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Targeted delivery of antisense oligonucleotides in cancer
F Pastorino1, D Stuart, M Ponzoni
1Department of Pharmacology 9-31 MSB, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Abstract:
Formulations of antisense oligonucleotides (asODNs) against c-myb or c-myc protooncogenes have been prepared by a new technique that sequesters cationic lipid in the interior of a lipid particle. This technique results in high loading efficiency for the asODNs, small particle size and good stability. When targeted against melanoma cells or neuroblastoma cells via anti-GD(2) coupled at the particle surface, increased cell binding to the cells could be demonstrated. Targeted formulations showed greater inhibition of cell proliferation compared to non-targeted formulations or free drug. Inhibition of cell proliferation was demonstrated to be due to down-regulation of c-myb or c-myc protein expression. The formulations have long-circulation times in vivo, and evaluation for in vivo antitumor activity is currently underway.
Insights
New lipid particle formulations effectively deliver antisense oligonucleotides (asODNs) targeting c-myb and c-myc protooncogenes, showing enhanced cell binding and proliferation inhibition in cancer models.
Area of Science:
- Nanotechnology in drug delivery
- Molecular oncology
- Antisense oligonucleotide therapeutics
Background:
- Protooncogenes c-myb and c-myc are critical in cancer development.
- Antisense oligonucleotides (asODNs) offer targeted gene silencing but require effective delivery systems.
- Targeted delivery to cancer cells can improve therapeutic efficacy and reduce off-target effects.
Purpose of the Study:
- To develop novel lipid particle formulations for efficient delivery of asODNs against c-myb and c-myc.
- To enhance cellular targeting of these formulations to melanoma and neuroblastoma cells.
- To evaluate the in vitro efficacy of targeted asODN formulations in inhibiting cancer cell proliferation.
Main Methods:
- A new technique was employed to sequester cationic lipid within lipid particles, encapsulating asODNs.
- Formulations were surface-coupled with anti-GD(2) antibodies for targeted delivery to cancer cells.
- In vitro assays assessed cell binding, cell proliferation inhibition, and protein expression levels (c-myb/c-myc).
Main Results:
- The novel technique achieved high asODN loading efficiency, small particle size, and good formulation stability.
- Targeted formulations demonstrated significantly increased binding to melanoma and neuroblastoma cells.
- Targeted asODN formulations exhibited superior inhibition of cell proliferation compared to non-targeted controls, correlating with c-myb/c-myc downregulation.
Conclusions:
- The developed lipid particle formulation is a promising and stable delivery system for asODNs.
- Surface targeting enhances cellular uptake and anti-proliferative effects of asODN formulations.
- These targeted asODN formulations represent a potential therapeutic strategy for c-myb/c-myc-driven cancers.