Page 72 - ASME_NEMB_2016_Program

Technical Program TRACK 6

phatic vessels lining the dural sinuses were identified as an important step in yl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe) and a NIR fluorescent
the drainage of the interstitial fluid into cerebrospinal fluid and the periphery. polymer poly[(9,9-dihexylfluorene)-co-2,1,3-benzothiadiazole-co-4,7-di(thio-
The brain ISF flow in the deep nuclei of the brain is also recently studied by phen-2-yl)-2,1,3-benzothiadiazole] (PFBTDBT10). The therapeutic formulation
using a tracer-based MRI, and a non-uniform flow was demonstrated with was optimized to achieve the highest thermal and fluorescence quantum
different distribution and flow speeds in different regions. More interestingly, efficiency. The PolyDOTS are spherical with hydrodynamic diameter of 120
the transportation of the brain ISF in the thalamus could not reach the ISS nm and zeta potential of -16.8 mV. The NP showed excellent colloidal stabil-
in the Caudate nucleus (Cn), and vice versa, although these two regions ity in acidic (pH 4), basic (pH 10), high salt buffer (10X PBS) as well as serum
located so close to each other. The result indicates that the brain ISS is not (10% FBS) conditions for over a month. The in vitro efficacy of photothermal
a highly connected system as speculated before, and there seems to exist ablation (PTA) therapy with the PolyDOTS was evaluated in non-tumorigenic
transportation barrier to the brain ISF flow in the ISS. The separated regions mouse epithelial cells (Balb/C.CL7) as well as two types of mouse breast
were characterized with different diffusion parameters, different distribution cancer cell lines, 4T1 and E0771 using various laser parameters and NP con-
and clearance process of the traced brain ISF. We also demonstrated that centrations. An in vivo model utilized luciferase transfected murine breast
the flow of ISF slowed significantly following neuronal activity in the thala- cancer cells (4T1) injected into the mammary fat pad of Balb/C mice. A 100
mus. This reduction in ISF flow continued for hours and was not accompa- µL NP solution at 0.1mg/mL concentration in PBS was injected into the tail-
nied by slow diffusion into the ISS. The tracer-based MR imaging is a novel vein. The fluorescence imaging was conducted at 0, 6, and 24 h to deter-
method developed by our group, which is the only measurement technique mine optimum time for NP accumulation in a tumor. The tumors were then
providing a three-dimensional visualization of the dynamic drainage flow of treated with NIR laser (K-laser 800 nm, 2W/2min) 24 h after NP injection and
the brain ISF on a whole-brain scale. Gadolinium-diethylene triamine penta- a response to PTA was monitored by measuring tumor size twice a week
cetic acid (Gd-DTPA) is used to label the water in the brain ISS and trace the over forty days. In addition to NP + laser treatment group, NP + no laser, PBS
flow of the brain ISF [1]. The water-soluble chelate Gd-DTPA is a stable extra- + laser and PBS + no laser served as control groups. Our results indicated
cellular MR imaging contrast agent. After being introduced into the brain ISS, significant decrease in tumor size as well as significant increase in overall
Gd-DTPA can shorten the spin-lattice relaxation time of hydrogen nuclei in survival in NP + laser group compared to control groups. Due to preferential
water molecules within a distance range of 2.41-2.5 angstroms. These affect- tumor accumulation, PolyDOTS can be of great use to highlight solid tumors,
ed water molecules show a high signal on a T1-weighted MR image (T1WI), tumor margins and micro-metastasis during surgery.
and the flow process of the traced brain ISF can be dynamically imaged us-
ing a series of MR scans [2]. To calculate the biophysical parameters of the
brain ISS, the sequential MR images at various time points are co-registered Towards the generation of functionalized iron nanowires to tar-
and the images before injection subtracted. The net signal enhancement get leukemic cells
can be converted to the tracer’s concentration using a pre-calibrated fitting
curve. According to the classical diffusion equation, the diffusion coefficient Poster Presentation. NEMB2016-5980
D and clearance coefficient k of the brain ISS can be calculated from the
concentration-time profile. Moreover, the flow properties of the traced brain
ISF can be quantitatively measured and depicted as Vdmax, time toVdmax, Nouf Alsharif, Jurgen kosel, Timothy Ravasi, Jasmeen Merz-
and half-life (t½,). aban, Samah Z. Gadhoum, Jose Perez, Aldo I. Martinez Ban-
deras, King Abdullah University of Science and Technology, Thuwal
1. Shi C, Lei Y, Han H et al. Transportation in the Interstitial Space of the Jeddah, Jeddah,Saudi Arabia
Brain Can Be Regulated by Neuronal Excitation. Sci Rep. 5:17673 (2015).
doi:10.1038/srep17673. In recent years, magnetic nanowires (NWs) have been widely used for
their therapeutic potential in biomedical applications. The use of iron NWs
2. Han H, Shi C, Fu Y etal. A novel MRI tracer-based method for measuring combines two important properties, biocompatibility and an anisotropy that
water diffusion in the extracellular space of the rat brain. IEEE J Biomed allows remote manipulation by magnetic fields. In addition the NWs can be
Health Inform. 18(3):978-83 (2014). doi: 10.1109/JBHI.2014.2308279. coated and functionalized to target cells of interest and, upon exposure
to an alternating magnetic field, have been shown to induce cell death on
several types of adherent cells, including several cancer cell types. For sus-
6-2 pension cells, however, using these NWs has been much less effective pri-
NANOPARTICLE-BASED DELIVERY marily due to the free-floating nature of the cells minimizing the interaction
between them and the NWs.
Leukemic cells express higher levels of the cell surface marker CD44, com-
Grand Ballroom 5:00pm - 8:00pm pared to normal blood cells. The goal of this study was therefore to function-
alize iron NWs with a specific monoclonal antibody towards CD44 in order
Theranostic Nanoparticles for Photothermal Ablation Therapy to target leukemic cells (HL-60 cells). This approach is expected to increase
and Fluorescence Imaging of Murine Breast Cancer the probability of a specific binding to occur between HL-60 cells and iron
NWs.
Poster Presentation. NEMB2016-5953
Iron NWs were fabricated with an average diameter of 50 nm and a length
Sneha Kelkar, Wake Forest School of Medicine, Winston-Salem, around 3-4 µm. Then, they were coated with bovine serum albumin (BSA)
in order to conjugate them with an anti-CD44 antibody (i.e. anti-CD44-iron
NC, United States, Elizabeth G. Gurysh, University of North Car- NWs). This antibody covalently reacts with the amine group in the BSA via
olina, Chapel Hill, NC, United States, Eleanor E. McCabe, Nicole the 1-Ethyl-3-3-dimethylaminopropyl-carbodiimide (EDC) and N-Hydroxysuc-
Levi-Polyachenko, Wake Forest School of Medicine, Winston-Sa- cinimide (NHS) coupling. The NWs functionalization was confirmed using
lem, NC, United States a number of approaches including: infrared spectroscopy, Nanodrop to
measure the concentration of CD44 antibody, as well as fluorescent-labeled
Theranostic materials that can simultaneously detect and treat diseases hold secondary antibody staining to detect the primary CD44 antibody. To deter-
great promise for treatment of debilitating diseases like cancer. The small mine that the antigenicity of the CD44 antibody was maintained following
size of nanoparticles (NP) allows for preferential accumulation in tumors due its functionalization to the NWs, a series of CD44 immunoprecipitation and
to enhanced permeability and retention effect. Our group has developed western blot studies were performed. To confirm that the anti-CD44-iron
polymer dynamic organic theranostic spheres (PolyDOTS) which are near-in- NWs and bare iron NWs, in the absence of a magnetic field, were not toxic
72 frared (NIR) fluorescent and generate hyperthermia upon 800 nm laser irra- to HL-60 cells, cytotoxicity assays using XTT (2,3-Bis-2-Methoxy-4-Nitro-5-
diation. The formulation comprises of a NIR heat generating, semiconducting Sulfophenyl-2H-Tetrazolium-5-Carboxanilide) were performed and resulted
polymer poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b’]dithiophene-2,6-di- in a high level of biocompatibility.