Showing papers by "Nathan C. Gianneschi published in 2013"

Enzyme-directed assembly of nanoparticles in tumors monitored by in vivo whole animal imaging and ex vivo super-resolution fluorescence imaging.

Abstract: Matrix metalloproteinase enzymes, overexpressed in HT-1080 human fibrocarcinoma tumors, were used to guide the accumulation and retention of an enzyme-responsive nanoparticle in a xenograft mouse model. The nanoparticles were prepared as micelles from amphiphilic block copolymers bearing a simple hydrophobic block, and a hydrophilic peptide brush. The polymers were end-labeled with Alexa Fluor 647 dyes leading to the formation of labeled micelles upon dialysis of the polymers from DMSO to aqueous buffer. This dye-labeling strategy allowed the presence of the retained material to be visualized via whole animal imaging in vivo, and in ex vivo organ analysis following intratumoral injection into HT-1080 xenograft tumors. We propose that the material is retained by virtue of an enzyme-induced accumulation process whereby particles change morphology from 20 nm spherical micelles to micron-scale aggregates, kinetically trapping them within the tumor. This hypothesis is tested here via an unprecedented super resolution fluorescence analysis of ex vivo tissue slices confirming a particle size increase occurs concomitantly with extended retention of responsive particles compared to unresponsive controls.

Nuclease-resistant DNA via high-density packing in polymeric micellar nanoparticle coronas.

Abstract: Herein, we describe a polymeric micellar nanoparticle capable of rendering nucleic acids resistant to nuclease digestion. This approach relies on utilizing DNA as the polar headgroup of a DNA-polymer amphiphile in order to assemble well-defined, discrete nanoparticles. Dense packing of DNA in the micelle corona allows for hybridization of complementary oligonucleotides while prohibiting enzymatic degradation. We demonstrate the preparation, purification, and characterization of the nanoparticles, then describe their resistance to treatment with endo- and exonucleases including snake-venom phosphodiesterase (SVP), a common, general DNA digestion enzyme.

Enzyme-directed assembly of a nanoparticle probe in tumor tissue.

Abstract: The goal of targeted therapeutics and molecular diagnostics is to accumulate drugs or probes at the site of disease in higher quantities relative to other locations in the body. To achieve this, there is tremendous interest in the development of nanomaterials capable of acting as carriers or reservoirs of therapeutics and diagnostics in vivo.[1] Generally, nanoscale particles are favored for this task[2] as they can be large enough to function as carriers of multiple copies of a given small mole cule, can display multiple targeting functionalities, and can be small enough to be safely injected into the blood stream.[3] The general goal is that particles will either target passively via the enhanced permeability and retention (EPR) effect, actively by incorporation of targeting groups, or by a combination of both.[3b,4] Nanoparticle targeting strategies have largely relied on the use of surface conjugated ligands designed to bind overexpressed cell-membrane receptors associated with a given cell-type.[5] We envisioned an alternative targeting strategy that would lead to an active accumulation of nanoparticles by virtue of a supramolecular assembly event specific to tumor tissue, occurring in response to a specific signal (Figure 1). The most desirable approach to stimuli-induced targeting would be to utilize an endogenous signal, specific to the diseased tissue itself, capable of actively targeting materials introduced via intravenous (IV) injection. Such an approach is in contrast to efforts to develop systems capable of targeting and release via the local application of external stimuli such as light[6] or magnetic fields.[7] With respect to viable endogenous signals, one could reasonably consider materials that accumulate in response to stimuli including pH changes,[8] temperature variation,[9] or redox reactions. [10] However, we aim to develop nanoparticles capable of assembling in vivo in response to selective, endogenous, biomolecular signals.[11] For this purpose, we aim to utilize enzymes as stimuli, rather than other recognition events, because they are uniquely capable of propagating a signal via catalytic amplification in vivo as in enzyme-prodrug therapy strategies.[12]

Enhanced magnetic resonance contrast of iron oxide nanoparticles embedded in a porous silicon nanoparticle host

Abstract: In this report, we prepared a porous Si nanoparticle with a pore morphology that facilitates the proximal loading and alignment of magnetite nanoparticles. We characterized the composite materials using superconducting quantum interference device magnetometry, dynamic light scattering, transmission electron microscopy, and MRI. The in vitro cytotoxicity of the composite materials was tested using cell viability assays on human liver cancer cells and rat hepatocytes. An in vivo analysis using a hepatocellular carcinoma (HCC) Sprague Dawley rat model was used to determine the biodistribution properties of the material, while naive Sprague Dawley rats were used to determine the pharmocokinetic properties of the nanomaterials. The composite material reported here demonstrates an injectable nanomaterial that exploits the dipolar coupling of superparamagnetic nanoparticles trapped within a secondary inorganic matrix to yield significantly enhanced MRI contrast. This preparation successfully avoids agglomeration issues that plague larger ferromagnetic systems. A Fe 3 O 4 :pSi composite formulation consisting of 25% by mass Fe 3 O 4 yields an maximal T2* value of 556 mM Fe −1 s −1 . No cellular (HepG2 or rat hepatocyte cells) or in vivo (rat) toxicity was observed with the formulation, which degrades and is eliminated after 4–8 h in vivo. The ability to tailor the magnetic properties of such materials may be useful for in vivo imaging, magnetic hyperthermia, or drug-delivery applications.

Themed issue on nanoparticles in biology

Abstract: Dan Peer Laboratory of NanoMedicine, Dept. of Ce and Immunology, George S. Wise Facu Sciences, Dept. of Materials Science and E Faculty of Engineering and the Center for N and Nanotechnology, Tel Aviv University 69978, Israel. E-mail: Peer@tauex.tau.ac.il Department of Chemistry & Biochemistry, U California, San Diego, La Jolla, CA, 92093, U ngianneschi@ucsd.edu Dept. of Biological and Environmental E Cornell University, 226 Riley-Robb Hall, 14853, USA. E-mail: dl79@cornell.edu Cite this: DOI: 10.1039/c3tb90114a