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Technical Program TRACK 2

data, we found only the targeted tissue which treated with magnetic field soft segment composition can be exploited for the co-encapsulation of mul-
showed detectable lucferase expression. These findings demonstrated tiple chemotherapeutics for more efficient chemotherapy.
our hybrid system can not only be directed to target tissue or organ, but
also be an idea triggerable gene delivery system by external magnetic [1] C. Mattu et al. J. Nanop. Res. 2012; 14:1306.
field in vivo. [2] C. Mattu et al. Eur. J. Pharm. Biopharm. 2013, 85(3); 463.

Overall, our hybrid system provides a promising way that could be adapted
for targeted delivering gene in vivo.
WEDNESDAY, FEBRUARY, 24
5:10pm Hybrid Polyurethane/Phospholipid Nanoformulations
for Anticancer Drug Delivery
2-6
Technical Presentation. NEMB2016-5991 TEMPERATURE-SENSITIVE NANOMEDICINE

Clara Mattu, Gianluca Ciardelli, Politecnico di Torino, Torino, Italy Sam Houston 9:30am - 11:00am

In this contribution application of polyurethane block copolymers with mod- Session Organizer: Zhenpeng Qin, University of Texas at Dallas,
ulated hydrophilic/hydrophobic balance for the preparation of drug-loaded Richardson, TX, United States
nanoparticles is described.
Polyurethanes are a versatile group of biocompatible polymers that can be 9:30am Antibody-Coated Nanoshells for Targeted Photother-
obtained with a wide range of different properties, based on the selection of mal Therapy and Signal Cascade Interference of Triple-Negative
their building blocks [1]. Breast Cancer

In this work, the polyurethane soft segment composition has been modulat- Keynote. NEMB2016-5927
ed by varying the ratio between the hydrophobic poly(ε-caprolactone)-diol
and the hydrophilic poly(ethylene glycol), (0, 20 and 30% PEG), so as to
obtain polymers containing both hydrophilic and lipophilic domains to host Rachel Edelstein, John Gagianas, Emily Day, University of Dela-
both, water-soluble and insoluble drugs. In previous works we have shown ware, Newark, DE, United States
that polyurethane nanoparticles are able to circulate can still be detected
in blood stream 3 hours post-injection and that the modulation of the soft Introduction: Triple Negative Breast Cancer (TNBC) is an aggressive disease
segment composition influences the hydrophilic/hydrophobic balance, the with higher mortality rates and lower progression-free survival rates than
cellular internalization and the drug-loading capacity of the nanoparticles [2]. other breast cancer subtypes. TNBC is difficult to treat because it does not
Using the nanoprecipitation method followed by self-assembly of phospho- express the necessary receptors to be susceptible to standard targeted
lipids on the particles surface, phospholipid/PUR hybrid nanoparticles (size or hormonal therapies. Recent studies demonstrate that hyperactive Wnt
< 200 nm), composed by a PUR core of varying hydrophilic/hydrophobic signaling drives TNBC. Therefore, we created a novel nanoparticle platform
balance and a surface corona of phospholipids. that can neutralize Wnt signaling in TNBC cells via signal cascade interfer-
ence and also provide targeted cell ablation via photothermal therapy. Here,
The effect of the core composition on nanoparticles mean size and size we describe our in vitro success using these nanoparticles to attack TNBC.
distribution has been investigates. Regardless of the polymer composition
small size carriers (80 - 100 nm mean size) have been obtained. At higher Our therapy consists of FZD7-NS, which are silica core/gold shell nanoshells
PEG content (30%) a significant decrease in particle’s mean size and in- (NS) coated with antibodies against Frizzled7 (FZD7), a receptor that plays
crease in PDI was observed. a critical role in regulating Wnt signaling in TNBC. Briefly, the key mediator
of Wnt signaling is beta-catenin. In the absence of wnt ligands, beta-catenin
Confocal analysis shows internalization of nanoparticles by glioblastoma is constitutively degraded. When wnt ligands bind FZD7 receptors that are
cancer cell line (U-87) and their localization in the cells cytoplasm. overexpressed on TNBC cells, beta-catenin is stabilized and enters the
The PUR matrix, composed of randomly-distributed hydrophilic and hy- nucleus where it activates transcription of several genes. These genes pro-
drophobic domains (as confirmed by TEM images) has been exploited to mote cell proliferation, survival, and migration, resulting in treatment resis-
successfully co-encapsulate hydrophilic and hydrophobic anti-neoplastic tance, metastasis, and a poor clinical prognosis. Since FZD7 is amplified in
drugs (Doxorubicin and Docetaxel). For both drugs, high loading efficiency 67% of TNBC, it provides an excellent biomarker for targeted therapy. Here,
and sustained release profiles has been obtained and a concentration and we demonstrate that FZD7-NS can bind TNBC cells to block wnt ligands
time-dependent in vitro cytoxic profile has been determined (using U-87 from binding FZD7, thereby reinstating beta-catenin degradation. This signal
cancer cells). cascade interference results in decreased rates of cell migration and prolif-
eration. In addition, we demonstrate that FZD7-NS can selectively destroy
As expected, the encapsulation efficiency of the hydrophobic drug DCTXL TNBC cells by producing heat upon exposure to near infrared light. These
is strongly dependent on the polymer composition. More hydrophobic poly- data support continued development of FZD7-NS as a multifunctional thera-
mer (with less PEG content) shows higher affinity with the drug and, thus, py for treatment of TNBC and other cancers with hyperactive Wnt signaling.
higher entrapment efficiency (of about 80 %). Moreover entrapment efficien-
cy appears to be independent from the initial drug input provided (20, 50 Methods: NS were coated with FZD7 antibodies using OPSS-PEG-NHS
and 100 µg). Drug release profile (Fig. 1C) also showed a dependence from linkers. Empty spaces on NS were filled with mPEG-SH. An ELISA quantified
the polymer composition with fastest release from hydrophilic carriers. antibodies bound. Control NS were coated with only mPEG-SH. We studied
treatment effects using MDA-MB-231 TNBC cells that overexpress FZD7 and
As for the hydrophilic drug Doxorubicin, loading efficacy was quite high for non-cancerous MCF10A breast cells with low FZD7 expression. Immuno-
all polymers ( at about 50 %) and release faster, regardless of the soft seg- histochemistry confirmed FZD7 expression in these cells. For all treatment
ment’s composition. Both drugs have been loaded in the PUR core without studies, cells were exposed to FZD7-NS or PEG-NS for 4 hours then rinsed
affecting the nanoparticles size. Drug release profiles and in vitro cytotoxici- to remove unbound particles. NS binding to cells was visualized with multi-
ty tests with combined therapy are in progress. photon microscopy. To assess photothermal therapy, samples were irradiat-
28 ed with 808nm light (80 W/cm2, 4 minutes) then cell viability was evaluated
This contribution shows that polyurethanes are suitable candidates for the with calcein AM and ethidium homodimer-1 staining. To assess the impact
preparation of drug-loaded nanoparticles and that the modulation of their of treatment on Wnt signaling, we used immunofluorescence and Western