CN101099723B - New use of taxol-like nano preparation - Google Patents
New use of taxol-like nano preparation Download PDFInfo
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- CN101099723B CN101099723B CN2006100287454A CN200610028745A CN101099723B CN 101099723 B CN101099723 B CN 101099723B CN 2006100287454 A CN2006100287454 A CN 2006100287454A CN 200610028745 A CN200610028745 A CN 200610028745A CN 101099723 B CN101099723 B CN 101099723B
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Abstract
The present invention discloses a new application of taxoloid nano preparation for preparing celiac lymphatic target chemotherapeutic medicine. The particles of said taxoloid nano preparation have hydrophilic surface modification, and average grain size of them is 100-300 nano. After the taxoloid nano preparation is injected into the abdominal cavity, said nano preparation can effectively reduce phagocytosis of celiac macrophage and can obviously raise target property of taxoloid to retroperitoneal lymph. Said administration system can be effectively used for target curing the diseases of oophoroma, carcinoma of stomach and rectal carcinoma, etc.
Description
Technical field
The present invention relates to a kind of new purposes of taxol-like nano preparation, can be used for preparing the lympha targeted therapeutic medicine of preventing and treating intraperitoneal lymphatic channel diffusions such as ovarian cancer, gastric cancer by lumbar injection.
Background technology
Ovarian cancer is the common tumor of domestic and international gynecological clinic, and mortality rate ranks first.In case existing 2/3rds belong to late period during clinical definite, operation is difficult to excision.Recurrence and transfer are the main causes that influences its prognosis.Ovarian cancer has the lymphatic metastasis rate of height, and during intravenous chemotherapy, abdominal cavity lymph metastasis kitchen range does not often reach effective treatment concentration, and can't avoid general toxicity.The tumor that has identical intraperitoneal lymphatic channel diffusion characteristic with ovarian cancer also has peritoneal cavity metastatic tumours such as gastric cancer, rectal cancer.
Lumbar injection is the above-mentioned tumor of treatment, prevents and treats its recurrence, transfer, consolidates an important route of administration of postoperative effect.Its advantage is: (1) intraperitoneal drug level is apparently higher than the peripheral blood drug level; (2) increase the contact surface and the time of focus and medicine, helped strengthening drug effect; (3) concentration is low after the conventional formulation medication used than the abdominal cavity of lympha targeted preparation plasma drug level, thereby the toxicity that causes is light; (4) control ascites effectively.But traditional lumbar injection preparation also has its limitation: (1) peritoneal adhesion also affects the treatment the medicine skewness; (2) the ordinary preparation medicine degree of depth that enters focus also only limits to 1～2mm; (3) medicine is shorter in the time of part stop; (4) after peritoneum absorbed, only small amount of drug can penetrate into retroperitoneal lymph node from intraperitoneal.The latter it is reported be the main focus that shifts of tumor cell such as ovarian cancer [Yang Xiaojun, Wang Wenfu, the anatomic basis of ovarian cancer lymphatic metastasis and clinical meaning. dissect with clinical 2002,7 (1-2): 52-54; Liu Aimin, Xu Yaohong, Wang Zhandong etc., the clinical observation of ovarian cancer posterior peritoneum lymphatic metastasis, Norman Bethune Medical University's journal, 1997,23 (3): 295-296].Studies show that: the feature of utilizing lymphatic capillary to have to engulf macromolecular substances and particulate matter, with the cancer therapy drug of small-molecular weight by the back injection that combines with macromole or particulate matter of physical absorption, parcel or chemical chain, make it enter lymphatic capillary to the drink of engulfing, wrap of particulate matter and macromolecular substances by lymphatic capillary, then by lymphatic drainage, hold back in the machinery filtration of lymph node place, reach in the malignant tumor regional lymph node metastasis kitchen range, this therapeutic modality to the capable targeted chemotherapy of metastasis cancer cell is called " lymphatic chemotherapy ".
Taxoid is meant the general name of bearing taxanes, is the active anticancer medicine that a class has diterpene ring mother nucleus structure.Comprise paclitaxel, Docetaxel (Docetaxel) and corresponding derivant, also comprise the active precursor medicine of various chemical modifications.These taxoid medicines all have definite curative effect to multiclass tumors such as ovarian cancer, breast carcinoma, pulmonary carcinoma.The taxoid injection of present clinical usefulness, with polyoxyethylene castor oil and 50: 50 (v/v) solubilisings of ethanol, often there are toxic and side effects such as severe anaphylactic reaction, neutrophilic granulocyte minimizing after the administration, have to add with glucocorticoid to reduce incidence rate of adverse reaction.For this reason, dosage form to taxoid class medicine has been carried out many improvement, the patent application that publication number is respectively CN1561987, CN1660073 discloses makes nanometer formulation with taxoid class drug encapsulation in the biodegradation high molecular polymer support, and finds that its targeting for tumor in situ is better.Yet, for tumor through lymphatic metastasis, particularly lymph node, as the control of retroperitoneal lymph node metastasis, be still stubborn problem in the present antineoplaston, directly influenced such as ovarian cancer, gastric cancer, rectal cancer etc. usually through the prognosis of the tumor of lymphatic channel diffusion.
Summary of the invention
Purpose of the present invention promptly is to solve above-mentioned problem, and a kind of new purposes of taxol-like nano preparation is provided, and is used to prepare the lympha targeted chemotherapeutics in abdominal cavity.
Inventor back after deliberation finds that taxol-like nano preparation surface hydrophilic sex modification and nano particle diameter are the parts of two keys.Because macrophage is abundant in the peritoneal cavity, is engulfed easily after common nanoparticle enters and is enriched in liver, spleen etc. and locate.And the particle surface of hydrophilic modification can be evaded catching of macrophage effectively and bites, and enters lymphoid chance thereby help increasing.On the other hand, also absorb lymph in nanoparticle chi footpath material impact.Test shows: mean diameter is too small, and during＜100nm, drug loading greatly reduces, and it is poor that lymph node filtration is simultaneously held back, and the targeting effect is also undesirable.Mean diameter is excessive, and when＞300nm even micron, the chance of being caught by macrophage increases, and the liver spleen is assembled to be increased, and the chance that enters lymphatic capillary greatly reduces, thereby lympha targeted effect is also poor; Cause the risk of peritoneal adhesion also to strengthen when meanwhile, particle diameter is big.So the average particle size of taxol-like nano preparation of the present invention is chosen between 100～300nm.
The present invention's said " taxol-like nano preparation " is meant the taxoid bag is stated from preparation in the pharmaceutically acceptable high molecular polymer carrier particle.Said " taxoid " is that a class has Cytotoxic bearing taxanes, is preferably now at clinical widely used antitumor drug paclitaxel or Docetaxel.Said " pharmaceutically acceptable high molecular polymer " is generally the high molecular polymer carrier of biological degradability and biocompatibility in the prior art, aliphatic polyester (polylactic acid for example, polyglycolic acid, poly lactic coglycolic acid, polycaprolactone, polyactide etc.), polyalkyl alpha-cyanacrylate, polyamino acid etc., and their derivant, as with the conjugate or the copolymer of hydrophilic segment
(Kumaresh S S, Tejraj M A, Anandrao R K.Biodegradable polymericnanoparticles as drug delivery devices.Journal of ControlledRelease, 2001,70 (1-2): 1-20).
And the present invention's said " water-wetted surface modification " or " surface hydrophilic sex modification " comprise chemical or physical property.
The water-wetted surface of the chemical " modify " typically refers to employed high molecular polymer carrier in the above-mentioned taxol-like nano preparation is hydrophilic modification, as above-mentioned aliphatic polyester, polyalkyl alpha-cyanacrylate, the conjugate or the copolymer of high molecular polymer such as polyamino acid and hydrophilic segment.Wherein, described hydrophilic segment is selected from Polyethylene Glycol, saccharide compound and derivant thereof, as (Gao Ping, Zhang Xiangrong, Xu Hui etc. such as chitosan, galactose, fucose, mannose and 6-amino-mannose, the modification of nano-particle and in the application of field of medicaments, China's journal of Practical Pharmacy, 2004,2 (6): 144-152).For the mean diameter that makes nanoparticle is in 100～300nm, and guarantee biocompatibility, the molecular weight of hydrophilic segment preferably between 1000～12000, accounts for carrier molecule amount proportion and is about between 1/20～1/3.
Have a preparation that " modification of chemical water-wetted surface " and mean diameter are in the taxol-like nano preparation of 100～300nm about above-mentioned, see also above-mentioned patent documentation CN1561987, CN1660073 in more detail.
Described " water-wetted surface of physical property is modified " is meant that in taxol-like nano preparation adopt above-mentioned aliphatic polyester, polyalkyl alpha-cyanacrylate during high molecular polymers such as polyamino acid, also additionally comprises the hydrophilic modification active.Described hydrophilic modification active can be selected any hydrophilic surfactant active of the prior art for use, as Polyethylene Glycol (PEG), the polyoxyethylene Span (Tween) that anhydrates, poloxamer (Poloxamer) and ethylene diamine derivative (poloxamine) thereof, Myrij (Myrij), Brij (Brij) etc.It is mixed with the aqueous surfactant solution of 0.5～2% (w/v) usually when using.
As seen, taxol-like nano preparation of the present invention is preferably the lumbar injection preparation, its lumbar injection comprises 0.9% normal saline with diluent, but the physiology test solution of 5% D/W or other lumbar injection or suspendible dispersion liquid, thus avoid the solubilizing agent of using toxicity bigger.In other words, owing to do not contain polyoxyethylene castor oil in the selected nanometer formulation composition of the present invention, polymer support only safe to use and a spot of surfactant have been avoided the anaphylaxis side effect, have improved the safety of medication.
The present invention has the taxol-like nano preparation of certain hydrophilic modification and suitable big small particle diameter can evade engulfing of peritoneal macrophage effectively, and improves the drug level of targeting in retroperitoneal lymph nodes such as lymph focus, particularly iliac lymph nodes.The Sprague-Dawley rat test shows that its lumbar injection effective dose is compared with commercially available general category formulation for paclitaxel between 3～12mg/kg, dosage can reduce 30%～50%.Lumbar injection 6～12 hours, at retroperitoneal iliac lymph nodes place, the average content of dispersion of the tissue of commercial preparation group is 6.34 μ g/g tissues, and nanometer formulation group of the present invention can reach 20.12 μ g/g tissue, has improved 2 times.Meanwhile, the liver content of dispersion reduces, and reduces by 30% than commercial preparation group.Blood level is lower, has significantly reduced system toxicity.Therefore, drug-carrying nanometer particle of the present invention utilizes lymphoid drain of patient's abdominal part and mechanical filters such as ovarian cancer through the lumbar injection medication, reaches the targeted therapy of lymph focus and the purpose that recurrence is prevented.
Description of drawings
Fig. 1 has each internal organs mean concentration of 6～12h behind the taxol-like nano preparation lumbar injection of certain hydrophilic modification and suitable big small particle diameter.
Fig. 2 is each internal organs mean concentration of 6～12h behind the commercially available common formulation for paclitaxel lumbar injection.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Mean diameter in the following example all is to adopt NICOMP-380ZLS type dynamic laser scattering particle size analyzer (U.S. PSS company) to detect (wavelength: 635nm, temperature: 23 ℃, viscosity: 0.933cp, tranmitting frequency 300MHz), the size of particle diameter is with macroscopical meansigma methods of Int-Wt (light intensity statistical weight) expression of Gaussian distribution.
Embodiment 1
Preparation process sees also the embodiment 3 of above-mentioned patent application CN1561987.The present invention improves slightly to it, and concrete steps are:
7.5mg paclitaxel and 50mg polylactide-Polyethylene Glycol diblock copolymer, two block molecule amounts are respectively 10000 and 5000 and are dissolved in the 3ml dichloromethane, it is in 2% the poly-vinyl alcohol solution that dichloromethane solution is joined 40ml concentration, ultrasonic emulsification 60 seconds, and emulsifying power is 40W.Then the gained emulsion is arrived 400ml with distilled water diluting, decompression volatilization 2 hours is at the centrifugal nanosphere of collecting down of 20000rpm, reuse distilled water wash four times, again be distributed in the water, it is the nanometer formulation of principal agent that lyophilization obtains with the paclitaxel, and mean diameter is 300 nanometers.Facing the time spent is diluted to the desired concn abdominal cavity with 0.9% normal saline and injects.
Embodiment 2
Prepare the polyenic taxusol nano preparation according to disclosed method in the above-mentioned patent application CN1660073 description page 4, concrete steps are:
Accurately take by weighing Docetaxel medicine 200mg and Pegylation poly (lactic acid-glycolic acid) copolymer 800mg is dissolved in the 10ml dichloromethane, this solution is infused among the polyvinyl alcohol water solution 500ml of 0.3% under the stirring of 15000rpm speed, continue high-speed stirred (15000rpm), form the O/W emulsion, (500rpm) stirs 4h subsequently at a slow speed, fling to dichloromethane, the curing nano grain, the nanoparticle suspension that obtains is passed through (15000rpm) centrifugal collection at a high speed, and with 3 after drying of distilled water 200ml washing, the nanoparticle of mean diameter 140nm.Facing the time spent is diluted to the desired concn abdominal cavity with 5% glucose solution and injects.
Embodiment 3
Paclitaxel: 100mg
Polylactic acid (molecular weight 6.6 ten thousand): 1000mg
Dichloromethane: 30ml
1.6% polyvinyl alcohol: 60ml
1% poloxamer, 409 aqueous solutions: 100ml
Paclitaxel and polylactic acid carrier are dissolved in dichloromethane, the polyvinyl alcohol of adding 1.6%, high speed shear (8000rpm, 2min) make colostrum, the ultrasonic concussion back (40W, 30 seconds) of popping one's head in adds the dilution of 1% poloxamer, 409 aqueous solutions, the fluid drying dichloromethane, nanoparticle purification, packing, lyophilizing.The mean diameter of the nanoparticle that obtains is 100nm.
Embodiment 4
With chitosan polylactic acid-glycolic guanidine-acetic acid nanoparticle being carried out surperficial coupling modifies.
20mg paclitaxel and 120mg PLGA (poly lactic coglycolic acid, the polymerization molar ratio is 50/50, molecular weight 20,000) is dissolved in the mixed solvent of 5ml acetone-dichloromethane (volume ratio is 2: 8), join 20ml concentration and be in 1% poloxamer 188 solution, the high speed shear 2min emulsifying of 20000rpm.Then gained emulsion chitosan (deacetylation 88.9%, intrinsic viscosity 45cps) 0.5% dilute acetic acid solution is diluted to 100ml, normal pressure stirs volatilization 8 hours, at the centrifugal nanosphere of collecting down of 20000rpm, reuse distilled water wash four times, again be distributed in the water, it is the nanometer formulation of principal agent that lyophilization obtains with the paclitaxel, and mean diameter is 150 nanometers.Facing the time spent is diluted to the desired concn abdominal cavity with 0.9% normal saline and injects.
Each raw material and reagent are conventional commercially available prod in the foregoing description.
Effect embodiment 1
The present invention is an example with the paclitaxel nano preparation of embodiment 3; and with the commercially available paclitaxel injection that contains polyoxyethylene castor oil (trade name: paclitaxel injection; Hualian Pharmaceutical Co., Ltd., Shanghai produces) for contrasting; behind the medicine to Sprague-Dawley rats by intraperitoneal injection dosage 7.5mg/kg; 6-12h puts to death; get tissues such as the lymph node (iliac lymph nodes and lymphonodi cervicales) and the heart, liver, spleen, lung, kidney, clean, blot, weigh.Carrying out HPLC behind the tissue homogenate detects.Calculate corresponding organize the pastille total amount after, be calculated as follows tissue and contain concentration:
Tissue contains (unit: μ g/g tissue) of concentration=organize pastille total amount/tissue weight
Every group of preparation tested 6 samples altogether.The concentration data of each tissue is averaged and calculation deviation, shows, compares with block diagram.The result as shown in Figure 1 and Figure 2.
As seen, under the Isodose, drug concentration level in lymph node and spleen is obviously more much higher than paclitaxel commercial preparation group for paclitaxel nano grain group of the present invention.Consider that spleen is important lymphatic organ, illustrate that the nanoparticle group can make drug main want targeting in lymphsystem.And meanwhile, liver, commercially available group of lung Chinese medicine concentration ratio are low, show nanoparticle after hydrophilic surface is modified to evade macrophage to catch the effect of biting obvious.In addition, the heart, kidney levels of drugs are compared the reduction that also has in various degree with commercially available group.
Effect embodiment 2
Plant in F344 type rat with SKOV-3 cell strain abdominal cavity, get the rat late tumor model of ovarian cancer after 2 week.Get 48 rat models and divide 6 groups at random, the nanometer formulation A that the present invention modifies with the hydrophilic surface of different mean diameters
1-A
3(embodiment 1,3,4) are test group, and respectively with the above-mentioned commercially available hydrogenated castor oil formulation of paclitaxel, non-hydrophilic nanometer formulation B and microball preparation are organized in contrast, carry out intraperitoneal administration with equal 7.5mg/kg dosage.Once in a week, 4 weeks of successive administration.
Wherein, the preparation method of nanometer formulation B does not as a comparison wherein add hydrophilic modification active 1% poloxamer 409 aqueous solutions referring to the foregoing description 3.And microball preparation is embodiment 1 preparation according to above-mentioned patent application CN1561987, be specially 15mg paclitaxel and 85mg polylactide-Polyethylene Glycol di-block copolymer, two block molecule amounts are respectively 60000 and 5000 and are dissolved in the 5ml dichloromethane, dichloromethane solution is joined in the poly-vinyl alcohol solution of 40ml 2%, ultrasonic emulsification 90 seconds, emulsifying power are 70W.Then the gained emulsion is arrived 500ml with distilled water diluting, decompression volatilization 2 hours is collected Nano microsphere under 18000rpm, reuse distilled water wash four times, again be distributed in the water, it is the nanometer formulation of principal agent that lyophilization obtains with the paclitaxel, about 0.8 micron of mean diameter.Facing the time spent is diluted to the desired concn abdominal cavity with 0.9% normal saline and injects.
Finish test the 4th weekend, the execution animal also cuts open the belly, takes a sample, observes.Add up iliac lymph nodes drug level, tumour inhibiting rate, ascites volume minimizing degree, survival rate, peritoneal adhesion degree simultaneously.Wherein, peritoneal adhesion investigation standard is the mutual binding degree of visceral peritoneum and stomach wall layer peritoneum.Do reference with normal rat, adhesion weight situation can be divided into following three states:
Well: each internal organs can freely be stirred, and visceral peritoneum and parietal peritoneum do not have obvious binding;
Generally: each internal organs still can freely be stirred, but visceral peritoneum and parietal peritoneum have slight binding;
Seriously: visceral layer and visceral layer, visceral layer and parietal layer all have obvious binding, and internal organs can not arbitrarily be stirred.
The results are shown in following table:
| Grouping | Hydrophilicity | Mean diameter (nm) | Iliac lymph nodes drug level (ug/ml) | Tumour inhibiting rate (%) | Ascites volume minimizing degree (%) | Survival rate (average, %) | The peritoneal adhesion degree |
| The commercial preparation | \ | \ | 6.34 | 67.8 | 52.6 | 75 | Generally |
| Nanometer formulation A 1 | Hydrophilic | 300 | 15.57 | 77.4 | 61.5 | 87.5 | Generally |
| Nanometer formulation A 2 | Hydrophilic | 100 | 20.12 | 88.2 | 78.1 | 87.5 | Well |
| Nanometer formulation A 3 | Hydrophilic | 150 | 16.40 | 73.8 | 67.3 | 87.5 | Generally |
| Nanometer formulation B | Non-hydrophilic | 100 | 10.87 | 61.2 | 55.4 | 75 | Generally |
| Microball preparation | Hydrophilic | 800 | 7.93 | 57.5 | 56.8 | 62.5 | Seriously |
The microball preparation effect when possible reason is that medicine carrying microgranule is big, forms the adhesion of foreign body intervention property on the contrary not as the commercial preparation easily in this table between peritoneum, will realize when particle diameter is big simultaneously that the lymphatic drainage path obstacle of lymph node picked-up also strengthens.Cause drug effect undesirable.
The index of each side shows: the lympha targeted property of taxol-like nano preparation when lumbar injection of appropriate particle size with hydrophilic modification is strong, curative effect is obvious, side effect is little.The new purposes of this of taxol-like nano preparation is expected to obtain the specific aim treatment of peritoneal cavity endolymph roads such as ovarian cancer, gastric cancer being spread typical tumor.
Claims (5)
1. the application of taxol-like nano preparation in the lympha targeted chemotherapeutics in preparation abdominal cavity, the particle of this taxol-like nano preparation has water-wetted surface and modifies, mean diameter is controlled between 100～300 nanometers, this taxol-like nano preparation comprises the taxoid bag is stated from the pharmaceutically acceptable high molecular polymer carrier particle, this high molecular polymer has the hydrophilic segment of link coupled or block copolymerization, described hydrophilic segment is selected from Polyethylene Glycol, saccharide compound and derivant thereof, the lympha targeted chemotherapeutics in this abdominal cavity is the medicine of control retroperitoneal lymph node metastasis.
2. application as claimed in claim 1 is characterized in that saccharide compound and derivant thereof are selected from chitosan, galactose, fucose, mannose and 6-amino-mannose.
3. application as claimed in claim 1, it is characterized in that also comprising in this taxol-like nano preparation the surfactant of hydrophilic modification, this hydrophilic modification active is selected from Polyethylene Glycol, polyoxyethylene anhydrate Span, poloxamer and ethylene diamine derivative thereof, Myrij and Brij.
4. application as claimed in claim 1 is characterized in that this taxol-like nano preparation is the lumbar injection preparation.
5. as each described application of claim 1～4, it is characterized in that this retroperitoneal lymph node metastasis is an ovarian cancer iliac lymph nodes metastasis.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1470289A (en) * | 2002-07-26 | 2004-01-28 | 北京华京五方实用纳米科技开发有限公 | Polymeric nano medicine carrier and preparation preparing method |
| WO2005020933A2 (en) * | 2003-09-02 | 2005-03-10 | University Of South Florida | Nanoparticles for drug-delivery |
| CN1660073A (en) * | 2004-12-30 | 2005-08-31 | 中国科学院上海药物研究所 | Nano granules of Docetaxel and preparing method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1470289A (en) * | 2002-07-26 | 2004-01-28 | 北京华京五方实用纳米科技开发有限公 | Polymeric nano medicine carrier and preparation preparing method |
| WO2005020933A2 (en) * | 2003-09-02 | 2005-03-10 | University Of South Florida | Nanoparticles for drug-delivery |
| CN1660073A (en) * | 2004-12-30 | 2005-08-31 | 中国科学院上海药物研究所 | Nano granules of Docetaxel and preparing method |
Non-Patent Citations (2)
| Title |
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| 王永中，方晓玲.聚合物胶束作为肿瘤靶向给药载体的研究.中国新药杂志14 10.2005,14(10),1127-1131页. |
| 王永中,方晓玲.聚合物胶束作为肿瘤靶向给药载体的研究.中国新药杂志14 10.2005,14(10),1127-1131页. * |
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