JPH0482893A - Peptide-derived phospholipid compound and production of polypeptide liposome using the same - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1>, R<2> are 8-24C alkyl, acyl; R<3m>, R<4n> are the side chain residue of alpha-amino acid; m, n are 0-5; M<+> is the counter ion of phosphate anion including H<+>; X is a releasing whose conjugated acid has a PKa of 7-16). EXAMPLE:A compound of formula II. USE:A raw material for lipids constituting bio-decomposable polypeptide liposomes. The compound gives readily the liposomes. PREPARATION:For example, a compound of formula IV obtained from a methylphosphorodichloridate of formula III is hydrolyzed and reacted with glycine propargyl ester trifluoroacetic acid salt. The produced compound of formula V is reacted with trifluoroacetic acid and simultaneously with Boc glycine anhydride. The produced compound of formula VI is successively reacted with lithium bromide and trifluoroacetic acid. The produced trifluoroacetic acid salt is converted in a sodium bicarbonate aqueous solution into the objective Na salt of formula I wherein M<+> is Na<+>.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to liposomes, particularly peptide-derived phospholipid compounds useful as polymerizable liposome-forming lipids, and a method for producing polypeptide liposomes.

(Prior art) In recent years, many attempts have been made in the medical and pharmaceutical fields to use liposomes as drug carriers and diagnostic agents by supporting water-soluble or lipophilic drugs (for example, Shomoto et al. Bioscience and Industry, No. 4
7, p. 475, 1989). However, liposomes are simply molecular aggregates due to hydrophobic interactions, and the following problems have been pointed out as major problems when used as drug carriers and diagnostic agents. That is, the encapsulated drug leaks out and disappears very quickly from the blood.

As a solution to these problems, polymerization of liposomes is being considered. (For example, Ringsdorf et al.
English (Angew, Chem.

Int, Ed, Engl.) Volume 20, Page 305, 1
981, Ringsdorf et al., same magazine, vol. 20, 9.
(Page 0, 1981) However, many of the polymer liposomes have poor biodegradability, which poses a problem from the viewpoint of biocompatibility.

R4ngsd as a biodegradable polymer liposome
Polypeptide liposomes have been reported by Orf et al.

Chem, Rapid, Commun,) Volume 3,
167 pages, 1982, Journal of the American Chemistry Society (J, Hachim, Chem
, Soc, Vol. 108, p. 487, 1986).

However, the former has the disadvantage that the hydrophilic part of the polymer liposome has weak hydrophilicity, and the latter only forms giant liposomes.

(Problems to be Solved by the Invention) Therefore, an object of the present invention is to provide a novel peptide-derived phospholipid compound that solves the conventional drawbacks and can easily form polypeptide liposomes having biodegradability, and a polypeptide using the same. An object of the present invention is to provide a method for producing liposomes.

(Means for Solving the Problems) An object of the present invention is to form a liposome using a peptide-derived phospholipid compound shown in -Formation (1) below and this as a liposome-constituting lipid raw material, and then polymerize this compound. This was achieved by a method for producing polypeptide liposomes characterized by the following.

II II 11H-
(NH-C)l-C) 1I-NH-CI-C-(N
)l-CI-C) □-XR3IICH2R" 0=P-0-M+ CHz CHCHz RI R2 In the formula, R1 and R2 represent an alkyl group or an acyl group having 8 to 24 carbon atoms. R1 and R2 are each linear It may be branched or branched. It may also have a substituent or unsaturated group. Preferred are a tetradecyl group, hexadecyl group, octadecyl group, myristoyl group, valmitoyl group, and stearoyl group.

R3'' and R4' each represent a side chain residue of an α-amino acid. Preferably, a hydrogen atom, a lysine side chain residue ((CH2
)4NH2), aspartic acid side chain residues (-C12Cool(), serine side chain residues (-CH2
OH). When m is 2 or more, R3'' may be the same or different. When n is 2 or more, R4'' may be the same or different. m and n each represent an integer of 0 to 5. Preferably, the sum of m and n is an integer of O to 3. M4 represents the counter ion of the phosphate anion. (Contains hydrogen atoms). Preferably, H“alkali metal ion (
Li", Na", K"Rb", Cs""). Further, the amino group at the end of the molecule may become an ammonium salt and form a counter ion with a phosphate anion within the molecule as shown in the following formula (n).

Synthetic route example C2゜ CH3 0=P-0CI3 CH-CH2 0=P-OCR3 CH2-CH-CH2 0=P-OCR.

CH2-CH-CH3 X represents a leaving group whose conjugate acid has a pka between 7 and 16. Preferably, a phenoxy group, a trichloroethoxy group,
They are dichloroethoxy group, monochloroethoxy group, ethoxy group, methoxy group, CH3CH:CCH20- group, CH-C=N-0- group.

Furthermore, as for the asymmetric carbon present in the molecule, it may be either a racemic form or an optically active form, but an optically active form is preferable.

The amino group at the end of the molecule becomes an ammonium ion and may form a salt (eg, trifluoroacetate, hydrochloride) with an appropriate acid component. Furthermore, a salt may be formed with a phosphate anion within the molecule.

An example of the synthetic route for the peptide-derived phospholipid of the present invention is shown below. However, the present invention is not limited to this.

Boc = (CH3) a-C-0-CCH.

CH2-CH-CH2 3m CH2-CFI-C)+3 R1R2 F.A. ・)13N=-CI-C (N-CH-C).

-CH-C (N-CH-C), -X R3+If CH2 114+1 0=P-OH CH2-CH-CH2 (N-CI-C).

-CH-C (N-CH-C), l 3ffi CH2 0=P-0-Na" CHz-CH-CHz (1) Sodium salt Synthetic route example Hz Boc -N-CH-C-OH Boc-N-CI-C (N-CIl-C) CH2 CH2 CH2-CH-CH2 CHz-CH-CT.

CH.

CH2 a) 8, ■ methylimidazole, THF.

b) 7, ■-Methylimidazole, THFC) 5% palladium on carbon, R7, ethyl acetate R4 (11 triethylamine e) trifluoroacetic acid, dichloromethane dichloromethane g) lithium bromide, methyl ethyl ketone; h) aqueous sodium bicarbonate solution, chloroform 1H11 - l(3N"-CH-C- (N-C)I-C), l
CIlz R" CHz-CH-CHz ・HJ+-CI-C-(N-C:H-C) l, l-+
-N-CH-C-(N-CH-C) 1l-XR3C
m-11CL 1174110=P-OH CHz-Ctl-CHz o O(1) Trifluoroacetate I R2 H-(N-CH-C), -N-C8-C-(N-1cH
-C). -XR"'C11211"0-P-〇"-Na" CHz-CH-Cliz oo (1) Sodium salt I R2 Here, the method for producing the polypeptide liposome of the present invention will be described.

Polymerization of the liposome according to the present invention is carried out by condensation polymerization of the peptide-derived phospholipid compound represented by the general formula (1) in the lipid bilayer membrane of the liposome to form an amide bond to form a polypeptide.

In the present invention, first, a liposome is prepared using the peptide-derived phospholipid compound of general formula (1) as a constituent material of the liposome. Liposome preparation methods include Vaultex swing method, ultrasonic irradiation method, surfactant removal method, reversed phase evaporation method (
REV method), ethanol injection method, ether injection method, pre-vesicle method, French press extrusion method, extrusion method
on method), annealing method,
Freeze-thaw method, W10/W emulsion method, and 5ta
All conventional methods such as the BLE Plurilamellar Vesicle method (SPLV method) can be used.

Regarding these liposome preparation methods, see Papahajo
A review by Pauls et al.
hys, Boioeng, +Volume 9, Page 467, 19
1980), Yatori et al., Bengami et al., Sokoki (Liposome, pp. 21-40, Nankodo (1988)).

Purification of liposomes may be carried out by conventional methods. (For example, gel filtration methods using Sephadex columns, Sepharose columns, etc., centrifugation methods, and dialysis methods are mentioned.) In the present invention, compounds that can be encapsulated in liposomes include various drugs, antibiotics, dyes, and fluorescent substances. Examples include.

Polymerization of the liposome prepared as described above may be carried out by allowing it to stand for an appropriate period of time, preferably several tens of minutes to several hours, after the liposome is prepared. The pH of the dispersion at this time is not particularly limited, but it is preferable to control amide formation within the range of pH 4 to 10.

Furthermore, during liposome preparation, the compound represented by the general formula (I) of the present invention and the lipid used in existing liposome manufacturing methods may be mixed as liposome-constituting lipids. (For example, Shiba 1 flumidoyl phosphatidylcholine (DPPC), simyristoyl phosphatidylcholine (DMPC), distearoyl phosphatidylcholine (DSPC), Shibalumi I
-yl phosphatidylethanolamine (DPPE),
dipalmitoylphosphatidylserine (DpPS),
Examples include Egg lecithin. ) When mixed, the number of lipids to be mixed may be one or two or more. It may also be mixed with cholesterol.

Preferred specific examples of the peptide-derived phospholipid compound represented by the general formula (1) of the present invention are shown below.

However, the present invention is not limited thereto.

■ ■ 0=P-ONa” Hzq Hzq 02P-011 1LzqH□.

■ 0-P-01( 11HII 0=P-OH H29H29 0-P-0-Na” H:17 H37 0=P-OH H37H3□ 0=P-011 H3?　H37 H2 0=P-0-Na+ tl z q Hz q ■ 0=P-OH I29 829 CH 0=P-0-Na' Hff7 I37 Hz 0=P−0”Na+ CHz-CH-CH2 CI4 Cl4 I29 I29 less than, Phase transition temperature of preferred embodiments of the invention or melting point.

CH 0=P-OH CIII CI[1 I37 I37 0=P-0-Na+ CI4 Cl4 I29 I29 Synthesis examples and examples of the present invention are shown below, but the present invention is not limited thereto.

Synthesis of Synthesis Example 2) 12.25 g of methyl phosphorodichloridate was dissolved in 20 d of tetrahydrofuran (THF). ditetradecyl-5n-glycerol 8 (R' = R'' in 8
=C+4Hz, ) 7.25gll-methylimidazole (1.25g) and THF mixed solution (50%) were added dropwise. After stirring for 1.5 hours at room temperature, Boc-1-serine benzyl ester 74°3811-methylimidazole 1.25
g, THE mixed solution 50rd was added dropwise and allowed to stand overnight.

After evaporation of the solvent and extraction with ethyl acetate, the organic layer was dried over sodium sulfate, ethyl acetate was distilled off under reduced pressure, and the product was purified by silica gel chromatography (hexane/ethyl acetate - 75/25). In R1-R2=Cl4H2
9) was obtained as a colorless liquid in an amount of 2.3 g.

2 obtained above (in 2 R' = R'' = C, , I2.
) was dissolved in 50% ethyl acetate, and 0.5 g of 5% palladium on carbon was added to perform hydrogenolysis.

(3 hours at room temperature) Filtration was performed using Celite, and the solvent was distilled off from the filtrate to obtain 3 (R' = R2 = C, , H2, in 3).

3 (R' = R2 = Cr p H29 in 3)
Dissolve 1.5 g in dichloromethane, add N,
0.5 g of N'dicyclohexylcarbodiimide (DCC) was added and stirred for 30 minutes. Next, 0.7 g of glycine propargyl ester trifluoroacetate, 0.3 g of triethylamine, and 10 volumes of dichloromethane solution were added and stirred for 4 hours.

Water was added to this, the organic layer was dried with sodium sulfate, and the product was purified by silica gel chromatography (hexane/ethyl acetate - 1/1
) and purified with 4 (R'-R2-CI4I2 in 4
9, X=-0-CH2C3CH1n=1, R persimmon-H) as a semi-solid substance with 0. I got 8g. 4 (R at 4
'=R2=CI4H29, X=CHz C=CH,,
R4′″=H) 0.7g) 7/L/10r of oroacetic acid
d.CH2Cl! ,, Ten Precepts were added and stirred for 30 minutes.

After evaporating the solvent, the residue was dissolved in CH, Cff125d, and 0.1 g of triethiamine and 0.7 g of Boc glycine anhydride were added.
g was added and stirred for 6 hours. After evaporation of the solvent, the product was purified by silica gel chromatography (hexane/ethyl acetate-3/7) to obtain 6 (R' = R2 = C + aHzq, X
--0-CH2c=cH, m=n=L R3m-R4
+″=H) was obtained as an ant-like substance. 6 (in 6, R′ = R2=C, 4H27, X--OCH2C=
CHXm=n=1, R"=R4I'I=H) 0.4g was dissolved in 3rd methyl ethyl ketone and 0.9g of lithium bromide
g was added and left overnight. The solvent was distilled off, extracted using dichloromethane and saturated brine, the organic layer was dried over sodium sulfate, and dichloromethane was distilled off under reduced pressure. The residue was dichloromethane 2rnI.

2 d of trifluoroacetic acid was added and stirred for 30 minutes. The solvent was distilled off, and the residue was recrystallized from ethyl acetate to obtain 150 mg of peptide-derived phospholipid (1-1).

An infrared absorption spectrum diagram is shown in FIG.

In addition, regarding the asymmetric carbon of each synthetic intermediate, the serine moiety is 8
body, the glycerol moiety is R body.

Synthesis Example 2 (Synthesis of (1-1)) Peptide-derived phospholipid (I2) obtained in Synthesis Example 1 100
(2) was dissolved in chloroform, saturated aqueous sodium bicarbonate solution was added and stirred, and the organic layer was dried with sodium sulfate and the solvent was distilled off to obtain peptide-derived phospholipid (I-1). An infrared absorption spectrum diagram is shown in FIG.

Synthesis Example 3 Synthesis of N1-4) 98.02 g of phenylphosphorodichloridate was added to TH
Dissolved in F60d, 78.85 g of Boc-1-serine benzyl ester, 3.12 g of 1-methylimidazole
100 ml of HF mixed solution was added dropwise. After stirring for 1.5 hours at room temperature, 17.88 g of dioctadecyl-5n-glycerol 8 (R1 = R" = C + 4 Hz in 8),
1-methylimidazole 3.12g, THF mixture 25
0-1 was added dropwise and left undisturbed for a day and night. After evaporating the solvent and extracting with ethyl acetate, the organic layer was dried over sodium sulfate, ethyl acetate was distilled off under reduced pressure, and chromatographed on silica gel (hexane/
Purify the product with ethyl acetate (70/30)
10.5 g of (RI=R2=C+s H37 in 10) was obtained as a colorless semi-solid.

10 obtained above (in 10 R' = R2 = CI
e Dissolve 2.9g of H37) in 50d of ethyl acetate to give 5%
Hydrolysis was carried out by adding 0.5 g of palladium carbon.

(At room temperature for 3 hours) Filtration was performed using Celite, and the solvent of the filtrate was distilled off to obtain 11.

(R' = R" = Cl8H37 in 11) 11
(R' = R2 = CI8H37 in 11) 2.2g
was dissolved in dichloromethane, and 0.53 g of N, N' dicyclohexylcarbodiimide (DCC) was added.
Stirred for 0 minutes. Next, glycine methyl ester 0.
Added 27 g of dichloromethane solution 10 and stirred for 6 hours. Water was added to this, the organic layer was dried with sodium sulfate, and the product was chromatographed on silica gel (hexane/ethyl acetate - 1/1).
Purified LL2 (12 niote R' = R2 = CIB
1.68 g of H37, X=OCH3, n=1, R''-H) was obtained as a semi-solid substance.
=R2CI8H37, X-OCH3, n=1, R"=H
20 d of trifluoroacetic acid and 20 ml of dichloromethane were added to 1.68 g of ) and stirred for 30 minutes. After evaporation of the solvent, the residue was dissolved in CH, (125d) and triethylamine 0.
18g of Boc glycine anhydride and 0160g of Boc glycine anhydride were added and stirred overnight. After evaporation of the solvent, the product was purified by silica gel chromatography (hexane/ethyl acetate - 3/7).
4, R' = R2 = CI8H37, X = -OCH
3, m=n=1, R3m=R"=H) as a spiral substance7
1.5g was obtained. 14 (in 14 R' - R2= C
+ a H37, X--OCH,, m=n=1, R""
=R"=H) 1.0g was dissolved in 20% ethyl acetate and Ad
0.3 g of ams catalyst was added for hydrolysis. It was filtered using Celite, and the filtrate was distilled off under reduced pressure. Dissolve the residue in 2 volumes of dichloromethane, add 2 volumes of trifluoroacetic acid, and dissolve
Stirred for 0 minutes. The solvent was distilled off and the residue was recrystallized from ethyl acetate to give peptide-derived phospholipid (1-4) 0.7
Obtained 0g. Figure 4 shows the infrared absorption spectrum diagram, “H-
The NMR spectrum diagram is shown in FIG.

Regarding the optical activity of the synthetic intermediate, there are 8 serine sites and R-form glycerol sites.

Synthesis Example 4 (Synthesis of (1-3)) Peptide-derived phospholipid (1-4) obtained in Synthesis Example 3 100
mg was dissolved in chloroform, saturated aqueous sodium bicarbonate solution was added and stirred, and the organic layer was dried with sodium sulfate and the solvent was distilled off to obtain peptide-derived phospholipid (1-3). An infrared absorption spectrum diagram is shown in FIG.

Synthesis Example 5 (Synthesis of (I-5)) 93.20 g of phenylphosphorodichloridate was dissolved in THF.
10 (dissolved in ltl!, 3.30 g of Boc-1-serine methyl ester, 1.2 g of 1-methylimidazole)
0 g and 50 d of THF mixed solution were added dropwise. After stirring for 1.5 hours at room temperature, dioctadecyl-5n-glycerol 8
(R+ in 8, ,=Rz-C+eH37) 8.
90 g, 1, methylimidazole 1.20 g, THF
100 rd of the mixed solution was added dropwise and allowed to stand overnight. After evaporating the solvent, extraction was performed with ethyl acetate (AcOEt), the organic layer was dried over sodium sulfate, ethyl acetate was distilled off under reduced pressure, and chromatographed on silica gel (hexane/ethyl acetate - 70/30).
) to obtain 3.93 g of a colorless semi-solid.

Trifluoroacetic acid 33 to acid 20 and 20 d of dichloromethane were added to 1.5 g of the colorless semisolid obtained above, stirred for 30 minutes, and the solvent was distilled off to obtain 1.5 g of a residue.

Z-glycylglycine 426 mg, carbonylimidazole (CDI) 260 μg, dimethyl sulfoxide (D
5 g of the previously obtained residue I, 162 ml of triethylamine and 162 ml of the DMSO mixture were added dropwise to 15 ml of the DMSO mixture. −
After standing in the sun, the solvent was distilled off, chloroform and water were added, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Chromatograph the residue on silica gel (methanol/chloroform)
Purification was performed to obtain 640 ml of a screw-like substance.

250 ml of this spiral material was dissolved in 10 d of ethyl acetate and 10 ml of methanol, and 100 mg of Adams catalyst was added thereto for hydrolysis.

After evaporation of the solvent, the residue was recrystallized from methanol to obtain 200 μm of peptide-derived phospholipid compound (I-5). The infrared absorption spectrum is shown in Figure 5, and the 'HNMR spectrum is shown in Figure 9.
As shown in the figure.

Regarding the asymmetric carbon atoms of each synthetic intermediate, there are 8 serine sites and R-configuration glycerol sites.

Synthesis Example 6 (Synthesis of (1-6)) 4 synthesized in the same manner as Synthesis Example 1 (R1=R in 4
2 = CIa H29, X--0-CH2C3CH.

0.1 g of n=1, R''-H) was dissolved in 2 mfl of methyl ethyl ketone, 0.1 g of lithium bromide was added, and the mixture was allowed to stand overnight. The solvent was distilled off, and the solution was dissolved using dichloro, methane, and saturated brine. The organic layer was dried with sodium sulfate, and dichloromethane was distilled off under reduced pressure.The residue was dissolved in 1 d of dichloromethane, 1 d of trifluoroacetic acid was added, and the mixture was stirred for 30 minutes. Recrystallization from acetic acid ester gave 50 μm of peptide-derived phospholipid (I-6).The infrared absorption spectrum is shown in FIG.

Regarding the asymmetric carbon atoms of each synthetic intermediate, the serine moiety is in three forms and the glycerol moiety is in R form.

Synthesis Example 7 (Synthesis of (1-7)) 12 synthesized in the same manner as Synthesis Example 3 (R' in 12
=R" = Cl8H37, X-OCH3, n = 1,
Dissolve 0.38 g of R”=H) in 10 d of ethyl acetate and
0.1 g of ms catalyst was added for hydrolysis.

It was filtered using Celite, and the filtrate was distilled off under reduced pressure.

The residue was dissolved in dichloromethane 2, 2 ml of trifluoroacetic acid was added, and the mixture was stirred for 30 minutes. By distilling off the solvent,
The residue was recrystallized from ethyl acetate to obtain 0.20 g of peptide-derived phospholipid (1-7).

An infrared absorption spectrum diagram is shown in FIG.

Furthermore, regarding the asymmetric carbon of each synthetic intermediate, the serine moiety is 3
body, the glycerol moiety is R body.

Example 1 (Production of polypeptide liposome) Peptide-derived phospholipid (I-1) 3■ was dissolved in chloroform,
Chloroform was distilled off under reduced pressure to form a thin film. Next, 1 ml of pure water was added (pH 8.5), and Vortex mixing was performed (1 minute, 3 times). Subsequently, ultrasonic irradiation was performed (probe type, 30 W, 1.5 minutes, twice).

The mixture was allowed to stand for 1 hour to complete polymerization and obtain polypeptide liposomes.

Furthermore, the morphology of the liposomes was observed using electron micrographs, and it was confirmed that liposomes with a particle size of 75 nm were formed.

Example 2 (Production of polypeptide liposome) Peptide-derived phospholipid (I-3) 3■ was dissolved in chloroform,
Chloroform was distilled off under reduced pressure to form a thin film. Next, a drop of pure water was added (pH 8.6), and Vortex mixing was performed (1 minute, 3 times). Subsequently, ultrasonic irradiation was performed (probe type, 30 W, 1.5 minutes, twice).

Polypeptide liposomes were obtained by allowing the mixture to stand for 8 days to complete polymerization. (Particle size: 150 nm) Example 3 (Encapsulation test of polypeptide liposomes) Peptide-derived phospholipids (
1-2) 3■ was dissolved in chloroform, and the chloroform was distilled off under reduced pressure to form a thin film. Next, 200mM carboxyfluorescein, oxalic acid buffer pH 9.01
ml, and Vortex mixing was performed (1
3 times per minute). Subsequently, ultrasonic irradiation was performed (probe type, 30 W, 1.5 minutes, twice).

Leave to stand for 1 hour to complete polymerization, and add Sepharose 4B.
We performed gel filtration using a column and found that polypeptide liposomes encapsulated carboxyfluorescein.

Example 4 (Polypeptide Liposome Encapsulation Test) Peptide-derived phospholipid (I-3) 3.1 was dissolved in chloroform, and the chloroform was distilled off under reduced pressure to form a thin film. Next, 200mM carboxyfluorescein, phosphate buffer pH 7, 41mf! was added and Vortex mixing was performed (1 minute, 3 times). Subsequently, ultrasonic irradiation was performed (probe type, 30 W, 1.5 minutes, twice).

Leave to stand for 8 days to complete polymerization, and Sepharose 4B
We performed gel filtration using a column and found that polypeptide liposomes encapsulated carboxyfluorescein.

[Brief explanation of the drawings] Figure 1: Infrared absorption spectrum of peptide-induced phospholipid compound ([-1), KBr method Figure 2: Infrared absorption spectrum of peptide-induced phospholipid compound (1-2), KBr method Figure 3 Infrared absorption spectrum of peptide-derived phospholipid compound (I-3), KBr method Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Peptide-derived phospholipid compound (I-3) Infrared absorption spectrum diagram of 4), Infrared absorption spectrum diagram of KBrBr dipeptide-derived phospholipid compound-5), Infrared absorption spectrum diagram of KBrBr dipeptide-derived phospholipid compound-6), KBrBr dipeptide-derived phospholipid compound -7) Infrared absorption spectrum diagram, 'H-NMR of KBrBr dipeptide-derived phospholipid compound -4)
Spectrum diagram (CD (in 13-D20) “H-NMR of peptide-derived phospholipid compound (1-5)
Spectrum diagram (CDCl2.”-I) in zO)

Claims (2)

[Claims] (1) A compound represented by the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 and R^2 represent an alkyl group or an acyl group having 8 to 24 carbon atoms. R^1 and R^2 may each be linear or branched. It may also have a substituent or unsaturated group. R^3^m and R^4^n each represent a side chain residue of α-amino acid. m and n each represent an integer of 0 to 5. M^+ indicates a counter ion to the phosphate anion (contains H). X represents a leaving group whose conjugate acid has a pka of between 7 and 16. Furthermore, the asymmetric carbon present in the molecule may be either a racemic form or an optically active form. The amino group at the end of the molecule may become an ammonium ion to form a salt. ] (2) Production of polypeptide liposomes by forming a liposome containing at least one of the liposome-constituting lipids, and then polymerizing this compound. Method.