Abstract
Modification of nanoparticle surfaces with PEG has been widely considered the gold standard for many years. However, PEGylation presents controversial and serious challenges including lack of functionality, hindered cellular interaction, allergic reactions, and stimulation of IgM production after repetitive dosing that accelerates blood clearance of the nanoparticles. We report the development of novel liposomal formulations surface-modified with a low molecular weight, branched polyethyleneimine (bPEI)–lipid conjugate for use as an alternative to PEG. The formulations had very good stability characteristics in ion- and protein-rich mediums. Protein adsorption onto the liposomal surface did not interfere with the cellular interaction. bPEI-modified liposomes (PEIPOS) showed enhanced association with three different cell lines by up to 75 times compared to plain or PEGylated liposomes and were without carrier toxicity. They also penetrated the deeper layers of 3D spheroids. Encapsulating paclitaxel (PTX) into PEIPOS did not change its main mechanism of action. PEIPOS complexed and intracellularly delivered siRNAs and downregulated resistance-associated proteins. Finally, tumor growth inhibition was observed in a mouse ovarian xenograft tumor model, without signs of toxicity, in animals treated with the siRNA/PTX co-loaded formulation. These complex-in-nature but simple-in-design novel liposomal formulations constitute viable and promising alternatives with added functionality to their PEGylated counterparts.
Highlights
Over the last four decades (DeVita, 1975; DeVita et al, 1975), it has been established that when cancer treatment strategies are pursued using a single drug, the chemotherapy will eventually fail due to either severe side effects caused by the high doses of the anticancer drug, or more likely, to resistance development (Diaz et al, 2012; Bozic et al, 2013)
Liposomes were incubated in phosphate buffer saline (PBS) with 10% (v/v) of fetal bovine serum (FBS) to various time-points at 37 C to mimic the in vivo salt and serum protein concentrations (Gaspar et al, 2014)
The results show that the profile of proteins adsorbed onto PEGylated liposomes (Figure 1(d), lane 4) is the same as on 0% and 0.5% PEIPOS, but to a lesser extent
Summary
Over the last four decades (DeVita, 1975; DeVita et al, 1975), it has been established that when cancer treatment strategies are pursued using a single drug, the chemotherapy will eventually fail due to either severe side effects caused by the high doses of the anticancer drug, or more likely, to resistance development (Diaz et al, 2012; Bozic et al, 2013). SiRNA delivery into cancer cells either alone or in combination with other drugs is a challenging task which requires overcoming unique barriers including plasma instability, very low cellular internalization and immediate degradation within the endosomal compartments of the cancer cells. Polyethylene glycol (PEG), the gold standard for surface modification of nanoparticles, increases their surface hydrophilicity and creates a shield that repels the opsonizing blood proteins and other components. These ‘stealth’ characteristics increase the residence time of liposomes in the blood circulation (Salmaso & Caliceti 2013). Careful studies have shown that repeated administration of PEG can generate IgM antibodies against it (Ishida et al, 2007) and may lead to rapid elimination of subsequent PEGylated formulations from the circulation, a phenomenon termed ‘accelerated blood clearance (ABC)’ (Abu Lila et al, 2013)
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