Cationic Liposomes − Rakyat Biologi

Since its first report two decades ago [100], significant progress has been made towards the use of cationic liposomes for the cellular delivery of nucleic acids, particularly siRNAs. This delivery system self-assembles with siRNA via electrostatic interactions between positively charged lipids and the negatively charged phosphate backbone of siRNA, forming lipoplexes. Lipoplexes protect encapsulated siRNA from nuclease degradation, and facilitate their transport across the cell membrane.

Cationic liposomes can be constituted from a variety of lipidic components, including phospholipids, cholesterols, cationic lipids and various lipid-like materials. Lipid composition can greatly influence the physical properties of liposomes [101] and their delivery efficiency [102]. For instance, cholesterols are commonly included to improve liposomal stability and uptake [103]. Some cationic derivatives of cholesterol can also facilitate endosomal escape [104]. PEGylated lipids can be incorporated to confer steric stabilisation to the nanoparticle, and prolong its blood circulation by evading the mononuclear phagocyte system [105, 106]. These PEG-displaying liposomes are termed stable nucleic acid lipid particles (SNALPs). Amino lipid derivatives containing cleavable ester bonds have recently been developed to improve biodegradability of liposomes [107]. A wide range of methods for liposome preparation are available, which can also influence important properties such as the size and dispersity of liposomes [108].

Nucleic acid delivery by cationic liposomes is well established, as demonstrated by the prevalence of commercially available products such as Lipofectin, Oligofectamine, Lipofectamine and RNAifect, which are commonly used in laboratories to enhance siRNA delivery in vitro [109-111]. Furthermore, nearly half of the most promising siRNA drug candidates currently in clinical trials are formulated with cationic liposome systems for delivery [112]. For example, Alnylam Pharmaceuticals' SNALP-based drug ALN-VSP02, which is used to treat liver cancer, delivers siRNAs targeted against the mRNAs of vascular endothelial growth factor and kinesin spindle protein, both of which have important roles in tumour proliferation and survival. ALN-VSP02 has suitable physical properties for delivering siRNA in vivo, including a diameter of 80-100 nm and a small zeta potential of <6 mV at pH 7.4. Intravenous administration of ALN-VSP02 in patients with advanced cancer and liver metastases gave encouraging results, including siRNA-mediated cleavage of targeted mRNAs in the liver and pronounced tumour regression [113]. One potential disadvantage of current liposomal siRNA drug candidates, including ALN-VSP02, is the lack of a targeting mechanism for cancer cells. As a result, significant levels of siRNA may be taken up by healthy cells alongside the cancer cells.

It is notable that liposomes are already clinically approved to deliver other drugs, such as doxorubicin and daunorubicin, in the treatment of various cancers [114]. Whether this platform will prove to be the most effective for delivering siRNA therapeutics remains to be seen.