CN102329335B - Pentaerythritol-based composite lipid and preparation method and application thereof - Google Patents
Pentaerythritol-based composite lipid and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to pentaerythritol-based composite lipid, a preparation method and use thereof, belonging to the field of a biomedical material. The defects of poor stability and low packaging rate of the existing liposome prepared with lipid can be overcome. The chemical structure formula of the composite lipid is shown as below figure (1) and (2). The pentaerythritol-based composite lipid is prepared via introduction of fat chain, siloxane, carboxyl, phenyl ring and the like on a pentaerythritol framework via chemical reaction. The liposome prepared with the lipid has a uniform size, the surface of the liposome has a silicate network structure and has good stability, medical leakage cannot be caused easily, and the packaging rate is 96.6-99.0 percent. Moreover, the process of the method is simple, and the clinical application and industrial production can be facilitated.
Description
Technical field
The invention belongs to biomedical materials field, be specifically related to take tetramethylolmethane as skeleton, the compound lipid that contains aliphatic chain, siloxanes, carboxyl, phenyl ring, preparation method and its usage.
Technical background
Since 20 century 70s, liposome is simple owing to having preparation, nontoxicity, non-immunogenicity reaction, degradability in vivo, and be easy to realize targeting, therefore be widely used in pharmaceutical carrier, it can improve and prolong drug curative effect, relaxes toxicity, avoids resistance and changes route of administration.But the practical application of liposome is subject to the restriction of its stability.Be in particular in that liposome is in storage process, due to drug leakage, aggregation of particles and phosphatide, to be easy to oxydrolysis etc. former thereby destroyed; After entering in body, due to the effect of the various materials such as the albumin in blood, Opsonin, antibody, liposome may break, and causes the quick seepage of entrapped drug, by some enzyme materials, degraded and macrophage phagocytic very soon, can not arrive target tissue and effectively bring into play drug effect.Therefore, developing stable liposome is that it moves towards practical prerequisite as pharmaceutical carrier, and tool is of great significance.
The encapsulation rate of liposome is also the criterion that can it practical, at present about improving a lot (Chinese Journal of Pharmaceuticals 2002 of method of liposome encapsulation, 33 (11), 564-568), by Intermolecular Forces or electrostatic attraction, improving liposome encapsulation has its significant advantage.Wherein, the liposome that contains benzene ring structure can with some medicines with similar group, as camptothecine etc., produce intermolecular conjugation, thereby effectively improve embedding (Journal of Controlled Release, 2008 to medicine, 127,231-238).And the liposome that the contains hydroxy-acid group free carboxylic acid groups abundant because surface has, be convenient on the one hand with the medicine that contains hydroxyl or amino as generation chemosynthesiss such as Zorubicins, make on the other hand liposome under specific pH value condition with abundant negative charge, thereby can, by electrostatic attraction effect by some positively charged medicine embeddings effectively, greatly improve encapsulation rate and drug loading.Meanwhile, the abundant hydroxy-acid group in surface is also convenient to the upper various targeted moleculars of liposome modification, improves its Targeting Effect.
Based on above-mentioned consideration, the inventor has developed the NEW TYPE OF COMPOSITE lipid based on tetramethylolmethane, and it has the feature of two aspects, is contain in such material molecular structure-Si (OEt) on the one hand
3or-Si (OCH
3)
3group, can form stable Si-O-Si network structure by hydrolytic condensation, and covalent linkage is even covered in the surface of liposome, thereby greatly strengthens its stability; Be in such material molecular structure, to contain phenyl ring or hydroxy-acid group on the other hand, can have an effect by the effects such as electron conjugated magnetism or electrostatic attraction and the hydrophobic or hydrophilic drugs that will seal, thereby improve the encapsulation rate to medicine.
Summary of the invention
The object of the invention is the shortcoming that liposome existence and stability is poor and encapsulation rate is low of preparing in order to solve existing lipid, and compound lipid based on tetramethylolmethane and preparation method thereof is provided.Lipid of the present invention can obtain the corresponding liposome (being referred to as porcelain body) that surface has silicate network structure by hydrolysis and condensation, and in liposome, contain phenyl ring or hydroxy-acid group, can have an effect with the hydrophobic or hydrophilic drugs that will seal by electron conjugated magnetism or electrostatic attraction effect, thereby improve the encapsulation rate to medicine; The liposome making has that stability is high, good biocompatibility, low toxicity are even nontoxic, and entrapment efficiency is high, easy to leak advantage not.
The structure of the compound lipid based on tetramethylolmethane of the present invention is as follows:
Wherein, R1=C6～18 alkyl, R2=C6～18 alkyl, R
1, R
2can be identical, also can be different; R
3=OEt or OCH
3; A=2 or 3; B=2 or 3, c=1, and when b=0, c=0; X=H, CH
3, CH
3o, halogen, NO
2.Its concrete syntheti c route is as follows:
The another kind of structural formula of the compound lipid based on tetramethylolmethane of the present invention is:
Wherein, R
1=C
6～18alkyl, R
2=C
6～18alkyl, R
1, R
2can be identical, also can be different; R
3=OEt or OCH
3; A=2 or 3; B=2 or 3, c=1, and when b=0, c=0; D=2 or 3.Its concrete syntheti c route is as follows:
Preparation method's reference literature of compound 1 (J.Am.Chem.Soc.118,8524-8530,1996)
Preparation method's reference literature of compound 4 (organic chemistry .2005,9,1049-1052)
Method of the present invention specifically describes as follows:
(1), in polar organic solvent, compound 1 reacts 24-48 hour with compound 2 at 25-70 ℃, then pickling, then wash, recrystallization can obtain compound 3.The molar ratio 1 of compound 1 and compound 2: 1.5-4, the molar ratio of recommendation is 1: 2-2.5.Described polar organic solvent can be tetrahydrofuran (THF), acetone, second eyeball, dimethyl formamide etc.
(2) in polar organic solvent, compound 3, dicyclohexylcarbodiimide (DCC), 4 dimethylamino pyridines (DMAP) and compound 4 can obtain compound 5 in 12-36 hour 50-80 ℃ of reaction.Compound 3, dicyclohexylcarbodiimide (DCC), 4 dimethylamino pyridines (DMAP), the mol ratio of compound 4 is 1: 1-3: 0.8-1.2: 3-6, the molar ratio of recommendation is 1: 1.5-2: 0.9-1.1: 4-5.Described polar organic solvent can be tetrahydrofuran (THF), acetone, second eyeball, dimethyl formamide etc.
(3) in non-proton organic solvent, compound 5, compound 6 and dibutyl tin laurate, at 40-70 ℃ of reaction 48-72 hour, can obtain compound 7.Compound 5, the molar ratio 1 of compound 6 and dibutyl tin laurate: 1-2: 0.2-0.8,, the molar ratio of recommendation is 1: 1-1.25: 0.3-0.5.Described non-proton organic solvent can be benzene, toluene, methylene dichloride, chloroform etc.
(4) in non-proton organic solvent, compound 5, DMAP, acid binding agent and compound 8 react 24-48 hour at 25-70 ℃, then pickling, then wash, column chromatography can obtain compound 9.Compound 5, DMAP, the molar ratio of acid binding agent and compound 8 is 1: 0.4-1: 1-6: 2-5, the molar ratio of recommendation is 1: 0.4-0.6: 3-5: 3-4.Described non-proton organic solvent can be benzene, toluene, and methylene dichloride, chloroform etc., acid binding agent can be triethylamine or pyridine etc.
(5) in non-proton organic solvent, compound 9, DCC and compound 10, at 25-40 ℃ of reaction 24-36 hour, can obtain compound 11.Compound 9, the molar ratio 1 of DCC and compound 10: 1-2: 1.1-1.5.Described non-proton organic solvent can be benzene, toluene, methylene dichloride, chloroform etc.
(6) in the mixed solvent of tetrahydrofuran (THF) and methyl alcohol or ethanol, compound 9, hydrogen reacts and can obtain compound 12 in 12-48 hour at 25-80 ℃ with catalyzer.Compound 9 is 1 with the mass ratio of catalyzer: 0.4-0.6, and hydrogen pressure is 1.0-1.2MPa, the mixed solvent volume ratio of described tetrahydrofuran (THF) and methyl alcohol or ethanol is 3-4: 1, catalyzer is palladium/carbon or palladium hydroxide/carbon.
(7) in non-proton organic solvent, compound 12, DCC and compound 10, at 25-40 ℃ of reaction 24-36 hour, can obtain compound 13.Compound 12, the molar ratio 1 of DCC and compound 10: 1-2: 1.1-1.5.Described non-proton organic solvent can be benzene, toluene, methylene dichloride, chloroform etc.
(8) in non-proton organic solvent, compound 13, DMAP, acid binding agent and compound 14 react 24-48 hour at 25-70 ℃, then pickling, then wash, column chromatography can obtain compound 15.Compound 13, DMAP, the molar ratio of acid binding agent and compound 14 is 1: 0.4-1: 1-6: 4-8, the molar ratio of recommendation is 1: 0.4-0.6: 3-5: 5-7.Described non-proton organic solvent can be benzene, toluene, and methylene dichloride, chloroform etc., acid binding agent can be triethylamine or pyridine etc.
The raw material cheapness that method of the present invention is related, reaction conditions is gentle, has stronger operability.Liposome size prepared by lipid of the present invention is even, and surface has silicate network structure, has improved its stability.The encapsulation rate of liposome prepared by lipid of the present invention is 96.6%～99.0%, this is owing to containing phenyl ring or hydroxy-acid group in liposome, can have an effect with the hydrophobic or hydrophilic drugs that will seal by electron conjugated magnetism or electrostatic attraction effect, thereby improve the encapsulation rate to medicine; And surface has silicate network structure, so medicine is difficult for leaking.
Accompanying drawing explanation
Fig. 1 is the chemical structural formula of the present invention's final compound lipid of containing phenyl ring group; Fig. 2 is the chemical structural formula of the present invention's final compound lipid of containing hydroxy-acid group; Fig. 3 is the transmission electron microscope picture of the prepared complex liposome of the method described by specific embodiment 9 of the lipid compounds 11 of specific embodiment 5 preparation; Fig. 4 is the transmission electron microscope picture of the prepared complex liposome of the method described by specific embodiment 9 of the lipid compounds 15 of specific embodiment 8 preparation.
Embodiment
By following embodiment, will contribute to understand the present invention, but not limit content of the present invention.R in following examples
1=R
2=C
16alkyl, a=b=d=2 and when b=0, c=0, R
3=OEt, X=H..
Embodiment 1
After the compound of 6mmol 1 (two cetylamine) is mixed with the compound 2 (Succinic anhydried) of 12mmol, be dissolved in the tetrahydrofuran (THF) of 60mL, after being heated to dissolve completely, stirring at room 26 hours, is spin-dried for solvent, add again 50mL chloroform to dissolve, gained solution is used 10% aqueous hydrochloric acid and saturated common salt water washing successively, and anhydrous magnesium sulfate drying, after filtration gained filtrate is spin-dried for, the column chromatography for separation compound 3 of purifying to obtain, productive rate 78%.
C
36H
71NO
3
1h NMR (400MHz, CDCl
3, TMS): δ=0.88 (t, J=6.6Hz, 6H, NCH
2cH
2(CH
2)
13cH
3), 1.26 (m, 52H, NCH
2cH
2(CH
2)
13cH
3), 1.54 (m, 4H, NCH
2cH
2(CH
2)
13cH
3), 2.69 (m, 4H, HOCO (CH
2)
2cON), 3.15 (t, 2H, J=7.8Hz, NCH
2cH
2(CH
2)
13cH
3), 3.32ppm (t, 2H, J=7.8Hz, NCH
2cH
2(CH
2)
13cH
3); MS theoretical value: 565.95, experimental value [M]+: 566.9
Embodiment 2
After the compound of 2mmol 3 is mixed with the compound 4 of 4mmol, be dissolved in the dimethyl formamide of 40mL, after being heated to dissolve completely, add successively again the DCC of 4mmol and the DMAP of 1mmol, at 55 ℃ of temperature, stir 16 hours, evaporated under reduced pressure solvent, gained crude product is through the column chromatography for separation compound 5 of purifying to obtain, productive rate 43%.
C
48H
85NO
6
1h NMR (CDCl
3, 400MHz) δ: 0.90 (t, J=6.8Hz, 6H, CH
3), 1.25 (s, 52H, NCH
2cH
2(CH
2)
13cH
3) (m, 4H, NCH
2cH
2(CH
2)
13cH
3), 2.64 (s, 4H, COCH
2cH
2cO), 3.18～3.30 (m, 4H, NCH
2cH
2(CH
2)
13cH
3), 3.77 (d, J=11.2Hz, 2H, CH
2oH), 3.96 (s, 4H, PhCHOCH
2), 4.15 (d, J=11.2Hz, 2H), 4.60 (s, 1H, OH), 5.42 (s, 1H, PhCHOCH
2), 7.35 (d, J=6.4Hz, 3H, Ph-H), 7.47 (d, J=7.2Hz, 2H, Ph-H) .MS theoretical value: 772.19, experimental value [M]
+: 772.9, [M+Na]
+: 794.9.
Embodiment 3
Under nitrogen protection; the compound of 1mmol 5 is dissolved in the methylene dichloride of 40mL; add successively again the compound 6 of 1.25mmol and the catalyzer dibutyl tin laurate of 0.4mmol; at 55 ℃, stir 48 hours; be spin-dried for solvent; gained crude product is through the column chromatography for separation compound 7 of purifying to obtain, productive rate 52.3%.
C
58H
106N
2O
10Si
1h NNR (CDCl
3, 400MHz) δ: 0.60 (t, J=8.0Hz, 2H, SiCH
2cH
2cH
2nH), 0.87 (t, J=7.2Hz, 6H, CH
3(CH
2)
13cH
2cH
2n), 1.19～1.27 (m, 61H, NCH
2cH
2(CH
2)
13cH
3and SiOCH
2cH
3), 1.45～1.57 (m, 6H, CH
3(CH
2)
13cH
2cH
2n and SiCH
2cH
2cH
2nH), 2.50～2.57 (m, 4H, COCH
2cH
2cO), 2.97～3.19 (m, 6H, SiCH
2cH
2cH
2nH and CH
3(CH
2)
13cH
2cH
2n), 3.71～3.85 (m, 6H, SiOCH
2cH
3), 3.90～4.01 (m, 8H, COOCH
2c), 5.42 (s, 1H, Ph-CH), 7.33～7.46 (m, 5H, ArH) .MS theoretical value: 1019.56, experimental value [M]
+: 1020.5.
Embodiment 4
After the compound of 4mmol 5 is mixed with the compound 8 of 16mmol, be dissolved in the methylene dichloride of 40mL, add successively again the DMAP of 2mmol and the triethylamine of 20mmol, at 35 ℃ of temperature, stir 26 hours, evaporated under reduced pressure solvent, gained crude product is through the column chromatography for separation compound 9 of purifying to obtain, productive rate 86%.
C
52H
89NO
9
1h NMR (CDCl
3, 400MHz) δ: 0.88 (t, J=7.2Hz, 6H, CH
3), 1.26～1.30 (m, 52H, NCH
2cH
2(CH
2)
13cH
3), 1.49～1.60 (m, 4H, NCH
2cH
2(CH
2)
13cH
3), 2.59～2.70 (m, 8H, COCH
2cH
2cO), 3.23～3.32 (m, 4H, NCH
2cH
2(CH
2)
13cH
3), 3.75～3.93 (m, 4H, PhCHOCH
2), 4.18 (d, J=12Hz, 2H, NCOCH
2cH
2cOOCH
2), 4.54 (d, J=24.4Hz, 2H, HOOCCH
2cH
2cOOCH
2), 5.44 (s, 1H, PhCHOCH
2), 7.35～7.46 (m, 5H, Ph-H) .MS theoretical value: 872.26, experimental value [M]
+: 873.2, [M+Na]
+: 895.2.
Embodiment 5
The compound of 0.5mmol 9 is dissolved in the methylene dichloride of 30mL, then adds successively at 10,30 ℃ of the DCC of 1.2mmol and the compounds of 1.5mmol and stir 30 hours, evaporated under reduced pressure solvent, gained crude product is through the column chromatography for separation compound 11 of purifying to obtain, productive rate 20%.
C
61H
110N
2O
11Si
1h NMR (CDCl
3, 400MHz) δ: 0.61 (t, J=8.0Hz, 2H, SiCH
2cH
2cH
2nH), 0.88 (t, J=7.2Hz, 6H, CH
3(CH
2)
13cH
2cH
2n), 1.20～1.26 (m, 61H, NCH
2cH
2(CH
2)
13cH
3and SiOCH
2cH
3), 1.47～1.58 (m, 6H, CH
3(CH
2)
13cH
2cH
2n and SiCH
2cH
2cH
2nH), 2.44～2.67 (m, 8H, COCH
2cH
2cO), 3.11～3.19 (m, 6H, SiCH
2cH
2cH
2nH and CH
3(CH
2)
13cH
2cH
2n), 3.69～3.75 (m, 6H, SiOCH
2cH
3), 3.79～4.47 (m, 8H, COOCH
2c), 5.43 (s, 1H, Ph-CH), 7.34～7.45 (m, 5H, ArH) .MS theoretical value: 1075.62, experimental value [M]
+: 1076.5.
Embodiment 6
The compound 9 of 2mmol (1.75g) is dissolved in the mixed solvent that volume ratio is the methyl alcohol of 1: 3 and tetrahydrofuran (THF), join in the reactor of 250mL, palladium hydroxide/the carbon that adds again 0.87g, at 50 ℃, vigorous stirring is 48 hours, evaporated under reduced pressure solvent, gained crude product is through the column chromatography for separation compound 12 of purifying to obtain, productive rate 52%.
C
45H
85NO
9
1h NMR (CDCl
3, 400MHz) δ: 0.88 (t, J=6.8Hz, 6H, CH
3), 1.25～1.30 (m, 52H, NCH
2cH
2(CH
2)
13cH
3), 1.47～1.58 (m, 4H, NCH
2cH
2(CH
2)
13cH
3), 2.64 (d, J=3.6Hz, 8H, COCH
2cH
2cO), 3.20～3.29 (m, 4H, NCH
2cH
2(CH
2)
13cH
3), 3.62 (s, 4H, HOCH
2), 4.11～4.16 (m, 4H, COCH
2cH
2cOOCH
2) .MS theoretical value: 784.16, experimental value [M]
+: 785.2, [M+Na]
+: 807.2.
Embodiment 7
The compound of 0.5mmol 12 is dissolved in the methylene dichloride of 30mL, add successively again at 10,30 ℃ of the DCC of 1.2mmol and the compounds of 1.5mmol and stir 30 hours, evaporated under reduced pressure solvent, gained crude product is through the column chromatography for separation compound 13 of purifying to obtain, productive rate 35%.
C
54H
106N
2O
11Si
1h NMR (CDCl
3, 400MHz) δ: 0.61 (t, J=8.0Hz, 2H, SiCH
2cH
2cH
2nH), 0.88 (t, J=7.2Hz, 6H, CH
3(CH
2)
13cH
2cH
2n), 1.20～1.26 (m, 61H, NCH
2cH
2(CH
2)
13cH
3and SiOCH
2cH
3), 1.47～1.58 (m, 6H, CH
3(CH
2)
13cH
2cH
2n and SiCH
2cH
2cH
2nH), 2.49～2.63 (m, 8H, COCH
2cH
2cO), 3.21～3.25 (m, 6H, SiCH
2cH
2cH
2nH and CH
3(CH
2)
13cH
2cH
2n), 3.58～3.60 (m, 4H, HOCH2), 3.69～3.85 (m, 6H, SiOCH
2cH
3), 4.11～4.17 (m, 4H, COOCH
2c) .MS theoretical value: 987.51, experimental value [M]
+: 988.4.
Embodiment 8
After the compound of 4mmol 13 is mixed with the compound 14 of 16mmol, be dissolved in the methylene dichloride of 40mL, add successively again the DMAP of 2mmol and the triethylamine of 20mmol, at 35 ℃ of temperature, stir 26 hours, evaporated under reduced pressure solvent, gained crude product is through the column chromatography for separation compound 15 of purifying to obtain, productive rate 56%.
C
62H
114N
2O
17Si
1h NMR (CDCl
3, 400MHz) δ: 0.61 (t, J=8.0Hz, 2H, SiCH
2cH
2cH
2nH), 0.88 (t, J=7.2Hz, 6H, CH
3(CH
2)
13cH
2cH
2n), 1.18～1.27 (m, 61H, NCH
2cH
2(CH
2)
13cH
3and SiOCH
2cH
3), 1.48～1.57 (m, 6H, CH
3(CH
2)
13cH
2cH
2n and SiCH
2cH
2cH
2nH), 2.48～2.63 (m, 16H, COCH
2cH
2cO), 3.20～3.26 (m, 6H, SiCH
2cH
2cH
2nH and CH
3(CH
2)
13cH
2cH
2n), 3.70～3.84 (m, 6H, SiOCH
2cH
3), 4.00～4.07 (m, 4H, COOCH
2c) .MS theoretical value: 1187.66, experimental value [M]
+: 1188.7.
Embodiment 9
The compound of 4mg 11 or compound 15 are placed in to the round-bottomed flask of 20mL, add 5mL chloroform to dissolve, then decompression is slowly revolved to steam and is made it at flask inwall, form film, dry to remove chloroform completely in 35 ℃ of vacuum drying ovens; Toward the deionized water that adds certain volume in film forming flask, making final solution concentration is again 1mmol/L.With the ultrasonic 5min of probe type ultrasonic instrument, obtain the solution of certain opacity, under room temperature, place the aqueous solution that can obtain corresponding liposome for 12 hours.As shown in Figure 3, the transmission electron microscope of the liposome of being prepared by compound 15 as shown in Figure 4 for the transmission electron microscope of the liposome of being prepared by compound 11.
Claims (6)
1. the compound lipid based on tetramethylolmethane, is characterized in that the structural formula of the compound lipid based on tetramethylolmethane is:
2. the compound lipid based on tetramethylolmethane as claimed in claim 1, is characterized in that X is H, CH
3, CH
3o, F, Cl, Br, NO
2.
3. the compound lipid based on tetramethylolmethane as described in claim 1 and 2, is characterized in that R
1for n-hexyl, n-octyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
4. the compound lipid based on tetramethylolmethane as described in claim 1 and 2, is characterized in that R
2for n-hexyl, n-octyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
5. a preparation method for the compound lipid based on tetramethylolmethane as claimed in claim 1, is characterized in that preparing by following method:
(1), in polar organic solvent, compound 1 reacts 24-48 hour with compound 2 at 25-70 ℃, then pickling, then wash, recrystallization can obtain compound 3; The molar ratio 1 of compound 1 and compound 2: 1.5-4; Described polar organic solvent is tetrahydrofuran (THF), acetone, second eyeball, dimethyl formamide;
(2) in polar organic solvent, compound 3, dicyclohexylcarbodiimide (DCC), 4 dimethylamino pyridines (DMAP) and compound 4 obtain compound 5 for 12-36 hour 50-80 ℃ of reaction; Compound 3, dicyclohexylcarbodiimide (DCC), 4 dimethylamino pyridines (DMAP), the mol ratio of compound 4 is 1: 1-3: 0.8-1.2: 3-6; Described polar organic solvent is tetrahydrofuran (THF), acetone, second eyeball, dimethyl formamide;
(3) in non-proton organic solvent, compound 5, compound 6 and dibutyl tin laurate, at 40-70 ℃ of reaction 48-72 hour, can obtain compound 7; Compound 5, the molar ratio 1 of compound 6 and dibutyl tin laurate: 1-2: 0.2-0.8; Described non-proton organic solvent is benzene, toluene, methylene dichloride, chloroform;
(4) in non-proton organic solvent, compound 5, DMAP, acid binding agent and compound 8 react 24-48 hour at 25-70 ℃, then pickling, then wash, column chromatography can obtain compound 9; Compound 5, DMAP, the molar ratio of acid binding agent and compound 8 is 1: 0.4-1: 1-6: 2-5; Described non-proton organic solvent is benzene, toluene, and methylene dichloride, chloroform, acid binding agent is triethylamine or pyridine;
(5) in non-proton organic solvent, compound 9, DCC and compound 10, at 25-40 ℃ of reaction 24-36 hour, obtain compound 11; Compound 9, the molar ratio 1 of DCC and compound 10: 1-2: 1.1-1.5; Described non-proton organic solvent is benzene, toluene, methylene dichloride, chloroform;
The structural formula of the above compound 1-11 is as follows:
6. a purposes for the compound lipid based on tetramethylolmethane as claimed in claim 1, is characterized in that the carrier as various kinds of drug.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010224640.2A CN102329335B (en) | 2010-07-13 | 2010-07-13 | Pentaerythritol-based composite lipid and preparation method and application thereof |
| US13/384,032 US8729257B2 (en) | 2009-07-17 | 2010-07-19 | Hybrid lipid compounds based on pentaerythritol, intermediates, preparation methods and use thereof |
| PCT/CN2010/075269 WO2011006453A1 (en) | 2009-07-17 | 2010-07-19 | Compound lipid based on pentaerythritol, intermediates, preparation method and use thereof |
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| CN201010224640.2A CN102329335B (en) | 2010-07-13 | 2010-07-13 | Pentaerythritol-based composite lipid and preparation method and application thereof |
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| CN106674315B (en) * | 2016-12-28 | 2019-07-19 | 北京大学 | Janus lipid and its intermediate, preparation method and purposes based on pentaerythrite |
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| US20040043952A1 (en) * | 2002-05-31 | 2004-03-04 | Genteric, Inc. | Multifunctional polyamines for delivery of biologically-active polynucleotides |
| US20060040891A1 (en) * | 2002-05-09 | 2006-02-23 | Biomira, Inc | Lipid a and other carbohydrate ligand analogs |
| US20080221238A1 (en) * | 2007-03-09 | 2008-09-11 | Su Shiu-Chin H | Epoxysilanes, processes for their manufacture and curable compositions containing same |
| US20080299043A1 (en) * | 2007-06-01 | 2008-12-04 | Fujifilm Corporation | Higher fatty acid triester compound having diethylenetriamine-type metal chelate structure |
| CN101724144A (en) * | 2008-11-03 | 2010-06-09 | 北京键凯科技有限公司 | Novel multi-arm polyethylene glycol, preparation method and application thereof |
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| US20060040891A1 (en) * | 2002-05-09 | 2006-02-23 | Biomira, Inc | Lipid a and other carbohydrate ligand analogs |
| US20040043952A1 (en) * | 2002-05-31 | 2004-03-04 | Genteric, Inc. | Multifunctional polyamines for delivery of biologically-active polynucleotides |
| US20080221238A1 (en) * | 2007-03-09 | 2008-09-11 | Su Shiu-Chin H | Epoxysilanes, processes for their manufacture and curable compositions containing same |
| US20080299043A1 (en) * | 2007-06-01 | 2008-12-04 | Fujifilm Corporation | Higher fatty acid triester compound having diethylenetriamine-type metal chelate structure |
| CN101724144A (en) * | 2008-11-03 | 2010-06-09 | 北京键凯科技有限公司 | Novel multi-arm polyethylene glycol, preparation method and application thereof |
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| Jie Xue等，.Pentaerythritol as the Core of Multivalent Glycolipids: Synthesis of a Glycolipid with Three SO3Lea Ligands.《Org. Lett.》.2005,第7卷(第17期),第3753-3756页. * |
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| CN102329335A (en) | 2012-01-25 |
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