Layer-by-Layer Nanoparticles for Systemic Codelivery of an Anticancer Drug and siRNA for Potential Triple-Negative Breast Cancer Treatment

A single nanoparticle platform has been developed through the modular and controlled layer-by-layer process to codeliver siRNA that knocks down a drug-resistance pathway in tumor cells and a chemotherapy drug to challenge a highly aggressive form of triple-negative breast cancer. Layer-by-layer films were formed on nanoparticles by alternately depositing siRNA and poly-l-arginine; a single bilayer on the nanoparticle surface could effectively load up to 3500 siRNA molecules, and the resulting LbL nanoparticles exhibit an extended serum half-life of 28 h. In animal models, one dose via intravenous administration significantly reduced the target gene expression in the tumors by almost 80%. By generating the siRNA-loaded film atop a doxorubicin-loaded liposome, we identified an effective combination therapy with siRNA targeting multidrug resistance protein 1, which significantly enhanced doxorubicin efficacy by 4 fold in vitro and led to up to an 8-fold decrease in tumor volume compared to the control treatments with no observed toxicity. The results indicate that the use of layer-by-layer films to modify a simple liposomal doxorubicin delivery construct with a synergistic siRNA can lead to significant tumor reduction in the cancers that are otherwise nonresponsive to treatment with Doxil or other common chemotherapy drugs. This approach provides a potential strategy to treat aggressive and resistant cancers, and a modular platform for a broad range of controlled multidrug therapies customizable to the cancer type in a singular nanoparticle delivery system.Janssen Pharmaceutical Ltd. (TRANSCEND Grant)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)National Health and Medical Research Council (Australia) (CJ Martin Fellowship)National Science Foundation (U.S.). Graduate Research FellowshipNatural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship

Radial Sizing of Lipid Nanotubes Using Membrane Displacement Analysis

We report a novel method for the measurement of lipid nanotube radii. Membrane translocation is monitored between two nanotube-connected vesicles, during the expansion of a receiving vesicle, by observing a photobleached region of the nanotube. We elucidate nanotube radii, extracted from SPE vesicles, enabling quantification of membrane composition and lamellarity. Variances of nanotube radii were measured, showing a growth of 40-56 nm, upon increasing cholesterol content from 0 to 20%

Sustained release of nucleic acids from polymeric nanoparticles using microemulsion precipitation in supercritical carbon dioxide

A general approach for producing biodegradable nanoparticles for sustained nucleic acid release is presented. The nanoparticles are produced by precipitating a water-in-oil microemulsion in supercritical CO2. The microemulsion consists of a transfer RNA aqueous solution (water phase), dichloromethane containing poly(L-lactic acid)-poly(ethylene glycol) (oil phase), the surfactant n-octyl beta-D-glucopyranoside, and the cosurfactant n-butanol

Mechanical tweezer action by self-tightening knots in surfactant nanotubes

Entanglements and trefoil knots on surfactant nanotubes in the liquid phase were produced by a combination of network self-organization and micromanipulation. The resulting knots are self-tightening, and the tightening is driven by minimization of surface free energy of the surfactant membrane material. The formation of the knot and the steady-state knot at quasi-equilibrium can be directly followed and localized by using fluorescence microscopy. Knots on nanotubes can be used as nanoscale mechanical tweezers for trapping and manipulation of single nano- and micrometer-sized high-aspect ratio objects. Furthermore, we demonstrate that by controlling the surface tension, objects captured by a knot can be transported along given trajectories defined by the nanotube axes