Remote Actuation of Magnetic Nanoparticles For Cancer Cell Selective Treatment Through Cytoskeletal Disruption

Motion of micron and sub-micron size magnetic particles in alternating magnetic fields can activate mechanosensitive cellular functions or physically destruct cancer cells. However, such effects are usually observed with relatively large magnetic particles (>250 nm) that would be difficult if at all possible to deliver to remote sites in the body to treat disease. Here we show a completely new mechanism of selective toxicity of superparamagnetic nanoparticles (SMNP) of 7 to 8 nm in diameter to cancer cells. These particles are coated by block copolymers, which facilitates their entry into the cells and clustering in the lysosomes, where they are then magneto-mechanically actuated by remotely applied alternating current (AC) magnetic fields of very low frequency (50 Hz). Such fields and treatments are safe for surrounding tissues but produce cytoskeletal disruption and subsequent death of cancer cells while leaving healthy cells intact

Multivalent Gd-DOTA Decorated Oligopeptide as Sensitive MRI Molecular Probes for <i>In Vivo</i> Imaging of Brain Connectivity

One of the most important goals of brain imaging is to define the anatomical connections within the brain. In addition to revealing normal circuitry, studies of neural connections and neuronal transport can show rewiring and degeneration following brain injury and diseases. In this work, a highly sensitive magnetic resonance imaging (MRI)-visible neural tracer that can be used to visualize brain connectivity in vivo is developed. It is based on an oligopeptide with gadolinium chelates appended to the peptide backbone. This peptide construct is a sensitive MRI contrast agent that was conjugated to the classical neurotracer, Cholera-toxin Subunit-B. Injection of this probe enabled it to be used to trace neural connections in vivo. This complements other MRI tracing techniques such as diffusion tensor imaging and manganese-enhanced MRI for neural tracing

Nanomedicine for intracellular therapy

Intracellular pathogens like Salmonella evade host phagocytic killing by various mechanisms. Classical antimicrobial therapy requires multiple dosages and frequent administration of drugs for a long duration. Intracellular delivery of antimicrobials using nanoparticle may effectively devise therapies for bacterial infections. This review will address the mechanisms used by Salmonella to avoid host pathogenic killing, reasons for therapeutic failure and advances in nanoparticle drug delivery technology for efficient intracellular bacterial clearance

Antibacterial efficacy of core-shell nanostructures encapsulating gentamicin against an in vivo intracellular Salmonella model

Pluronic based core-shell nanostructures encapsulating gentamicin were designed in this study. Block copolymers of (PAA −+ Na- b -(PEO- b -PPO- b -PEO)-b-PAA −+ Na) were blended with PAA − Na + and complexed with the polycationic antibiotic gentamicin to form nanostructures. Synthesized nanostructures had a hydrodynamic diameter of 210 nm, zeta potentials of −0.7 (±0.2), and incorporated ∼20% by weight of gentamicin. Nanostructures upon co-incubation with J774A.1 macrophage cells showed no adverse toxicity in vitro . Nanostructures administered in vivo either at multiple dosage of 5 μg g −1 or single dosage of 15 μg g −1 in AJ-646 mice infected with Salmonella resulted in significant reduction of viable bacteria in the liver and spleen. Histopathological evaluation for concentration-dependent toxicity at a dosage of 15 μg g −1 revealed mineralized deposits in 50% kidney tissues of free gentamicin-treated mice which in contrast was absent in nanostructure-treated mice. Thus, encapsulation of gentamicin in nanostructures may reduce toxicity and improve in vivo bacterial clearance

Magnetic Block Ionomer Complexes for Potential Dual Imaging and Therapeutic Agents

Magnetic block ionomer complexes (MBICs) containing a combination of therapeutic and imaging agents are of great interest for delivering drugs and tracking their biodistribution with magnetic resonance imaging. With an aim to develop nanocarriers with high drug loadings that integrate magnetic nanoparticles into one system, we herein report antibiotic-laden MBICs based on assembly of poly­(ethylene oxide-<i>b</i>-acrylate) (PEO-<i>b</i>-PAA) ionomers with nanomagnetite and gentamicin. The polymer was bound to the magnetic nanoparticle surfaces via ligand adsorption of the PAA block, thereby creating a double corona structure with a nonionic PEO shell and an ionic region rich in PAA. The portion of carboxylates that were not bound to the magnetite provided binding sites for drug loading via ionic complexation. PEO was chosen as a block copolymer segment to improve biocompatibility and aid in dispersion through interparticle steric repulsion. Intensity average diameters increased from 34 to 62 nm upon adding the drug, suggesting that the particles formed small clusters. Zeta potentials decreased from approximately −40 without gentamicin to approximately −10 mV with the drug, indicating that the drug effectively localized the charges in the MBIC cores. Approximately 35 wt % of the encapsulated gentamicin was released under physiological conditions within 10 h, and this was followed by slower release of another 7% by 18 h. The solid magnetite core serves as a multifunctional substrate for block ionomers to stably adsorb, thus acting as a pseudo-crosslinking site in the complexes that enhances their stability. Complexes between PEO-<i>b</i>-PAA and gentamicin without magnetite instantaneously dissociate in saline buffer. When the same copolymer was adsorbed onto magnetite, subsequent complexation with gentamicin resulted in stable complexes that withstood media with physiological ionic strength