Page 70 - ASME_NEMB_2016_Program

Technical Program TRACK 6

TRACK 6 POSTERS Results: TEM confirmed successful synthesis of UCNP@HMSN with high uni-
formity. By changing the “yolk” to QD or SPION, we confirmed the general
applicability of this protocol. The stability of as-designed nanosystem in PBS
SUNDAY, FEBRUARY, 21 was significantly improved due to the incorporation of PEG. In vitro CD105
targeting in HUVEC (CD105+) and MCF-7 (CD105-) cells showed strong/spe-
cific binding of FITC-conjugated UCNP@HMSN-PEG-TRC105 to CD105+ cells
6-1 with negligible non-specific binding. In vivo tumor targeting and PET imaging
NANOIMAGING demonstrated CD105-specific targeting of 64Cu-UCNP@HMSN-PEG-TRC105
in 4T1 tumor-bearing mice, with peak tumor uptake of ~6.5 %ID/g at 6 h
post-injection. CD105 specificity was confirmed by blocking and ex vivo
Grand Ballroom 5:00pm - 8:00pm histology studies. With large interior cavity inside the core/shell structure,
enhanced drug loading was achieved with UCNP@HMSN compared to
UCNP@dSiO2@MSN (same nanoparticle without a hollow cavity inside).
Activatable and Cell-Penetrable Multiplex FRET Nanosensor for
Profiling MT1-MMP Activity in Single Cancer Cells Conclusion: We report the generalized syntheses of yolk/shell structured
nanosystems for tumor targeted PET imaging and drug delivery. With UCNP,
QD, SPION or other nanocrystals inside each yolk/shell structure, this
Poster Presentation. NEMB2016-6092
nanoplatform is highly versatile for future multimodality image-guided drug
delivery. By introducing tumor vasculature targeting, the as-designed nano-
Eddie Chung, Peter Yingxiao Wang, Shaoying Lu, UCSD, La Jolla, systems will benefit from reduced side-effects and enhanced therapeutic
CA, United States efficacy due to enhanced targeting specificity.

We developed a quantum-dot-based fluorescence resonance energy trans-
fer (QD-FRET) nanosensor to visualize the activity of matrix metalloprotein- Synthesis and Characterization of Dextran-Polycaprolactone Di-
ase (MT1-MMP) at cell membrane. A bended peptide with multiple motifs was block Copolymers for the Preparation of Highly Stable Micelles
engineered to position the FRET pair at a close proximity to allow energy
transfer, which can be cleaved by active MT1-MMP to result in FRET changes with Facile Surface Functionalization
and the exposure of cell penetrating sequence. Via FRET and penetrated
QD signals, the nanosensor can profile cancer cells. Poster Presentation. NEMB2016-6006

Elizabeth Higbee-Dempsey, Lesan Yan, Andrew Tsourkas, Uni-
Generalized Syntheses of Tumor Targeted Yolk/Shell Structured versity of Pennsylvania, Philadelphia, PA, United States
Multifunctional Nanosystems
Nanoparticle-based imaging probes are often coated with so-called “stealth”
Poster Presentation. NEMB2016-5965 polymers: hydrophilic neutrally-charged polymers that help prolong blood
circulation by minimizing particle aggregation and minimizing interactions
Sixiang Shi, University of Wisconsin-Madison, Madison, WI, United with serum and tissue proteins. Currently, the most popular choice of poly-
mer for this purpose is polyethylene glycol (“PEG”). Despite its near-ubiquity,
States, Feng Chen, Stephen A. Graves, University of Wiscon- PEG has several important limitations. For example, PEG can only be modi-
sin-Madison, Madison, WI, United States, Shreya Goel, Todd E. fied at its two ends, which limits its ability to be crosslinked. Crosslinking may
Barnhart, University of Wisconsin-Madison, Madison, WI, United be desirable if improved stability (e.g. lower critical micelle concentration)
States, Weibo Cai, University of Wisconsin-Madison, Madison, WI, is required or if drug leakage is high. Also, while PEG’s stealth properties
United States help particles avoid nonspecific recognition, PEG brushes can also uninten-
tionally conceal targeting ligands or other surface modifications. Due to the
Objectives: Hollow mesoporous silica nanoparticles (HMSNs), with a large flexibility of linear PEG chains, terminal moieties may become buried within a
cavity inside each original mesoporous silica nanoparticle (MSN), have re- PEG corona, particularly if these moieties are not highly hydrophilic.
cently gained increasing interest due to their tremendous potential for future
cancer imaging and therapy. Dual-modality imaging can be achieved by in- To overcome these particular challenges, we have developed an alternative
tegrating various types of inorganic functional nanocrystals into HMSN nano- polymer micelle system based on dextran, a glucose polymer. We have
structures, which provides synergistic advantages over each modality. Our synthesized a biodegradable diblock copolymer combining dextran (“Dex”)
goal is to develop a generally applicable protocol for yolk/shell structured and the hydrophobic polymer polycaprolactone (PCL). Click chemistry was
multifunctional nanosystems, to combine positron emission tomography employed in order to obtain the copolymer Dex-PCL in high yield and purity,
(PET) with other imaging modalities for image-guided drug delivery. and the product was thoroughly characterized using NMR and IR spectros-
copy. These polymers were then self-assembled into nanoparticles using a
Methods: Upconversion nanoparticle (UCNP, with NIR-in-NIR-out upconver- two-phase emulsion method, yielding spherical micelles with narrow polydis-
sion luminescence) was used as the initial example. UCNP was first coated persity. The resulting nanoparticles can be aminated and chemically cross-
with a dense silica (dSiO2) shell, forming UCNP@dSiO2, followed by re- linked in order to minimize cargo leakage and improve stability at low mi-
growth of a shell-thickness controllable MSN to form UCNP@dSiO2@MSN. celle concentration. Furthermore, while aminated dextran-coated nanoparti-
A Na2CO3 etching protocol was then used to selectively etch away dSiO2, cles are known to display favorable cellular uptake profiles, for cell tracking
leaving behind yolk/shell structured nanoparticles denoted as UCNP@ studies, these Dex-PCL particles can also be further chemically modified in
HMSN. A step-by-step surface engineering process was then adopted to order to introduce targeting ligands on the micelle surface.
conjugate NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), polyethylene
glycol (PEG) linkers, TRC105 (an antibody that binds to CD105, a receptor To explore the potential of these materials to be used as imaging probes,
overexpressed on tumor vasculature), and 64Cu radiolabel to form 64Cu- a variety of substances were encapsulated within the hydrophobic micelle
UCNP@HMSN-PEG-TRC105. Both hydrophobic (i.e. Sunitinib) and hydrophilic cores. Micelles were loaded with superparamagnetic iron oxide (SPIO) in
(i.e. Doxorubicin) drugs could be loaded inside UCNP@HMSN. Systematic order to form nanoparticles with magnetic resonance (MR) contrast capabil-
in vivo PET imaging and biodistribution studies were performed in 4T1 tu- ities. Compared to previously reported dextran-coated iron oxide nanopar-
mor-bearing mice to evaluate and confirm tumor targeting capability, validat- ticles, these Dex-PCL micelles contain a significantly higher SPIO payload,
70 ed by in vitro/ex vivo studies. Similar protocol was also applied to prepare which should result in greater contrast sensitivity per particle concentra-
quantum dot (QD)@HMSN and superparamagnetic iron oxide nanoparticle tion. Dex-PCL micelles were also loaded with indocyanine green (ICG), a
(SPION)@HMSN core/shell structured nanosystems. near-infrared dye that can be used for both fluorescence, absorbance, and