Cationic liposomes loaded with proapoptotic peptide D-(KLAKLAK)(2) and Bcl-2 antisense oligodeoxynucleotide G3139 for enhanced anticancer therapy.

Abstract

The treatment of cancer using macromolecular therapeutics such as oligonucleotides or peptides requires efficient delivery systems capable of intracellular penetration and may also benefit from use of a combination of therapeutics with different mechanisms of action. With this possibility in mind, we constructed cationic liposome loaded with the proapoptotic peptide, d-(KLAKLAK)(2) and the Bcl-2 antisense oligodeoxynucleotide, G3139, and determined whether the combination of the proapoptotic macromolecules in a single cationic liposome can enhance antitumor efficacy. Advantage was taken of alternating charge interaction to entrap macromolecules of opposite charge. The polycationic peptide d-(KLAKLAK)(2) was first condensed with the polyanionic oligodeoxynucleotide G3139 to obtain overall negatively charged peptide/oligodeoxynucleotide complexes. The complexes were then entrapped into DOTAP/DOPE cationic liposomes (CL). This sequential charge interaction ensured efficient entrapment of d-(KLAKLAK)(2) and G3139 with a high loading efficiency (50%) and capacity (7.5 wt %). In vitro treatment of mouse melanoma B16(F10) with CL loaded with d-(KLAKLAK)(2)/G3139 led to significantly enhanced antitumor efficacy, mediated by stimulated induction of apoptotic (caspase 3/7) activity, when compared to CL loaded with G3139 alone. Intratumoral injection of CL loaded with d-(KLAKLAK)(2)/G3139 in B16(F10) mice xenograft also led to suppressed tumor growth associated with enhanced apoptotic activity. Thus, the combination of proapoptotic peptide d-(KLAKLAK)(2) and antisense oligonucleotide G3139 in a cationic liposome led to enhanced apoptotic/antitumor efficacy and may provide a promising tool for cancer treatment.

• Authors: Young Tag Ko, Claudio Falcao, Vladimir P Torchilin
• Journal: Molecular pharmaceutics (Mol Pharm) 2009 May-Jun Vol. 6 Issue 3 Pg. 971-7 ISSN: 1543-8384 [Print] United States
• PMID: 19317442 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA, Antisense
• Liposomes
• Peptide Fragments
• Proto-Oncogene Proteins c-bcl-2
• Caspase 3
• Caspase 7

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Line, Tumor
• DNA, Antisense (chemistry, genetics, physiology)
• Genetic Therapy (methods)
• In Situ Nick-End Labeling
• Liposomes (chemistry)
• Male
• Melanoma, Experimental (therapy)
• Mice
• Mice, Inbred C57BL
• Peptide Fragments (chemistry)
• Proto-Oncogene Proteins c-bcl-2 (genetics)