Inhibiting HER3 Hyperphosphorylation in HER2-Overexpressing Breast Cancer through Multimodal Therapy with Branched Gold Nanoshells.

Treatment failure in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2) is associated mainly to the upregulation of human epidermal growth factor receptor 3 (HER3) oncoprotein linked to chemoresitence. Therefore, to increase patient survival, here a multimodal theranostic nanoplatform targeting both HER2 and HER3 is developed. This consists of doxorubicin-loaded branched gold nanoshells functionalized with the near-infrared (NIR) fluorescent dye indocyanine green, a small interfering RNA (siRNA) against HER3, and the HER2-specific antibody Transtuzumab, able to provide a combined therapeutic outcome (chemo- and photothermal activities, RNA silencing, and immune response). In vitro assays in HER2+ /HER3+ SKBR-3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p-AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p-AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor-bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarrier.

Combined Therapeutics for Atherosclerosis Treatment Using Polymeric Nanovectors.

Atherosclerosis is an underlying risk factor in cardiovascular diseases (CVDs). The combination of drugs with microRNAs (miRNA) inside a single nanocarrier has emerged as a promising anti-atherosclerosis strategy to achieve the exploitation of their complementary mechanisms of action to achieve synergistic therapeutic effects while avoiding some of the drawbacks associated with current systemic statin therapies. We report the development of nanometer-sized polymeric PLGA nanoparticles (NPs) capable of simultaneously encapsulating and delivering miRNA-124a and the statin atorvastatin (ATOR). The polymeric NPs were functionalized with an antibody able to bind to the vascular adhesion molecule-1 (VCAM1) overexpressed in the inflamed arterial endothelium. The dual-loaded NPs were non-toxic to cells in a large range of concentrations, successfully attached overexpressed VCAM receptors and released the cargoes in a sustainable manner inside cells. The combination of both ATOR and miRNA drastically reduced the levels of proinflammatory cytokines such as IL-6 and TNF-α and of reactive oxygen species (ROS) in LPS-activated macrophages and vessel endothelial cells. In addition, dual-loaded NPs precluded the accumulation of low-density lipoproteins (LdL) inside macrophages as well as morphology changes to a greater extent than in single-loaded NPs. The reported findings validate the present NPs as suitable delivery vectors capable of simultaneously targeting inflamed cells in atherosclerosis and providing an efficient approach to combination nanomedicines.

Cubic Anisotropic Co- and Zn-Substituted Ferrite Nanoparticles as Multimodal Magnetic Agents.

The use of magnetic nanoparticles as theranostic agents for the detection and treatment of cancer diseases has been extensively analyzed in the last few years. In this work, cubic-shaped cobalt and zinc-doped iron oxide nanoparticles with edge lengths in the range from 28 to 94 nm are proposed as negative contrast agents for magnetic resonance imaging and to generate localized heat by magnetic hyperthermia, obtaining high values of transverse relaxation coefficients and specific adsorption rates. The applied magnetic fields presented suitable characteristics for the potential validation of the results into the clinical practice in all cases. Pure iron oxide and cobalt- and zinc-substituted ferrites have been structurally and magnetically characterized, observing magnetite as the predominant phase and weak ferrimagnetic behavior at room temperature, with saturation values even larger than those of bulk magnetite. The coercive force increased due to the incorporation of cobalt ions, while zinc substitution promotes a significant increase in saturation magnetization. After their transfer to aqueous solution, those particles showing the best properties were chosen for evaluation in in vitro cell models, exhibiting high critical cytotoxic concentrations and high internalization degrees in several cell lines. The magnetic behavior of the nanocubes after their successful cell internalization was analyzed, detecting negligible variations on their magnetic hysteresis loops and a significant decrease in the specific adsorption rate values.