Biology Reference
In-Depth Information
greater cationic lipid content than the SNALPs, have induced not only effective
gene silencing, but also cytokine induction, interferon response and complement
activation as well as coagulation cascades and liver toxicity and, thus, cannot be
used for clinical evaluation.
Considering the significant toxicities that have been associated with cationic
liposomes, neutral charged liposomes are very promising carriers for systemic
delivery of siRNAs. 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) non-
PEGylated liposomes encapsulating siRNAs against different molecules expressed
on melanoma and ovarian cancers inhibited tumour growth in human xenograft
models [
48,
49
]. The accumulation of these liposomes in cancerous tissues is attrib-
uted to the EPR effect.
Cationic lipidoid (synthetic lipid-like molecules)-containing liposomes are
another siRNA delivery system that has been shown to induce effective gene silenc-
ing (80% reduction in murine ApoB and Factor VII mRNAs levels) in the liver.
Single intravenous injection of cationic lipidoid-containing liposomes encapsulat-
ing ApoB-siRNA resulted in 50% decrease in the protein level 3 days and up to
2 weeks after the treatment. Although no immune response was indicated, increases
in the levels of two liver enzymes suggest some degree of liver toxicity [
50,
51
] .
HK peptides are another effective delivery system for siRNAs. This system is
based on the addition of histidine into poly-lysine peptides. While lysine is impor-
tant for binding the siRNAs, histidine stabilises the particles and has an important
role in buffering acidic endosomes, thereby leading to endosomal disruption and
payload release. Specific ratios and patterns of histidine and lysine have been found
to augment the siRNA delivery, while carriers with a higher ratio of histidine to
lysine content seemed to be more effective [
52
]. HK peptides carrying Raf-1-siRNA
or human rhomboid family-1-siRNA induced significant silencing of target genes
and growth inhibition of tumour xenografts [
53,
54
] .
Atelocollagen is a biomaterial that consists of a low-immunogenic fraction of
pepsin-digested type I collagen from calf dermis. Rich in positively charged lysine
and hydroxylysine residues it complexes the negatively charged siRNA and inter-
acts with the plasma membrane, hence facilitates incorporation of the siRNA into
the cells. Although these particles have not been modified to target tumours, passive
targeting due to the EPR effect causes the selective accumulation within the cancer-
ous tissues as shown in several studies with different tumour xenografts [
21,
55-
57
] .
Initial studies indicated that atelocollagen particles could be administered safely
without induction of cytokines or observed toxicity to the tissues.
6.4.2
Active Cellular Systemic RNAi Delivery
siRNAs conjugated to a targeting moiety or to specific cell penetrating entity
(such as cholesterol, specific phospholipids, natural receptor ligands, monoclonal
antibodies and their fragments) is a common strategy for active cellular delivery.
This class of cell-specific delivery is becoming more popular and feasible due to
Search WWH ::
Custom Search