CN105726483B - Active targeting liposome for resisting lung cancer and preparing method and application of active targeting liposome - Google Patents

Active targeting liposome for resisting lung cancer and preparing method and application of active targeting liposome Download PDF

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CN105726483B
CN105726483B CN201610075758.0A CN201610075758A CN105726483B CN 105726483 B CN105726483 B CN 105726483B CN 201610075758 A CN201610075758 A CN 201610075758A CN 105726483 B CN105726483 B CN 105726483B
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liposome
lung cancer
active targeting
acid
targeting liposome
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CN105726483A (en
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卢凯华
何靓
张梅玲
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Dispersion Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention aims at providing an active targeting liposome for resisting lung cancer.The active targeting liposome is a liposome composition including sunitinib and smallanthus sonchifolius diterpene acid compounds and has targeting stability.It is verified through animal and cell tests that smallanthus sonchifolius diterpene acid compounds have a huge synergistic effect on killing cancer cells with sunitinib, an excellent cancer inhibiting effect is achieved, smallanthus sonchifolius diterpene acid compounds are delivered to lung cancer cells in an oriented mode through the liposome, and thus a new page in the cancer resisting liposome field is developed.

Description

Anti-lung cancer active targeting liposome and its preparation method and application
Technical field
The invention belongs to pharmaceutical technology field and in particular to a kind of anti-lung cancer active targeting liposome and preparation method thereof and Application.
Background technology
Lung cancer is that M ＆ M increases the soonest, one of malignant tumour maximum to population health and life threat. The many countries of immediate and mid-term all report that the M ＆ M of lung cancer all substantially increases, and male lung cancer M ＆ M is equal Account for first of all malignant tumours, the women incidence of disease accounts for second, the death rate accounts for second.The cause of disease of lung cancer is not still complete so far Entirely clear and definite, great mass of data shows, a large amount of smokings for a long time have very close relationship with lung cancer.Existing research has shown that： The probability that a large amount of smokers suffer from lung cancer for a long time is 10～20 times of non-smoker, and the age starting smoking is less, suffers from the several of lung cancer Rate is higher.Additionally, smoking not only directly affects my healthy, also harmful effect is produced to the health of surrounding population, lead Involuntary smoker's lung cancer illness rate is caused substantially to increase.
The incidence of disease of city dweller's lung cancer is higher than rural area, this may with urban atmospheric pollution and flue dust in contain carcinogen Relevant.Serious all the more with nowadays haze, people also more pay attention to the concern of lung cancer.
The clinical manifestation of lung cancer is more complicated, and the morning and evening of the presence or absence of sings and symptoms, weight and appearance, depending on tumour Happening part, histological type, have or not transfer and have or not complication, and the difference of reaction degree and tolerance.Lung cancer Early symptom is often relatively slight, or even can no any discomfort.Early and weight in central type carcinoma of lung symptom, and peripheral type carcinoma of lung symptom occurs Late and relatively light or even asymptomatic, often it is found in health check-up.
The treatment of lung cancer has chemotherapy, radiotherapy and surgical intervention, and wherein, radiotherapy is a kind of local treatment, usually Need combined chemotherapy；And surgical operation does not apply to all patients, therefore, chemotherapy is the primary treatments of lung cancer, 90% Above lung cancer needs to accept chemotherapeutic treatment, and effect in lung cancer for the chemotherapy in recent years has been no longer confined to inoperable advanced lung cancer Patient, and the comprehensive therapeutic plan of lung cancer is listed in frequently as whole body therapeutic.Develop effective lung cancer chemicals and there is important meaning Justice.
Sutent was approved by the FDA in the United States treatment kidney prior to 2006, and in November, 2010 obtains European Union committee member The approval of meeting can be used to treat Pancreatic Neuroendocrine Tumors（pancreatic neuroendocrine tumors）.2011 In May in year, U.S. FDA also have approved Sutent for treating Pancreatic Neuroendocrine Tumors.Sutent also just at it Test in his a lot of tumours, including breast cancer, lung cancer, thyroid cancer with connect intestinal cancer, but PRELIMINARY RESULTS shows：With such medicine Treatment kidney is similar to, but has certain effect effect incomplete, not lasting.
Liposome (liposomes) is a kind of Bilayer vesicle of similar biofilm structure.From the English sixties in 20th century Since the reported first liposome structures such as state scholar Bangham, liposome has obtained increasing attention.Section of Britain in 1971 Scholar Rymen et al. starts liposome as pharmaceutical carrier so as to be widely applied in pharmaceutical field, develops rapidly For newtype drug induction system.Liposome has the advantages that long-acting, reduction toxicity and protection entrapped drug, also exists simultaneously Shortcoming：The targeting of general liposome focuses primarily upon the organ that reticuloendothelial cell enriches, if wanting to other histoorgans Carry out treating its targeting inconspicuous；The stability of liposome not, is easy to assemble and melt with the liposome that conventional method is obtained With the term of validity is shorter；The leakage of liposomal contents, usual liposome during preserving, more or less all can send out by content Raw leakage, especially to some water soluble drugs；To different medicines, the envelop rate of liposome and drugloading rate difference are very big, have The drugloading rate of a little medicines is extremely low, and this is difficult to play the effect of medicine.
Content of the invention
For above-mentioned prior art, present invention aim at providing a kind of anti-lung cancer active targeting liposome, it is containing easypro Buddhist nun replaces Buddhist nun and Yacon diterpene acid compounds, and has the liposome composition of targeting stability.
Wherein Yacon diterpene acid compounds are the compounds extracting from plant Asia tribute, including sub- tribute diterpenoid acid A, Asia Tribute diterpenoid acid B, sub- tribute diterpenoid acid C or sub- tribute diterpenoid acid D, its structure is as follows：
The mass ratio of described Sutent and Yacon diterpene acid compounds is（1-3）：6, preferably（2-2.5）：6.
Present invention also offers the preparation method of described liposome, specifically include following steps：
1）Synthesis targeting RGD peptide -6-aminocaprolc acid arm compound：Synthesize RGD peptide -6-aminocaprolc acid arm by solid-phase synthesis Compound；
2）Weigh Sutent and the Yacon diterpene acid compounds of weight ratio, with phosphatide, stabilizer, RGD peptide -6- amino Caproic acid arm compound, DSPC-PEG2000 and nonionic surfactant are dissolved in ether by a certain percentage, add certain volume PBS, ultrasonic agitation in ice-water bath, form emulsion, first rotating pressure-decreasing evaporation in the case that vacuum is little under normal temperature, then heighten true Reciprocal of duty cycle continues to be evaporated under reduced pressure, and forms aqueous suspension, is brushed with argon gas, add distilled water, and in last ice-water bath, short time mixing surpasses Sound, uses high pressure homogenizer average, 0.2 micrometer polycarbonate end extrusion, pvdf membrane aseptic filtration, is distributed into cillin bottle, freezing is dry Dry, lead to argon gas in cillin bottle, gland seals.
Further, step 1）Described in RGD peptide sequence be：Gly-Ala-Arginine-Tyrosine-half Guang ammonia Acid-arginine-glycine-aspartic acid-Cys-Phe-aspartic-glycine.
Further, step 2）Described in phosphatide be hydrogenation saturated phospholipid, preferably hydrogenation saturation soybean lecithin, hydrogenation is full With lecithin or DSPC.
Further, step 2）Described in stabilizer be cholesterol and polyhydroxy substance combination, described cholesterol with The weight of polyhydroxy substance is than for 1:2-4.
Described polyhydroxy substance is glucose, mannose, galactolipin, fructose, sucrose, maltose, lactose, cyclodextrin, second Glycol, xylitol, sorbierite or glycerine.
Further, step 2）Described in phosphatide, stabilizer, RGD peptide -6-aminocaprolc acid arm compound, DSPC- The weight of PEG2000 and nonionic surfactant is than for 10:1.5-2.0:0.03-0.035:0.5-0.6:100, preferably 10: 1.5:0.03：0.55:100.
Further, step 2）Middle Yacon diterpene acid compounds with the mass ratio of phosphatide are：3：1.
The present invention also provides a kind of preparation containing described liposome composition, and described liposome composition is wrapped in marine alga Hydrochlorate-chitosan gum is intracapsular.This preparation can make the sour environment of liposome composition safety stomach arrive the neutrality of enteron aisle Environment, is allowed to smoothly absorb.
Liposome composition of the present invention passes through technique adjustment, overcomes parcel Multiple components encapsulation ratio not high, no Stable problem, meanwhile, applicant's first passage drug efficacy study finds that Yacon diterpene acid compounds can the easypro Buddhist nun of effectively solving replace Buddhist nun's drug effect is incomplete, unabiding problem.Verified by animal and test cell line, Yacon diterpene acid compounds are to easypro Buddhist nun Kill tumour cell for Buddhist nun and there is huge cooperative effect, zooblast test all shows very successful experimental result, reaches The effect of fabulous suppression tumour, has opened up the new page in antitumor liposome field.
Brief description
Fig. 1 is the result figure to A549 lung carcinoma cell therapeutic effect for the composition of the present invention.
Specific embodiment
Below in conjunction with specific embodiment, the present invention is described in detail, and following examples target RGD peptide -6-aminocaprolc acid Arm compound is synthesized by Shanghai Huada Tianyuan Biotechnology Co.ltd, and agents useful for same is commercially available.Animal used as test used Model building method is：SPF level BALB/c Female nude mice, weight is 18 ± 2g, and human umbilical vein endothelial cell is cultivated by 4 week old To exponential phase, pancreatin digests, is then diluted to cell suspension with serum-free medium, takes 1 × 106Individual（1ml）Cell connects Plant subcutaneous in the right armpit of BALB/c nude mice.The computational methods of tumor size, gross tumor volume V（mm3）=solid tumor major diameter（mm）× real Body knurl minor axis（mm）2/2.
Embodiment 1
A kind of preparation method for antineoplastic liposome composition, specifically includes following steps：
1）Weigh Sutent 5g, sub- tribute diterpenoid acid A 30g, hydrogenate saturation soybean lecithin 10g, cholesterol 0.5g, ring is pasted Smart 1.0g, RGD peptide -6-aminocaprolc acid arm compound 0.03g, DSPC-PEG2000 is 0.5g, nonionic surfactant 100g;
2）Synthesis targeting RGD peptide -6-aminocaprolc acid arm compound：Synthesize RGD peptide -6-aminocaprolc acid arm by solid-phase synthesis Compound, RGD peptide sequence is：Gly-Ala-Arginine-Tyrosine-cysteine-arginine-glycine-asparagus fern ammonia Acid-Cys-Phe-aspartic-glycine；
3）By the proportional quantity having weighed up Sutent and Ya Gong diterpenoid acid A, solid with hydrogenation saturation soybean lecithin, courage Alcohol, cyclodextrin, RGD peptide -6-aminocaprolc acid arm compound, DSPC-PEG2000 and nonionic surfactant are dissolved in ether, plus Enter the PBS of 150ml, ultrasonic agitation in ice-water bath, form emulsion, under normal temperature, first rotating pressure-decreasing steams in the case that vacuum is little Send out, then heighten vacuum and continue to be evaporated under reduced pressure, form aqueous suspension, brushed with argon gas, add 50ml distilled water, last frozen water In bath, short time mixing is ultrasonic, uses high pressure homogenizer average, 0.2 micrometer polycarbonate end extrusion, pvdf membrane aseptic filtration, is distributed into Cillin bottle, freeze-drying, lead to argon gas in cillin bottle, gland seals.
Embodiment 2
A kind of preparation method for antineoplastic liposome composition, specifically includes following steps：
1）Weigh Sutent 10g, sub- tribute diterpenoid acid A 30g, hydrogenate saturation lecithin 10g, cholesterol 0.4g, grape Sugared 1.6g, RGD peptide -6-aminocaprolc acid arm compound 0.035g, DSPC-PEG2000 is 0.6g, nonionic surfactant 100g;
2）Synthesis targeting RGD peptide -6-aminocaprolc acid arm compound：Synthesize RGD peptide -6-aminocaprolc acid arm by solid-phase synthesis Compound, RGD peptide sequence is：Gly-Ala-Arginine-Tyrosine-cysteine-arginine-glycine-asparagus fern ammonia Acid-Cys-Phe-aspartic-glycine；
3）By the proportional quantity having weighed up Sutent and Ya Gong diterpenoid acid A, solid with hydrogenation saturation lecithin, courage Alcohol, glucose, RGD peptide -6-aminocaprolc acid arm compound, DSPC-PEG2000 and nonionic surfactant are dissolved in ether, plus Enter the PBS of 150ml, ultrasonic agitation in ice-water bath, form emulsion, under normal temperature, first rotating pressure-decreasing steams in the case that vacuum is little Send out, then heighten vacuum and continue to be evaporated under reduced pressure, form aqueous suspension, brushed with argon gas, add 50ml distilled water, last frozen water In bath, short time mixing is ultrasonic, uses high pressure homogenizer average, 0.2 micrometer polycarbonate end extrusion, pvdf membrane aseptic filtration, is distributed into Cillin bottle, freeze-drying, lead to argon gas in cillin bottle, gland seals.
The envelop rate of the liposome composition prepared by experiment one, embodiment 1 and 2
Liposome composition prepared by embodiment 1 and 2, after 11000r/min ultrafiltration 1h, collects lower clear liquid, efficient liquid Phase chromatography measures Sutent therein and Ya Gong diterpenoid acid A content respectively, is designated as WFree, by liposome composition through anhydrous After the complete rupture of membranes of ethanol, high performance liquid chromatography measures Sutent therein and Ya Gong diterpenoid acid A content respectively, is designated as WAlways, Envelop rate=（WAlways-WFree）/WAlways× 100%, after measured the envelop rate of Sutent be（97.01±3.26）%, sub- tribute diterpenoid acid A's Envelop rate is（93.21±3.10）%.
Liposome composition stability test prepared by experiment two, embodiment 1 and 2
Liposome composition prepared by embodiment 1 and 2 stores in 10 DEG C of long term storages and at room temperature, is redissolved with water Afterwards, the results are shown in Table 1 and table 2：
Table 1 liposome composition is in 10 DEG C of extended storage stability results
Table 2 liposome composition storage stability result at room temperature
Experiment three, the Tissue distribution of detection liposome composition
The tumor size of model of nude mice bearing tumor grows to 100-200mm3When, it is divided into 2 groups, every group 5, tail vein note respectively Penetrate the liposome composition prepared by embodiment 1（Experimental group）, the Sutent of active ingredient equivalent and Ya Gong diterpenoid acid A are formed Composition（Control group）, respectively 0.15,0.6,1,2,4,8h after drug injection, take the heart of mouse, liver, spleen, lung, kidney, swell Knurl cleaning is weighed, and tissue is homogenized, measures by HPLC method the amount of medicine in tissue.
Experiment finds that in liposome, insoluble drug release is more slow, after injection during 8h, remains to measure higher concentration, specifically Drug entities distribution as shown in table 3 it can be seen that in tumour cell the cumulative amount of medicine increase, and in the heart, liver, spleen and kidney Drug distribution has reduced.
The Tissue distribution of table 3 medicine
Experiment four, to A549 lung carcinoma cell treatment effectiveness evaluation
Lung cell A549 respectively with normal incubation medium（Blank group）, 200nM Asia tribute diterpenoid acid A, in Deficiency nutrition（It is The mechanism of action of Sutent, can be used for the effect replacing it in test cell line）Or carry out respectively under normal condition being incubated 48 Hour, wherein anoxic refers to oxygen content 0.5%, scarce trophonemata sugar-free, then analyzes the cellular level of survival, with the Dan Rong of Promega Liquid cell proliferation detecting kit is analyzing.
Experimental result is as shown in figure 1, Sutent（Deficiency nutrition replaces）When combining with sub- tribute diterpenoid acid A, in lung cancer In cell A549, inhibiting rate has reached 92%, has obvious cooperative effect.
Experiment five, in vivo antitumor effect
After model of nude mice bearing tumor sets up 7 days, it is randomly divided into 4 groups, every group 6, the composition tail prepared by Example 3 is quiet Arteries and veins is administered, and administering mode is：Isopyknic physiological saline（Control group）, inject embodiment 3 institute respectively by the injection volume of 4ml/kg The sub- tribute diterpenoid acid A of the composition, the Sutent of 2mg/ml and 6mg/ml of preparation, and press 50mg/kg embodiment 2 preparation Liposome, observes the situation of tumor-bearing mice from the 7th day, lateral body weighs and gross tumor volume 2 times a week simultaneously, when control group tumor size More than 2000 mm3When terminate to observe, weigh, eyeball takes blood, cervical dislocation is put to death mouse and simultaneously peeled off tumour, record knurl weight, knurl weight Change is as shown in Figure 1.Tumor control rate computing formula：Inhibiting rate=[（Control group knurl weight-administration group knurl weight）/ control group knurl weight] × 100%, the results are shown in Table shown in 4.
Table 4 tumor control rate calculates
By table 1 data, Sutent and Ya Gong diterpenoid acid A are used in combination, and have fabulous synergy, are in Show significant antitumous effect, and the use of liposome, by targetting drug delivery to lung carcinoma cell, therefore, small amount Active material be that aa can reach significant antitumous effect.

Claims (2)

1. a kind of anti-lung cancer active targeting liposome is it is characterised in that be containing Sutent and Yacon diterpene acid compounds, And there is the liposome composition targetting stability, wherein Yacon diterpene acid compounds refer to sub- tribute diterpenoid acid A, sub- tribute diterpenoid acid B, sub- tribute diterpenoid acid C or sub- tribute diterpenoid acid D.
2. anti-lung cancer active targeting liposome according to claim 1 is it is characterised in that described Sutent and Ya Gong bis- The mass ratio of terpene acids compound is 1-3：6.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101225042A (en) * 2008-02-18 2008-07-23 珍奥集团股份有限公司 Yacon diterpene acid compounds, medicine composition, preparation method and use in preparation of medicine treating diabetes mellitus
CN102485212A (en) * 2010-12-01 2012-06-06 沈阳药科大学 Sunitinib malate liposome and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101225042A (en) * 2008-02-18 2008-07-23 珍奥集团股份有限公司 Yacon diterpene acid compounds, medicine composition, preparation method and use in preparation of medicine treating diabetes mellitus
CN102485212A (en) * 2010-12-01 2012-06-06 沈阳药科大学 Sunitinib malate liposome and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
高效液相色谱-质谱法测定亚贡叶中亚贡二萜酸A和C的含量;吴振等;《厦门大学学报(自然科学版)》;20120131;第51卷(第1期);第72-76页 *

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Address after: 210029 Department of Oncology, Jiangsu People's Hospital, No. 300 Guangzhou Road, Nanjing, Jiangsu Province

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