Liposome-coated lipoplex-based carrier for antisense oligonucleotides

• Published in: Cancer biology & therapy 2015-01, Vol.16 (1), p.66-76
• Main Authors: Wyrozumska, Paulina, Meissner, Justyna, Toporkiewicz, Monika, Szarawarska, Marta, Kuliczkowski, Kazimierz, Ugorski, Maciej, Walasek, Marta A, Sikorski, Aleksander F
• Format: Article
• Language: English
• Subjects: acute leukemia; Animals; antisense deoxynucleotides; BCL-2 gene; cationic lipids; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Disease Models, Animal; Drug Carriers - chemistry; Drug Stability; Female; gene therapy; Genes, bcl-2; Humans; lipid carrier; lipoplex; liposome coated lipoplex; Liposomes - chemistry; Male; Mice; Oligonucleotides, Antisense - administration & dosage; Oligonucleotides, Antisense - chemistry; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - pharmacokinetics; Research Papers; Tissue Distribution; Transfection; Xenograft Model Antitumor Assays
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/15384047.2014.987009

The chemical nature of genetic drugs (e.g. antisense oligonucleotides, siRNA, vectors) requires a suitable carrier system to protect them from enzymatic degradation without changing their properties and enable efficient delivery into target cells. Lipid vectors for nucleic acid delivery that have been widely investigated for years can be very effective. As the majority of attempts made in the field of cancer gene therapy have focused on solid tumors, while blood cancer cells have attracted less attention, the latter became the subject of our investigation. The lipid carrier proposed here is based on liposomes constructed by others but the lipid composition is original. A liposome-coated lipoplex (L-cL) consists of a core arising from complexation of positively charged lipid and negatively charged oligodeoxynucleotide (ODN) or plasmid DNA coated by a neutral or anionic lipid bilayer. Moreover, our lipid vector demonstrates size stability and is able to retain a high content of enclosed plasmid DNA or antisense oligodeoxynucleotides (asODNs). Observed transfection efficacies of the tested preparation using a plasmid coding for fluorescent protein were up to 60-85% of examined leukemia cells (Jurkat T and HL-60 lines) in the absence or the presence of serum. When BCL-2 asODN was encapsulated in the L-cL, specific silencing of this gene product at both the mRNA and protein level and also a markedly decreased cell survival rate were observed in vitro. Moreover, biodistribution analysis in mice indicates prolonged circulation characteristic for PEG-modified liposomal carriers. Experiments on tumor-engrafted animals indicate substantial inhibition of tumor growth.