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Amphoteric liposomes
Inactive Publication Date: 2007-05-10
MARINA BIOTECH INC
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[0015] An object of the present invention therefore is to provide liposomes and mixtures of lipids capable of forming such liposomes having improved stability upon contact with human or animal serum.
[0016] In particular, an object of the present invention is to provide amphoteric liposomes having such improved serum stability.
Problems solved by technology
It is known in the art that nucleic acid therapeutics, irrespective of their actual chemical origin, may lack therapeutic efficacy owing to their instability in body fluids or because of inefficient uptake into cells, or both.
However, such carriers lack encapsulation efficiency and do not provide an endosomolytic signal that facilitates further uptake into cells (Journal of Pharmacology and experimental Therapeutics (2000), 292, 480-488 by Klimuk, et al.).
Although cationic systems provide high loading efficiencies, they lack colloidal stability, in particular after contact with body fluids.
However, the use of PEG does not solve the intrinsic toxicity problems associated with cationic lipids.
Method used
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example 1
Preparation of Carboxyfluorescein (CF) Loaded Liposomes with the Amphoteric Ii Lipids MoChol and CHEMS
[0135] Stock solutions of lipids in chloroform were mixed and finally evaporated in a round bottom flask to dryness under vacuum. Lipid films were hydrated with 100 mM CF in PBS pH 7.5. The resulting lipid concentration was 20 mM. The suspensions were hydrated for 45 minutes in a water bath at room temperature, sonicated for 5 minutes following by three freeze / thaw cycles at −70° C. After thawing the liposomal suspensions were extruded 15 times through polycarbonate membranes with a pore size of 100 nm. Non-encapsulated CF was removed by gel filtration, whereas the liposomes were diluted by a factor three. Lipid recovery and concentration was analysed by organic phosphateassay. Particle size was measured by dynamic light scattering on a Malvern Zetasizer 3000 HSA.
TABLE 1Variation of the ratio DOPE / POPC and thetotal amount of charged componentsLipidsCompositionDOPE / MoChol / CHEMS60...
example 2
Preparation of Carboxyfluorescein (CF) Loaded Liposomes with the Amphoteric H Lipids MoChol and DMGSucc
[0138] Liposomes were prepared as described in Example 1.
TABLE 6Variation of ratio DOPE / POPC and thetotal amount of charged componentsLipidsCompositionPOPC / DOPE / MoChol / DMGSucc4:16:27:53POPC / DOPE / MoChol / DMGSucc6:24:23:47POPC / DOPE / MoChol / DMGSucc8:32:20:40POPC / DO...
example 3
Preparation of Carboxyfluorescein (CF) Loaded Liposomes with the Amphoteric Ii Lipids MoChol and DOGSucc
[0141] Liposomes were prepared as described in Example 1.
TABLE 7Variation of the ratio MoChol / DOGSucc andthe total amount of charged componentsLipidsCompositionSerum stabilityPOPC / DOPE / MoChol / DOGSucc12.5:37.5:17:33+POPC / DOPE / MoChol / DOGSucc12.5:37.5:33:17+POPC / DOPE / MoChol / DOGSucc7.5:22.5:23:47−POPC / DOPE / MoChol / DOGSucc7.5:22.5:47:23+
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Abstract
A serum-stable mixture of lipids capable of encapsulating an active agent to form a liposome, said mixture comprising phosphatidylcholine and phosphatidylethanolamine in a ratio in the range of about 0.5 to about 8. The mixture may also include pH sensitive anionic and cationic amphiphiles, such that the mixture is amphoteric, being negatively charged or neutral at pH 7.4 and positively charged at pH 4. Amphoteric liposomes comprising such a mixture may be used for encapsulating nucleic acid therapeutics, such as oligonucleotides and DNA plasmids. The drug / lipid ratio may be adjusted to target the liposomes to particular organs or other sites in the body.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority from U.S. Provisional Application Ser. No. 60 / 717,199, filed on Sep. 15, 2005; European Application No. 05020218.3, filed on Sep. 15, 2005; European Application No. 05020217.5, filed on Sep. 15, 2005; PCT Application No. PCT / EP2005 / 011905, filed on Nov. 4, 2005; PCT Application No. PCT / EP2005 / 011908, filed on Nov. 4, 2005; U.S. application Ser. No. 11 / 266,999, filed on Nov. 4, 2005; U.S. application Ser. No. 11 / 267,423, filed on Nov. 4, 2005; European Application No. 06113784.0, filed on May 10, 2006; and European Application No. 05090322.8, filed on Nov. 21, 2005. [0002] Each of the applications and patents cited in this text, as well as each document or reference cited in each of the applications and patents (including during the prosecution of each issued patent; “application cited documents”), and each of the U.S. and foreign applications or patents corresponding to and / or claiming priority from any ...
Claims
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