Page 27 - ASME_NEMB_2016_Program

TRACK 2 TRACK 2 Technical Program

Technical Presentation. NEMB2016-5993 Cystic fibrosis is a well-studied systemic genetic disorder that affects mostly
the lungs. Gene therapy has long been regarded as the ultimate cure for
Alessandro Grattoni, Houston Methodist Research Institute, Hous- cystic fibrosis. Although clinical development of gene therapy started over
ton, TX, United States two decades ago, there are no gene therapy products approved in the
U.S. The current development of gene therapy is mainly hampered by in-
Silicon nanochannel platforms leveraging nano-constrained diffusion for effective nucleic acid delivery. Gene therapy can be classified by the gene
tightly controlled therapeutic release and immunoisolated cell transplan- delivery method as viral and non-viral delivery. About 70% of gene therapy
tation: Through cutting-edge implementation of fabrication techniques de- clinical trials performed to date utilized viral delivery. Although viral gene
delivery usually can achieve high gene expression, it is also limited by im-
veloped in the microelectronics industry, our group is able to create dense
arrays of nanochannels ranging from nanometers to millimeters in height munogenicity, DNA packaging capacity and difficulty for large-scale vector
with a precision of ±5%. Two device platforms have been invented in order production. In contrast, non-viral gene delivery has the potential to address
to leverage these capabilities: a silicon nanochannel membrane for drug many of the limitations associated with viral gene delivery, including lower
delivery and a surface-modified polymer system for cell transplantation. The immunogenicity, use of essentially unlimited size of DNA, and cost-effective
scalability. Intravascular injection of naked plasmid DNA in a large volume,
drug delivery system employs adaptable channel sizes down to 2.5 nm to
closely constrain molecular transport, linearizing Fickian diffusion to achieve known as hydrodynamic delivery, can achieve gene expression in the liver
constant administration. Implantable drug delivery devices are fashioned and muscle, but with a relatively low expression level. Both organic and in-
by integrating these nanochannel membranes within bioinert metallic or organic materials have been used to formulate nanoparticles (NPs) in order
polymeric capsules. These devices are minimally-invasive, can be implanted to enhance the efficacy of plasmid DNA delivery. Similar to hydrodynamic in-
jection of free plasmids, some of these nanoparticles predominantly express
subcutaneously, and provide linear (zero-order) release of drugs and bio-
molecules. Clinically-relevant dosages of testosterone for hormone replace- genes in liver hepatocytes, which holds the promise to treat liver related dis-
ment have been released for more than 6 months at a constant rate with eases. However, gene delivery to the lung has not been extensively studied.
this platform. Further innovations include active, on-board control systems to It was reported that linear PEI mediated systemic gene delivery can achieve
permit remote manipulation or activation, enabling telemedicine or chrono- preferential gene expression in the lung, which was unfortunately attributed
to aggregation of NPs in vivo and can cause life-threatening lung embolism.
therapy regimens. The polymeric cell transplantation system was primarily
developed for pancreatic islet allografts. This device, the “NanoGland”, is
used to provide an immunoprotective environment for bioactive allografts by In this contribution, we will introduce a new strategy-regulated membrane
isolating cells from inflammation and rejection mechanisms while permitting activation (RMA) for gene delivery that is completely different from the pre-
interaction with glucose, insulin, nutrients, and waste exchange from the viously reported viral and non-viral based strategies. Taking advantage of
a precisely engineered biodegradable polymer, we can transiently activate
interstitial environment. Combining the NanoGland with the silicon nano-
channel membranes has allowed controlled release of immunosuppressive cell membranes to significantly enhance plasmid delivery to the lung in mice.
material or factors for cell growth and vascularization following cell trans- In addition, we demonstrated that this RMA process is safe and reversible in
plantation. vivo and does not induce appreciable toxicity and organ damage. Therefore,
we expect RMA as a novel gene therapy strategy for lung diseases.
4:50pm A Magnetic Switch for Controlling Gene Delivery in
2-5 Vivo
NANOPARTICLE ENGINEERING
Technical Presentation. NEMB2016-5987
Sam Houston 4:00pm - 5:30pm
Haibao Zhu, Sheng Tong, Gang Bao, Rice University, Houston, TX,
Session Organizer: Zhenpeng Qin, University of Texas at Dallas, United States
Richardson, TX, United States
Targeted delivery of vehicle to specific tissue or organ is a critical quest for
gene delivery in clinical therapy. Intravascular administration of vectors is the
4:00pm Leveraging Physiology for Precision Drug Delivery main approaches to transport of the exogenous gene to the target tissue or
organ. However, most of the delivery vehicle will be blocked in liver, lung,
Keynote. NEMB2016-6157 and spleen, duo to high speed blood flow and tissue microstructure. Even
there are several approaches, such as nano particles vector or optical trig-
Zhen Gu, University of North Carolina at Chapel Hill and North Car- ger system, can direct the gene of interest expression in target tissue. Still
olina State University, Raleigh, NC, United States those systems are hard to match the clinical therapy requirement. To devel-
op efficiency targeted system for gene delivery in vivo still urgent.
Spurred by recent advances in materials chemistry, molecular pharma-
Here, we have developed a hybrid system, consists of magnetic nanopar-
ceutics and nanobiotechnology, stimuli-responsive “smart’ systems offer
opportunities for delivering drugs in dose-, spatial- and temporal-controlled ticles associated with baculovirus which is an insect virus with large
fashions. In this talk, I will discuss our ongoing efforts in using physiological foreign DNA loading capacity and serum associated inactivation. Duo
signals, such as blood sugar level, enzyme activity and ATP gradient for to magnetic nanopartilces association, the virus can be guided to target
on-demand drug delivery in a programmed manner. I will first present the tissue by using a magnetic field in a noninvasive manner. Meanwhile the
virus fusion into cells process also can be facilitated by magnetic force,
glucose-responsive synthetic systems for biomimetic delivery of insulin for
diabetes treatment. I will further discuss programmable delivery of antican- so as to avoid serum inactivation. In our study, the magnetic nanoparticles
cer therapeutics, the release of which can be activated in the tumor micro- conjugated with TAT peptide, which show positive charge, were firstly syn-
environment or subcellular environment. thesized. The positively charge nanoparticels associated with baculovirus
was confirmed by TEM. In vitro study, the hybrid system can be directed
by external magnetic field to accumulate and mediate EGFP expression
4:30pm Lung Specific Gene Delivery through Regulated Mem- in target cells in hydrodynamic and physiology flow condition. Also based
brane Activation on serum inactivation assay, we found the external magnetic field can
protect baculovirus from serum inactivation in vitro. Several criteria, such
Technical Presentation. NEMB2016-5922 as virus/particles ratio, particles size, magnetic strength, and incubation
time, determine the protection efficiency. The viruses also were success- 27
Jin Wang, Baylor College of Medicine, Houston, TX, United States fully directed to the target tissue in vivo, such as lung and liver, by external
magnetic field, respectively. And based on the in vivo image and qRT-PCR