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TRACK 2 TRACK 2 Technical Program

blotting to measure beta-catenin expression. Finally, scratch assays and EdU 10:20am Sustained Delivery of GC-1 from a Nanochannel De-
incorporation assays were performed to elucidate the functional impact of vice for Metabolic Syndrome
FZD7-NS and PEG-NS on cell migration and proliferation.
Technical Presentation. NEMB2016-5962
Results: The ELISA revealed ~100 antibodies bound per FZD7-NS. Immu-
nohistochemistry confirmed that MDA-MB-231, but not MCF10A, express
FZD7. Accordingly, FZD7-NS bound MDA-MB-231 but not MCF10A cells, and Carly Filgueira, Eugenia Nicolov, R. Lyle Hood, Houston Meth-
PEG-NS did not bind either cell type. The level of FZD7-NS binding to MDA- odist Research Institute, Houston, TX, United States, Jenaro Gar-
MB-231 cells was sufficient to enable selective photothermal therapy. In ad- cia-Huidobro, University of Miami, Miami, FL, United States, Jean
dition, immunofluorescence and Western blotting confirmed that beta-caten- Z. Lin, Boston University School of Medicine, Boston, MA, United
in expression decreased in MDA-MB-231 cells exposed to FZD7-NS relative States, Daniel Fraga, Omaima M. Sabek, A. O. Gaber, Houston
to controls. This resulted in reduced rates of cell migration and proliferation, Methodist Research Institute, Houston, TX, United States, Kevin J.
validating Wnt inhibition as a viable strategy to treat TNBC.
Phillips, Baylor College of Medicine, Houston, TX, United States,
Conclusions: Our results confirm that FZD7-NS can bind TNBC cells to en- Alessandro Grattoni, Houston Methodist Research Institute, Hous-
able selective photothermal therapy and inhibition of Wnt signaling, resulting ton, TX, United States
in decreased cell proliferation and migration. These findings support con-
tinued development of FZD7-NS as a multifunctional therapy for treatment Rising at alarming rates, obesity affects over 500 million adults and 42
of TNBC and other cancers with hyperactive Wnt signaling. In addition, they million children worldwide. In mammals, white adipose tissue (WAT) stores
suggest that nanoparticles coated with other antibodies may be useful as excess energy as lipid in fat, while brown adipose tissue (BAT) can uniquely
tools to elicit signal cascade interference against a variety of disease-pro- perform adaptive thermogenesis to maintain body temperature. Nuclear
moting pathways. receptors (NRs) play central roles in metabolic syndrome, making them
attractive drug targets. Specifically, thyroid hormone receptors (TRs) are
10:00am Thermal transport in porous biological tissue due to ligand activated NRs that regulate genes involved in lipid metabolism and
gold/magnetic nanoparticle heating homeostasis. Thyroid hormone receptor beta (TRβ) agonists stimulate BAT,
releasing energy in the form of heat by uncoupling the respiratory chain
Technical Presentation. NEMB2016-6118 through uncoupling protein 1 (UCP1). Deleterious effects of excess agonists
signal a need for therapies where beneficial influences on weight loss and
Daipayan Sarkar, Abdolhosse Haji-Sheikh, Ankur Jain, The Uni- insulin sensitivity are enhanced with minimal side effects. Existing tech-
versity of Texas at Arlington, Arlington, TX, United States nologies to deliver therapies cannot sustain constant release and require
frequent dosing adjustments. Nanotechnology based strategies offer novel
Recent studies in hyperthermia have demonstrated the importance of lo- delivery mediums to overcome these limitations. The nanochannel delivery
calized heating of tissue by gold or magnetic nanoparticles. In order to un- system (nDS) utilizes customizable nanochannels for constant, sustained
derstand the physical phenomenon of thermal transport in biological tissue, release of molecules without actuation or moving components, has demon-
the most common transport equation to estimate temperature distribution strated scalability to 12 months in vivo for various drugs, and is industrially
was developed by Pennes and is popularly known as the Pennes bioheat fabricated in FDA compliance. We validate the use of the nDS capable of
transfer equation. A generalized Pennes bioheat transfer equation accounts releasing the TRβ-selective agonist GC-1 (sobetirome). GC-1 is of particular
for the effect of various physical phenomena such as conduction, advection, interest as it has the potential to be used as a therapeutic agent for a variety
volumetric heat generation due to metabolism and spatial heating. In the of disorders, such as obesity, hyperlipidaemia, and hypercholesterolaemia.
scenario of a thermal therapy based on nanoparticle heating, the transport GC-1 as a weight loss inducing drug has recently garnered significant media
and localized heating of tissue becomes a challenging problem and re- attention. Two separate Phase 1 studies have shown that when compared to
quires optimization. Gold or magnetic nanoparticles are introduced in the a placebo, GC-1 elicited reduced levels of low-density lipoprotein (LDL) in a
blood vessel and are attracted towards the malignant tissue as the surfaces healthy volunteer population not enriched for elevated LDL levels and that
of these nanoparticles are coated with ligands. Then, a laser beam or an the drug was generally well tolerated. It is a subtype-selective TR agonist
alternating magnetic field is applied externally to the targeted region. In the that selectively binds to and activates TRbeta over TRalpha and also offers
presence of an external field these nanoparticles produce thermal energy tissue selective thyromimetic properties.
and heat the malignant tissue locally. The size, density of the nanoparticles
and the intensity of the external field are some crucial parameters in de- In our work, diet induced obese (DIO) C57BL/J6 male mice aged 18 weeks
termining the specific absorption rate (SAR) for efficient design of thermal were fed a high-fat diet to induce obesity and implanted with capsules load-
based therapy for cancer. In this theoretical work, a dual phase lag model ed with either GC-1 or PBS as a control. Overall, we observed significant re-
for the Pennes bioheat transfer is considered to govern thermal transport in ductions in body weight and fat mass for nDS-GC-1 treated mice compared
porous biological tissue. to control nDS-PBS and genes involved in adaptive thermogenesis were
generally increased in the WAT of nDS-GC-1 treated mice. Decreases in both
The model considered in this work accounts for the phase lag times, which cholesterol and glucose further demonstrate the cholesterol-lowering and
are expressed in terms of the properties of blood and tissue and the in- anti-diabetic actions of nDS-released GC-1. Our drug/device combination
terphase convective heat transfer coefficient and blood perfusion rate. A offers a new product and is not restricted to TR agonists alone, but applica-
detailed mathematical analysis for temperature distribution in a tissue is ble for nuclear receptor agonists, antagonists, as well as partial and inverse
presented which uses the method of separation of variables. The tissue agonists, and selective nuclear receptor modulators. Most reported studies
external surface is exposed to flux intensities that are considered uniform with TRβ-selective agonists so far involve either oral gavage, i.p. administra-
and varying with time as two test cases. Results from the analytical model tion, or s.c. injection. The present studies show administration from a novel
are compared with a Galerkin based integral solution and are found to be drug delivery system, the nDS, consisting of an implantable nanofluidic
in good agreement. Based on the different combinations of heat generat- membrane capable of tunable long-term zero-order release of therapeutic
ing rates and applied external field, a correlation between SAR and rate of agents in ranges relevant for clinical applications. Release of agonists from
temperature rise in tissue is determined. Results from this work may help the nDS allows for sustained, long-term constant release and a personalized
in proper optimization of therapeutic treatments involving gold/magnetic molecular drug-delivery system. Our preliminary data from this short term
nanoparticle heating. In addition, a separate example scenario is considered dosing study suggest that TR agonism by nDS-released GC-1 elicits striking
where the tumor region is modeled as an inclusion in the dense tissue ma- anti-obesogenic and anti-diabetic effects. GC-1’s ability to decrease fat mass
trix, where the thermophysical properties of the tumor are different to the while sparing lean mass, coupled with its sustained release from the nDS,
surrounding tissue. For this case, a semi-analytical Galerkin based integral illustrate the potential of this system to treat obesity and metabolic syn- 29
solution is presented that closely predicts the temperature solution in the drome. These results have implications for understanding the etiology and
tissue. treatment of diabetes and metabolic disease. We believe there is strong po-