April 21-25, 2014 | San Francisco
Meeting Chairs: Jose A. Garrido, Sergei V. Kalinin, Edson R. Leite, David Parrillo, Molly Stevens
Disease diagnosis and treatment benefit greatly from multi-modal approaches. In addition to a range of other benefits, nanoparticles of various compositions can provide these multimodal approaches. For example, nanoparticles can provide treatment through drug delivery along with hyperthermia or photodynamic therapy. Iron oxide nanoparticles (IONPs), which can provide magnetic resonance image contrast and therapeutic heat, are emerging as a key player in this field. Combining these properties with the controlled release of drug further enhances the therapeutic efficacy of the IONP system. However, IONPs on their own are subject to disadvantages such as aggregation and dissolution in biological environments. Additionally, controlled release of drug from IONPs has been limited by low drug loading. In this work, we employ a mesoporous silica coating to confer IONPs with colloidal stability, protection against oxidation and dissolution, and a large pore volume for drug loading, making this platform a valuable tool for multi-modal therapy. In this portion of the study, this platform is used as a controlled-release system whereby IONP-generated heat acts as the controlled release mechanism. Previous work has demonstrated that surface modification with a short polyethylene glycol chain and a hydrophobic chloro-trimethylsilane group allows high loading of a cancer therapeutic, Doxorubicin. Further, the hydrophobic form of this drug can be retained within the particle for over 24 hours without the use of any additional capping agent simply due to hydrophobic-hydrophobic interactions. Herein, we investigate system-wide temperature increases (via IONP-heating or a water bath) as a driver for increased molecular diffusion resulting in drug delivery. The effects of various drug cargoes, pore diameters, heating profiles, and release media will be presented.
Magnetic nanoparticles, (MNP), are the building-blocks for developing innovative nanodevices with multi-fold therapeutic and diagnostic activities, including magnetic fluid hyperthermia, (MFH), contrast agents for Magnetic Resonance Imaging, (CA-MRI), and targeting of tumor cells. Among the different functionalization strategies developed so far, the approaches using protein-cage structures, like those of the ferritin (Ft) family, are particularly promising, since Fts present a number of favorable properties: they have high solubility and stability in water, blood and buffers, low toxicity, and they can be easily functionalized through genetic engineering and/or chemical reactions involving one of the many chemical groups exposed to the exterior (primary amines, carboxylates, thiols). In this contribution we present some examples of the application of a human H chain ferritin, HFt, for the realization of magnetic-based theranostic agents for the treatment of melanoma. We will show how, through the fine tuning of the composition of the ferrite nucleus grown within the proteic shell of HFt, this system can become an efficient heat mediator in the tumor treatment via MFH. Indeed, the main constraint of HFt-based MNPs is that their size cannot exceed the protein shell inner diameter (ca. 8 nm). As far as iron oxide is concerned, this size is large enough for MRI application, but it is too small for MFH, as theoretical and experimental studies demonstrated that the maximum MFH efficiency is reached for magnetite MNP of d=16-18 nm, while very poor effects are expected for d<10 nm.In particular, we will focus on highly monodisperse doped iron oxides NPs mineralized inside a genetically modified variant of HFt, carrying several copies of alfa-melanocyte-stimulating hormone peptide, which has excellent targeting properties towards melanoma cells with high selectivity, and conjugated to polyethylene glycol molecules to increase their in vivo stability.  L. Lartigue et al. J. Am. Chem. Soc. 133, 10459 (2011) L. Vannucci et al., Int. J. of Nanomed. 7 1489 (2012)
Radiotherapy bears the risk of long-term adverse effects as being severe cardiac complications. Strategies to improve radiotherapy therefore aim to increase the impact on the tumor or to decrease the radiation dosage in order to prevent the healthy tissue from damage. We could show that superparamagnetic iron oxide nanoparticles (SPION) may increase the therapeutic efficiency of radiotherapy by catalyzing and, thereupon, enhancing the X-ray induced production of reactive oxygen species (ROS). Two different synthesis routes were followed to prepare citrate-coated SPION that have maghemite and magnetite structures and sizes between 3 and 20 nm. Human breast cancer (MCF-7), mouse human colon cancer cells (Caco-2) and mouse fibroblasts (3T3) cells were incubated with uncoated or citrate-coated SPION and exposed to X-rays at a single dose of 3 Gy or left non-irradiated. The ablation effect of X-ray irradiation for SPION surface structures was verified using XANES spectroscopy. The ROS concentration was measured via the fluorescence intensity of the 2&’,7&’-dichlorofluorescein dye. Obviously, all internalized SPION species resulted into an enhancement of ROS formation and an additional enhancing effect due to X-ray treatment was as well manifest. Citrate-coated SPIONs in X-ray treated cells were observed to provide an enhancement in ROS formation for 240 % when compared with X-ray treated cells without internalized SPION. On the other hand, SPION internalized in non-irradiated cells caused an increase of ROS concentration up to 77 %. This implies that SPIONs do not only enhance the efficiency of X-rays on ROS formation. They also may act via their surfaces as catalyst for the Haber-Weiss cycle and moreover, contribute via releasing iron ions to the generation of ROS through the Haber-Weiss and Fenton reaction. The substantial enhancing effect due to the high-energy X-ray treatment is explained with efficient ablation of the SPION surface chemistry. The freshly formed surfaces consist now of easier accessible iron ions and thus may more effectively catalyze the ROS production than completely coated surface. The catalytic function of SPION surfaces has a promising potential for radiotherapy.
Different techniques can be used to image the biodistribution of a molecular marker in vivo, each with its own advantages and limitations. The combination of complementary modalities has attracted much attention in the past few years. For example, MRI allows in-depth whole body imaging albeit with a low sensitivity. Near infrared fluorescence imaging is more sensitive and provides resolution down to sub-cellular levels but is limit