Liposome combination and the use thereof

Abstract

The present invention relates to a liposome combination, which wrapped hydrophilic drugs in water layer and wrapped hydrophobic drugs in lipid bilayer; hydrophobic drugs are photosensitizers. Using light with appropriate wavelength to activate the photosensitizer in the hydrophobic layer can result in the production of singlet oxygen and the free radical, and cause the oxidizing and breaking of the carbon chain of the phospholipid, and influences the stability of the liposome and the releases of the drug. The singlet oxygen and the free radical will attack the cancer cells at the same time as a result of combining the photodynamic- and chemo-effects.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will become apparent upon reading of the following detailed description of the present invention in conjunction with the drawings, as follows:

FIG.1 is a diagram of the stability analysis of different liposomes stored at 4° C. according to the present invention; DSPC: Egg PC: Cholesterol: PEG-DSPE=8:2:1:0.2 μmole, (▪) 9:1:1:0.2 μmole, (▴) 10:0:1:0.2 μmole, (×) 10:0:2:0.2 μmole, (*) 10:0:3:0.2 μmole.

FIG. 2 is a diagram of drug release from the liposome in 37° C. PBS after light activating, the encapsulated drug is Hp.

FIG. 3 is a diagram of drug release from the liposome in 37° C. PBS after light activating, the encapsulated drug is PpIX.

FIG. 4 is a diagram of the lipid bilayer permeability change of the liposome in the absence of photosensitizer after 30 J/cm² light irradiation, the model drug used to monitor the permeability of the membrane is Doxorubicin.

FIG. 5 is a diagram of the lipid bilayer permeability change of the liposome in the absence of photosensitizer after 30 J/cm² light irradiation, the model drug used to monitor the permeability of the membrane is Calcein.

FIG. 6 is a diagram of the lipid bilayer permeability change of the liposome encapsulating a photosensitizer (Hp) after 30 J/cm² light irradiation, the model drug used to monitor the permeability of the membrane is Doxorubicin.

FIG. 7 is a diagram of the lipid bilayer permeability change of the liposome encapsulating a photosensitizer (Hp) after 30 J/cm² light irradiation, the model drug used to monitor the permeability of the membrane is Calcein;

FIG. 8 is a diagram of the toxicity of various formulation to CL1-0 cell Liposomal-Hp and free-Hp were added into the cell culture system and light irradiation was provided with doses from 0 J, 2 J, 4 J, 6 J, to 8 J;

FIG. 9 is a diagram of the toxicity of various formulation to A431 cells, Liposomal Doxorubicin (LD), Free Doxorubicin (FD), Liposomal-Dox-Hp (LDH),

Liposomal Hp (LH), and LDH treating with 1 J, 10 J, 20 J, and 30 J of light were compared;

FIG. 10 is a diagram of the toxicity of various formulation to CL1-0 cells.

Liposomal Doxorubicin (LD), Free Doxorubicin (FD), Liposomal-Dox-Hp (LDH), and LDH treated with 1 J, and 10 J of light were compared.

Claims

1. A liposome combination comprising: (a) a liposome(b) a hydrophilic drug that is encapsulated in a hydrophilic layer of a liposome; and(c) a hydrophobic drug that is encapsulated in a lipid bilayer of said liposome;wherein said hydrophobic drug is a photosensitive substance selected from porphyrins which can excite said hydrophilic drug release by photodynamic action when said liposome is illuminated from a light source, andwherein the liposome comprises phospholipids with saturated fatty acid.

2. (canceled)

3. The combination of claim 1, wherein said photosensitive substance is hematoporphyrin.

4. The combination of claim 1, wherein said photosensitive substance is protoporphyrin.

5. The combination of claim 1, wherein said light source is a red light.

6. The combination of claim 4, wherein the wavelength of said red light is 600 to 670 mm.

7. The combination of claim 6, wherein the red light source is 635 mm.

8. The combination of claim 4, wherein said red light source is a red light-emitting diode.

9. A method of using a combination of liposome as a drug releasing control system, comprising: (a) exciting a photosensitive substance encapsulated in the hydrophilic layer in the lipid bilayer of said liposome by a light source;(b) producing free radicals and singlet oxygen from said excited photosensitive substance;(c) reducing the stability of said liposome by said free radicals and singlet oxygen; and(d) releasing a drug that is encapsulated in the hydrophilic layer of said liposome,wherein said photosensitive substance is selected from porphyrins and,wherein the liposome comprises phospholipids with saturated fatty acid.

10. The method of claim 9, wherein said light source is a red light source.

11. The method of claim 10, wherein the wavelength of said red light source is 600 to 670 mm.

12. The method of claim 10, wherein said red light source is a red light-emitting diode.

13. (canceled)

14. The method of claim 9, wherein said photosensitive substance is hematoporphyrin.

15. The method of claim 9, wherein said photosensitive substance is protoporphyrin.

16. A method of using a liposome formulation combination in a photodynamic therapy and chemotherapy, comprising: (a) using a light to excited a liposome exciting a photosensitive substance encapsulated in the hydrophilic layer in the lipid bilayer of said liposome by a light source;(b) producing free radicals and singlet oxygen from said excited photosensitive substance;(c) reducing the stability of said liposome and causing cytotoxicity by said free radicals and singlet oxygen; and(d) releasing a chemotherapy drug that is encapsulated in the hydrophilic layer of said liposome;wherein said photosensitive substance is selected from porphyrins and,wherein the liposome comprises phospholipids with saturated fatty acid.

17. The combination of claim 1, wherein said phospholipids with saturated fatty acid is 1,2-disteroyl-sn-glycero-3-phosphocholine.

18. The method of claim 16, wherein said phospholipids with saturated fatty acid is 1,2-disteroyl-sn-glycero-3-phosphocholine.

19. The method of claim 9, wherein said phospholipids with saturated fatty acid is 1,2-disteroyl-sn-glycero-3-phosphocholine.