 annulus
The micelle particle diameter of described cisplatin nano-micelle prodrug is 70～100nm, and outside at described micelle is 1000～10000 Polyethylene Glycol with some molecular weight, at the end of Polyethylene Glycol with folate molecule.
The preparation method of the cisplatin nano-micelle prodrug that the present invention relates to may further comprise the steps:
Polyethylene Glycol aminoderivative (the FA-PEG-NH of the first step, synthetic single-ended modified with folic acid
2): taking polyethylene glycol diamino (NH at first
2-PEG-NH
2), folic acid and N; the N-dicyclohexylcarbodiimide is dissolved in the dimethyl sulfoxide; add then behind the pyridine at room temperature with nitrogen protection environment stirring reaction 48 hours; after the reuse distilled water diluting filters filtrate carried out successively molecular weight and be 1000 dialysis freezing processing and purification process, make FA-PEG-NH
2
Described dialysis freezing processing is meant: with bag filter filtrate is placed at dialysis 72h postlyophilization in the deionized water;
Described purification process is meant: with the DEAE-sepharose anion-exchange column filtrate after freezing is carried out purification;
Second step, synthetic polysuccinimide (PSI): at first be dissolved in the L-aspartic acid in the sulfolane and add phosphoric acid; under the environment of nitrogen protection, use oil water separator to dewater then; carry out reflux processing and the processing of cooling sucking filtration more successively, obtain the polysuccinimide solid.
Described reflux is handled and is meant: be heated under the 60 degree environment back flow reaction 24 hours;
Described cooling sucking filtration is handled and is meant: adopt the water pump decompressor to carry out sucking filtration under the room temperature environment behind the natural cooling, filtrate is precipitated with methanol or absolute ether again, at last precipitate is carried out drying under vacuum environment.
The 3rd step, FA-PEG-NH
2Part open loop PSI (FA-PEG-g-PSI): be dissolved in the polysuccinimide solid for preparing in second step in the dimethyl formamide and place under the nitrogen protection environment; With the FA-PEG-NH for preparing in the first step
2Be dissolved in addition and make folic acid nano-carrier-dimethyl formamide solution in the dimethyl formamide, again folic acid nano-carrier-dimethyl formamide solution is splashed in polysuccinimide-dimethyl formamide solution, carry out reflux then successively and handle, cool off the sucking filtration processing, make the folic acid nano-carrier.
The concentration of polysuccinimide is 50g/L in described polysuccinimide-dimethyl formamide solution;
The concentration of described folic acid nano-carrier-dimethyl formamide solution middle period acid activity material is 62.5g/L;
The 4th step, synthesizing amino malonic acid: diethyl acetamido is dissolved in forms diethyl acetamido-alcoholic solution in the dehydrated alcohol, at room temperature reacted 24 hours after feeding hydrogen chloride gas then, make amidomalonic acid diethylester hydrochlorate, again amidomalonic acid diethylester hydrochlorate is dissolved in the potassium hydroxide solution, carrying out reflux successively handles and the frozen water cooling processing, regulate pH value to 6 with acetic acid at last, and cool off sucking filtration processing back and carry out the secondary crystallization processing with ammonia-alcoholic solution, get amidomalonic acid.
The concentration of diethyl acetamido is 1mol/L in described diethyl acetamido-alcoholic solution;
The consumption of described hydrogen chloride gas is 34g;
The concentration of described potassium hydroxide solution is 10mol/L, and its consumption is 200mL;
The mass percent concentration of described acetic acid is 30%;
Described secondary crystallization is handled and is meant: with ammonia-alcohol mixed solution recrystallization;
The 5th step, the whole open loop FA-PEG-g-PSI of aminoacid (FA-PEG-g-PAspM): get the FA-PEG-g-PSI aqueous solution that makes in the 3rd step and add in the amidomalonic acid that makes in the 4th step, splashed into behind the triethylamine under the lucifuge environment stirring at room 24 hours, regulate pH value to 5 with hydrochloric acid then and cool off successively that sucking filtration is handled and molecular weight is 3500 dialysis freezing processing, carry out lyophilization at last and handle, obtain folic acid nanometer colloid bundle.
The 6th step, assembling cisplatin nano-micelle prodrug: cis dichloro two ammino platinum and FA-PEG-g-PAspM carrier are soluble in water, under 37 ℃ of lucifuge benign environments, stirred 48 hours, the freezing processing of dialysing then makes cisplatin nano-micelle prodrug (FA-PEG-g-PAspM-CDDP).
Adopt o-phenylenediamine platinum complex/ultraviolet absorption method to measure cisplatin nano-micelle that the present invention prepares and obtain wherein that the content of platinum (II) is 28%, it is 89nm that dynamic light scattering records particle diameter.
Change the molecular weight of PEG or the nano-micelle that percent grafting can obtain different-grain diameter.
The present invention's its advantage compared to existing technology is: (1) is by molecular weight that changes PEG or the nano-micelle that percent grafting can obtain different-grain diameter, thus optimization passive target effect; (1) by changing FA-PEG-NH
2To the number of the open loop chlorine may command nano-micelle of PSI surface folic acid, thereby optimize initiatively targeting effect.
Description of drawings
Fig. 1 is the sketch map of cisplatin nano-micelle prodrug assembly.
Fig. 2 is FA-PEG-NH
2The NMR spectrogram.
Fig. 3 is the NMR spectrogram of FA-PEG-g-PSI.
Fig. 4 is the NMR spectrogram of FA-PEG-g-PAspM.
Fig. 5 is particle diameter and the particle size distribution figure of FA-PEG-g-PAspM-CDDP;
Wherein: (a) PEG1000,70nm; (b) PEG2000,89nm; (c) PEG4000,105nm.
Fig. 6 is the Release Performance contrast sketch map of embodiment 1;
Wherein: (a) FA-PEG-g-PAspM-CDDP; (b) FA-PEG-g-PAspG-CDDP; (c) FA-PEG-g-PAspA-CDDP.
Fig. 7 is embodiment 1 a toxicity contrast sketch map;
Wherein: (a) CDDP; (b) PBS; (c) FA-PEG-g-PAspM-CDDP.
Fig. 8 is that embodiment 1 growth of cancer cells suppresses the effect sketch map;
Wherein:
1: PBS;
2: FA-PEG-g-PAspM-CDDP, amount to CDDP 5mg/kg;
3: FA-PEG-g-PAspM-CDDP, amount to CDDP10mg/kg.
The specific embodiment
Below in conjunction with accompanying drawing embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Wherein: a=5, b=95, x=45, m=0, FA be folic acid.
As shown in Figure 1, the micelle particle diameter of described cisplatin nano-micelle prodrug is 89nm, and outside at described micelle is 1000～4000 Polyethylene Glycol 1 with some molecular weight, at the end of Polyethylene Glycol 1 with folate molecule 2.
Present embodiment prepares by following steps:
The first step, synthetic FA-PEG-NH
2:
1.1) get NH
2-PEG-NH
2(Mw2K, 1.0g, 0.5mmol), folic acid (FA, 0.22g, 0.5mmol), N, the N-dicyclohexylcarbodiimide (DCC, 0.12g 0.6mmol) are dissolved in the 10mL dimethyl sulfoxide (DMSO),
1.2) add 20 μ L pyridines, under the room temperature, N
2Protection stirring reaction 48h.Reactant liquor 10mL distilled water diluting filters, and removes by-product N, and N-1,3-Dicyclohexylurea (DCU) is the 1000 bag filters 72h postlyophilizations of dialysing in deionized water with filtrate with molecular cut off.
1.3) be further purified with the DEAE-sepharose anion-exchange column at last, get FA-PEG-NH
20.5g, its
1H NMR characterizes as shown in Figure 2.
Second step, synthetic PSI:
2.1) take by weighing 25g L-aspartic acid, be dissolved in the 60mL sulfolane, add 0.6mL phosphoric acid, nitrogen protection uses oil water separator to dewater reflux 24h.Be cooled to room temperature, sucking filtration except that not tolerant, is used the methanol reprecipitation, sucking filtration, and vacuum drying gets product 18g.
The 3rd step, synthetic FA-PEG-g-PSI:
3.1) (1g 10.2mmol) is dissolved in the 20mL dimethyl formamide, logical nitrogen protection with the PSI for preparing in second step;
3.2) get the FA-PEG-NH for preparing in the first step
2(2.5g 1.02mmol) is dissolved in the 40mL dimethyl formamide and with it and splashes in the PSI solution, after dripping, is heated to 60 degree, reacts 24 hours.
3.3) being cooled to room temperature, sucking filtration concentrates subnatant, uses the absolute ether reprecipitation, sucking filtration, vacuum drying gets product F A-PEG-g-PSI2g, its
1H NMR as shown in Figure 3.Change PSI and FA-PEG-NH
2Mol ratio can get the carrier of different folate contents.
The 4th step, synthesizing amino malonic acid:
4.1) get diethyl acetamido (0.2mol) and be dissolved in the 200ml dehydrated alcohol, feed the 34g hydrogen chloride gas, room temperature reaction 24h.Steam unnecessary HCl,
4.2) the amidomalonic acid diethylester hydrochlorate that generates is dissolved in 200mlKOH (2mol) solution, reflux 15min, the ice-water bath cooling, acetic acid with 30% is transferred PH=6, adds 200ml ethanol, must precipitate, sucking filtration, thick product, with ammonia-alcohol mixed solution recrystallization, amidomalonic acid (Mal) 0.13mol.
The 5th step, synthetic FA-PEG-g-PAspM:
5.1) (1.0g 10mmol) is dissolved in the 30ml water, adds amidomalonic acid (Mal) 15mmol, splashes into triethylamine to mixture and all dissolves (about 15ml), lucifuge, stirring at room 24h to get the FA-PEG-PSI that makes in the 3rd step.Transfer PH=5 with concentrated hydrochloric acid, sucking filtration except that not tolerant, concentrates subnatant, and (M=3500Da) dialysis is three days in the bag filter of packing into, changes distilled water three times.Concentrate, remove distilled water, lyophilization gets FA-PEG-g-PAspM0.8g, its
1H NMR characterizes as shown in Figure 4.Same method is used glutamic acid respectively, and aspartic acid open loop FA-PEG-PSI can get FA-PEG-g-PAspG, FA-PEG-g-PAspA.
The 6th step, assembling cisplatin nano-micelle prodrug
6.1) 15mg cisplatin and 20mgFA-PEG-g-PAspM are dissolved in the 10mL water, 37 ℃ of lucifuge gentle agitation 48h, dialysed 3 days, lyophilization, get final product cisplatin nano-micelle prodrug FA-PEG-g-PAspM-CDDP, the content of measuring platinum (II) with o-phenylenediamine platinum complex/ultraviolet absorption method is 28%, and it is 89nm that dynamic light scattering records particle diameter.The molecular weight that changes PEG can obtain the nano-micelle (Fig. 5) of different-grain diameter.
The Release Performance experiment of present embodiment is as follows:
In 10mL FA-PEG-g-PAspM-CDDP (the 90 μ g/mL) bag filter of packing into, place 480mL PBS (pH=7.4 again, NaCl=0.15g/L) in the beaker, stir dialysis in 37 ℃, take out the 1mL dialysis solution every 1 hour and replenish 1mL water, measure the content of platinum (II) with o-phenylenediamine platinum complex/ultraviolet absorption method.Its Release Performance as shown in Figure 6, wherein: (a) being FA-PEG-g-PAspM-CDDP, (b) is FA-PEG-g-PAspG-CDDP, (c) is FA-PEG-g-PAspA-CDDP.
Conclusion: regulate the rate of releasing drug of the adjustable size control cisplatin nano-micelle of complex ring between cisplatin and carrier, rate of releasing drug is followed successively by (a) FA-PEG-g-PAspM-CDDP (6 annulus)＜(b) FA-PEG-g-PAspG-CDDP (8 annulus)＜(c) FA-PEG-g-PAspA-CDDP (7 annulus)
The toxicity test of present embodiment is as follows:
(5-7 week 20-23g) is divided into 3 groups (between groups Mus great cause identical), 10 every group to healthy active ICR mice at random.With CDDP, FA-PEG-g-PAspM-CDDP (the amount intravenous injection that conversion is pressed 5mg/kg for CDDP, injection in per two days once, injection is 3 times continuously, matched group injection PBS is illustrated in figure 7 as embodiment 1 toxicity contrast sketch map, wherein: (a) be cisplatin CDDP, (b) being the PBS phosphate buffer solution, (c) is the FA-PEG-g-PAspM-CDDP nano-micelle.
Conclusion: after the administration, the body weight of CDDP group mice alleviates rapidly, loses weight about 40% in 12 days; The body weight of FA-PEG-g-PAspM-CDDP nano-micelle group mice increases gradually, after 18 days, mice is still healthy, the phenomena of mortality do not occur, the result is similar to the PBS group, illustrates that the toxicity specific ionization CDDP of FA-PEG-g-PAspM-CDDP nano-micelle is much lower.
It is as follows that present embodiment suppresses the pulmonary carcinoma growth experiment:
Choose healthy active BALB/c-nu nude mice, in Mus 4-6 in age week, body weight 18-20g inoculates lung cancer carcinoma cell M109 down in its preceding butt, and inoculating cell density is 1 * 10
8Individual/mL, every Mus inoculum concentration is 100 μ L.When tumor is long during to about 5mm left and right sides (being set at the 0th day), tumor bearing nude mice is divided into 3 groups (between groups Mus great cause identical), 8 every group at random.With CDDP, FA-PEG-g-PAspM-CDDP (conversion is CDDP) presses 5mg/kg, the amount intravenous injection of 10mg/Kg respectively, injection in per two days is once injected 3 times continuously, matched group injection PBS, per two days sizes with the vernier caliper measurement tumor, and be calculated as follows gross tumor volume V:
V＝3.14(a×b
2)/6
A wherein, b is respectively the minimum and maximum size of tumor, be illustrated in figure 8 as embodiment 1 growth of cancer cells and suppress the effect sketch map, wherein: 1 is PBS, 2 are preparation gained cisplatin nano-micelle prodrug, amount to cisplatin CDDP 5mg/kg, 3 for preparation gained cisplatin nano-micelle prodrug, amounts to cisplatin CDDP 10mg/kg.
Conclusion: FA-PEG-g-PAspM-CDDP has the obvious suppression effect to the nude mice liver tumor, and be certain concentration dependence, as FA-PEG-g-PAspM-CDDP during with 10mg/kg (amounting to into the dosage of CDDP) administration, tumor growth slowly (curve 3) in 20 day time; As FA-PEG-g-PAspM-CDDP during with the 5mg/kg administration, tumor growth is slow in 10 day time, after 10 days, and tumor growth very fast (curve 2); Phosphate buffer solution does not suppress the effect (curve 1) of tumor growth.
Claims (3)
1. the preparation method of a cisplatin nano-micelle prodrug is characterized in that, may further comprise the steps:
The Polyethylene Glycol aminoderivative FA-PEG-NH of the first step, synthetic single-ended modified with folic acid
2Concrete steps are: at first taking polyethylene glycol diamino, folic acid and N; the N-dicyclohexylcarbodiimide is dissolved in the dimethyl sulfoxide; add then behind the pyridine at room temperature with nitrogen protection environment stirring reaction 48 hours; after the reuse distilled water diluting filters filtrate carried out successively molecular weight and be 1000 dialysis freezing processing and purification process, make FA-PEG-NH
2
Second step, synthetic polysuccinimide PSI, concrete steps are: at first be dissolved in the L-aspartic acid in the sulfolane and add phosphoric acid, under the environment of nitrogen protection, use oil water separator to dewater then, carry out reflux processing and the processing of cooling sucking filtration more successively, obtain the polysuccinimide solid;
The 3rd step, FA-PEG-NH
2Part open loop PSI makes FA-PEG-g-PSI, and concrete steps are: the polysuccinimide solid for preparing in going on foot second is dissolved in the dimethyl formamide and places under the nitrogen protection environment; With the FA-PEG-NH for preparing in the-step
2Be dissolved in addition and make folic acid nano-carrier-dimethyl formamide solution in the dimethyl formamide, again folic acid nano-carrier-dimethyl formamide solution is splashed in polysuccinimide-dimethyl formamide solution, carry out reflux then successively and handle, cool off the sucking filtration processing, make the folic acid nano-carrier;
The 4th step, synthesizing amino malonic acid, concrete steps are: diethyl acetamido is dissolved in forms diethyl acetamido-alcoholic solution in the dehydrated alcohol, at room temperature reacted 24 hours after feeding hydrogen chloride gas then, make amidomalonic acid diethylester hydrochlorate, again amidomalonic acid diethylester hydrochlorate is dissolved in the potassium hydroxide solution, carrying out reflux successively handles and the frozen water cooling processing, regulate pH value to 6 with acetic acid at last, and cool off sucking filtration processing back and carry out the secondary crystallization processing with ammonia-alcoholic solution, get amidomalonic acid;
The 5th step, the whole open loop FA-PEG-g-PSI of aminoacid make FA-PEG-g-PAspM, concrete steps are: get the FA-PEG-g-PSI aqueous solution that makes in the 3rd step and add in the amidomalonic acid that makes in the 4th step, splashed into behind the triethylamine under the lucifuge environment stirring at room 24 hours, regulate pH value to 5 with hydrochloric acid then and cool off successively that sucking filtration is handled and molecular weight is 3500 dialysis freezing processing, carry out lyophilization at last and handle, obtain folic acid nanometer colloid bundle;
The 6th step, assembling cisplatin nano-micelle prodrug, concrete steps are: cis dichloro two ammino platinum and FA-PEG-g-PAspM carrier are soluble in water, under 37 ℃ of lucifuge benign environments, stirred 48 hours, the freezing processing of dialysing then makes cisplatin nano-micelle prodrug FA-PEG-g-PAspM-CDDP.
2. a cisplatin nano-micelle prodrug for preparing according to the described method of claim 1 is characterized in that, its micelle particle diameter is 70～100nm, and its component and mass percent are: the macromolecule carrier 95～70% of cisplatin 5～30% and modified with folic acid; Chemical constitution is as follows:
Wherein: a and b are respectively more than or equal to 10 and smaller or equal to 60 integer, and x is more than or equal to 23 and smaller or equal to 92 integer, FA is a folic acid, m=0,1 or 2.
3. cisplatin nano-micelle prodrug according to claim 2 is characterized in that, described complex ring
For: 6,7,8 annulus.
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