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Systemic delivery of serum stable plasmid lipid particles for cancer therapy

a systemic delivery and cancer technology, applied in the field of tumors in mammals, can solve the problems of rapid degradation of naked dna in the blood, non-satisfactory criteria, and the use of systemic delivery systems, and achieve the effects of improving the properties or characteristics of formulations, reducing toxicities, and encapsulation efficiency

Inactive Publication Date: 2005-06-02
PROTIVA BIOTHERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] In the above methods, the nucleic acid and the first compound can be delivered in lipid formulations that can be the same or different. The lipid formulations, whether used to deliver the nucleic acid or first compound (e.g., prodrug), can be prepared from a variety of lipids, lipid conjugates and additional compatible components known in the art. The lipid formulations can be prepared, for example, from sphingomyelin and cholesterol. Moreover, the lipid formulations can contain additional components that improve the properties or characteristics of the formulations, such as leakiness, longevity

Problems solved by technology

Unfortunately, there are well-known drawbacks to these popular methods that prevent their use as systemic delivery systems.
For instance, cationic lipid-plasmid aggregates are rapidly cleared by the liver, lung or spleen after intravenous delivery and, therefore, do not satisfy the criteria for systemic delivery since they demonstrate little useful transfection elsewhere.
Moreover, adenoviral and retroviral systems are immunogenic, are rapidly cleared from circulation and do not permit repeat dosing.
In addition, naked DNA is rapidly degraded in the blood and, thus, is not suitable for systemic delivery.

Method used

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  • Systemic delivery of serum stable plasmid lipid particles for cancer therapy
  • Systemic delivery of serum stable plasmid lipid particles for cancer therapy
  • Systemic delivery of serum stable plasmid lipid particles for cancer therapy

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0093] This example illustrates the synthesis of 5 lipid-plasmid particle formulations for systemic delivery.

[0094] Materials: Plasmids are preferably supercoiled, 4000 to 15000 bp in length, encoding genes and enhancer elements, etc. as desired. Cationic lipid, N,N-dioleyl-N,N-dimethyl ammonium chloride (“DODAC”) and monomethoxy polyethylene2000 glycol succinate-(C8:0-ceramide) (“PEG-Cer-C8”) were synthesized at Inex Pharmaceuticals Corp. Dioleyl-phosphatidylethanolamine (DOPE) was supplied by Northern Lipids, Vancouver. Standard dialysis membranes: Spectro / Por 5 regenerated Cellulose (12-14,000 MWCO) was purchased from VWR (Manufactured by Spectrum Medical Industries Inc.). Sodium Citrate was purchased from BDH. Sodium Chloride, Triton X-100 and Octyl-beta-D-glucopyranoside (“OGP”) were obtained from VWR Scientific, Fisher Scientific or Sigma Chemical Company.

Formulation 1.1 (Or, Alternatively, INEX 303 or INEX 303i)

[0095] Plasmid (50-400 μg) is incubated with DODAC in 500 μL ...

example 2

[0128] This example illustrates the measurement of the therapeutic effect of lipid formulated ganciclovir on subcutaneous tumors transfected with lipid encapsulated HSV-TK.

Mice perGroupTumorPlasmidProdrugRouteAssayGroupAB16L018PBSIVTumor Volume6 C57BB16L018GCVIVTumor Volume6 C57CB16pTK010PBSIVTumor Volume6 C57DB16pTK010GCVIVTumor Volume6 C57

[0129] On day zero, 24 female C57 mice (Harlan Sprague Dawley, Inc., Indianapolis, Ind.) are seeded sub-cutaneously with 100,000 B16 mice melanoma cells (NCI catalog B 16BL-6) in a total volume of 50 μL (groups A, B, C, D). Tumor volume is determined daily by measuring the length, width and height of the tumor with skin calipers as soon as possible and every day thereafter. Groups A to D are treated with 100 μg plasmid of the appropriate lipid-formulated plasmid, formulated according to Example 1, once daily beginning at 9:00 a.m. on day five and on every day following. The plasmid formulation is injected IV in the tail vein in a total volume o...

example 5

[0132] This example sets forth the protocol for stable transfection of B16 tumor cells with HSV-TK, for use in Examples 6 and 7, as described in Short Protocols in Molecular Biology, Third Edition, page 9-13 to 9-15, with the following modifications.

[0133] According to the method, the following materials were used. Plasmids: pCMVTKIRESneo is based on plasmid pBR322 and includes a CMV promoter, HSV-TK gene, internal ribosome entry site and neomycin resistance gene. L018 is also based on pBR322, but carrying a CMV promoter and a luciferase gene. First, plate B 16 murine melanoma cells in a tissue culture flask (T-75) at 5×105 cells / flask in 10 mL MEM media with addition of 10% FBS and Glutamine and grow overnight in CO2 incubator at 37° C. to 70% confluency. Next, aspirate media and feed cells with 3.8 mL fresh media per flask 2 h prior to transfection and prepare plasmid / lipid Lipofectin (GIBCO BRL) aggregate in a polystyrene tube according to manufacturer's instructions. Alternativ...

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Abstract

The present invention relates to methods and compositions for treating a neoplasia in a mammal.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application Ser. Nos. 60 / 101,429, filed Sep. 22, 1998 and 60 / 086,917, filed May 27, 1998, which are incorporated herein by reference in their entirety for all purposes. This application is also related to U.S. Patent Application Ser. No. ______, filed Feb. 2, 1999 (Attorney Docket No. 016303-006220), and claims the benefit of U.S. Provisional Patent Application Ser. Nos. 60 / 112,384, filed Dec. 14, 1998, and 60 / 073,598, filed Feb. 3, 1998, which are incorporated herein by reference in their entirety for all purposes.FIELD OF THE INVENTION [0002] This invention relates to methods and compositions for treating a neoplasia and, in particular, a tumor in a mammal. BACKGROUND OF THE INVENTION [0003] Systemic delivery of therapeutic nucleic acids for gene therapy applications is a highly desirable goal. Systemic delivery using blood or lymph circulatory systems will permit therape...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K31/522A61K31/711A61K9/14A61K38/20A61K38/45A61K38/46A61K38/51A61K45/00A61K47/16A61K47/24A61K47/42A61K47/44A61K48/00A61P35/00A61P43/00C12N15/09C12N15/88
CPCA61K38/208A61K38/45C12N15/88A61K48/00A61K38/51A61K9/127A61K31/382A61K31/522A61K31/675A61K31/70A61K38/47A61K38/50A61K45/06Y10S977/804A61P35/00A61P43/00A61K2300/00
Inventor MACLACHLAN, IANGRAHAM, ROGER W.
Owner PROTIVA BIOTHERAPEUTICS
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