Systemic delivery and pre-clinical evaluation of nanoparticles containing antisense oligonucleotides and siRNAs

Area of Science:

• Oncology
• Drug Delivery
• Molecular Biology

Background:

• Antisense oligonucleotides (ASO) and small interfering RNAs (siRNA) offer targeted cancer therapy by silencing oncogenic molecules.
• Clinical application of ASO/siRNA is limited by poor pharmacokinetics, biodistribution, and suboptimal tumor target suppression.
• Raf-1 kinase is a key signaling molecule and a target for cancer therapy.

Purpose of the Study:

• To evaluate a modified formulation of systemically delivered cationic liposomes containing raf antisense oligonucleotide (md-LErafAON).
• To assess the toxicology, pharmacokinetics, biodistribution, target selectivity, and anti-tumor efficacy of md-LErafAON in preclinical models.

Main Methods:

• Cationic liposomes were formulated using dimyristoyl 1,2-diacyl-3-trimethylammonium-propane (DMTAP), phosphatidylcholine (PC), and cholesterol (CHOL).
• Studies in athymic mice bearing human tumor xenografts were conducted to evaluate md-LErafAON.
• Comprehensive analysis included toxicology, pharmacokinetics, biodistribution, target selectivity, and anti-tumor efficacy assessments.

Main Results:

• The modified liposomal formulation (md-LErafAON) demonstrated favorable pharmacokinetics and biodistribution.
• Effective target selectivity and significant anti-tumor efficacy were observed in preclinical models.
• The md-LErafAON formulation exhibited a good safety profile with no significant toxicity.

Conclusions:

• Modified liposomes represent a promising system for the systemic delivery of antisense oligonucleotides.
• md-LErafAON is a well-tolerated, next-generation antisense therapeutic with potential for clinical evaluation in cancer treatment.
• This approach enhances the therapeutic potential of ASO/siRNA by overcoming delivery challenges.