Targeted Sterically Stabilized Phospholipid siRNA Nanomedicine for Hepatic and Renal Fibrosis

Since its discovery, small interfering RNA (siRNA) has been considered a potent tool for modulating gene expression. It has the ability to specifically target proteins via selective degradation of messenger RNA (mRNA) not easily accessed by conventional drugs. Hence, RNA interference (RNAi) therapeutics have great potential in the treatment of many diseases caused by faulty protein expression such as fibrosis and cancer. However, for clinical application siRNA faces a number of obstacles, such as poor in vivo stability, and off-target effects. Here we developed a unique targeted nanomedicine to tackle current siRNA delivery issues by formulating a biocompatible, biodegradable and relatively inexpensive nanocarrier of sterically stabilized phospholipid nanoparticles (SSLNPs). This nanocarrier is capable of incorporating siRNA in its core through self-association with a novel cationic lipid composed of naturally occuring phospholipids and amino acids. This overall assembly protects and delivers sufficient amounts of siRNA to knockdown over-expressed protein in target cells. The siRNA used in this study, targets connective tissue growth factor (CTGF), an important regulator of fibrosis in both hepatic and renal cells. Furthermore, asialoglycoprotein receptors are targeted by attaching the galactosamine ligand to the nanocarries which enhances the uptake of nanoparticles by hepatocytes and renal tubular epithelial cells, the major producers of CTGF in fibrosis. On animals this innovative nanoconstruct, small interfering RNA in sterically stabilized phospholipid nanoparticles (siRNA-SSLNP), showed favorable pharmacokinetic properties and accumulated mostly in hepatic and renal tissues making siRNA-SSLNP a suitable system for targeting liver and kidney fibrotic diseases

Improvement of drug safety by the use of lipid-based nanocarriers

Drug toxicity is an important factor that contributes significantly to adverse drug events in current healthcare practice. Application of lipid-based nanocarriers in drug formulation is one approach to improve drug safety. Lipid-based delivery systems include micelles, liposomes, solid lipid nanoparticles, nanoemulsions and nanosuspensions. These carriers are generally composed of physiological lipids well tolerated by human body. Delivery of water-insoluble drugs in these formulations increases their solubility and stability in aqueous media and eliminates the need for toxic co-solvents or pH adjustment to solubilize hydrophobic drugs. Association or encapsulation of peptides/proteins within lipid-based carriers protects the labile biologics against enzymatic degradation, hence reducing the therapeutic dose required and risk of dose-dependent toxicity. Most importantly, lipid-based nanocarriers alter the pharmacokinetics and biodistribution of drugs through passive and active targeting, leading to increased drug accumulation at target sites while significantly decreasing non-specific distribution to other tissues. Furthermore, surface modification of these nanocarriers reduces immunogenicity of drug-carrier complexes, imparts stealth by preventing opsonization and removal by phagocytes and minimizes interaction with circulating blood components. In view of heightening attention on drug safety in patient treatment, lipid-based nanocarrier is therefore an important and promising option for formulation of pharmaceutical products to improve treatment safety and efficacy

Polymyxin B Self-Associated With Phospholipid Nanomicelles

Context: Although Polymyxin B (PXB) is an effective antibiotic for Gram-negative bacterial infections, clinical use is hampered by toxicity and protein binding, which may be overcome by delivering PXB using a safe nanocarrier. Objective: To determine whether PXB self-associates with long-circulating biocompatible/biodegradable PEGylated phospholipid nanomicelles (SSM) and change in vitro bioactivity. Materials and Methods: PXB and SSM (15 nm) composed of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) were prepared in 10 mM HEPES buffered saline. Interactions between PXB and SSM were determined by dynamic light scattering and fluorescence spectroscopy. Anti-infective effects of PXB-SSM were tested against Pseudomonas aeruginosa strain PA01 in vitro. Results: Approximately four PXB molecules self-associated with each SSM. However, significant decrease in P. aeruginosa killing was observed with PXB-SSM relative to PXB alone (p<0.05). Empty SSM had no significant effect on bacterial growth. Discussion: PXB’s self-association with SSM resulted in mitigation of the in vitro antibacterial activity. This phenomenon could be attributed, in part, to PEG2000 hindering electrostatic interactions between cationic PXB and anionic bacterial cell wall. Conclusion: PXB association with SSM formed a stable nanomedicine, resulting in decreased bioactivity of the drug in vitro. Effectiveness of this nanomedicine in vivo is yet to be studied