Showing papers by "Yuan-Chih Chang published in 2016"

Improving Nanoparticle Penetration in Tumors by Vascular Disruption with Acoustic Droplet Vaporization.

Abstract: Drug penetration influences the efficacy of tumor therapy. Although the leaky vessels of tumors can improve the penetration of nanodrugs via the enhanced permeability and retention (EPR) effect, various aspects of the tumor microenvironment still restrict this process. This study investigated whether vascular disruption using the acoustic vaporization of micro- or nanoscale droplets (MDs or NDs) induced by ultrasound sonication can overcome the limitations of the EPR effect to allow drug diffusion into extensive regions. The intravital penetration of DiI-labeled liposomes (as a drug model with red fluorescence) was observed using an acousto-optical integrated system comprising a 2-MHz focused ultrasound transducer (transmitting a three-cycle single pulse and a peak negative pressure of 10 MPa) in a window-chamber mouse model. Histology images of the solid tumor were also used to quantify and demonstrate the locations where DiI-labeled liposomes accumulated. In the intravital image analyses, the cumulative diffusion area and fluorescence intensity at 180 min were 0.08±0.01 mm(2) (mean±standard deviation) and 8.5±0.4%, respectively, in the EPR group, 0.33±0.01 mm(2) and 13.1±0.4% in the MD group (p<0.01), and 0.63±0.01 mm(2) and 18.9±1.1% in the ND group (p<0.01). The intratumoral accumulations of DiI-labeled liposomes were 1.7- and 2.3-fold higher in the MD and ND groups, respectively, than in the EPR group. These results demonstrate that vascular disruption induced by acoustic droplet vaporization can improve drug penetration more than utilizing the EPR effect. The NDs showed longer lifetime in vivo than MDs and provided potential abilities of long periods of treatment, intertissue ND vaporization, and intertissue NDs-converted bubble cavitation to improve the drug penetration and transport distance.

Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson's Disease.

Abstract: Glial cell line-derived neurotrophic factor (GDNF) supports the growth and survival of dopaminergic neurons. CNS gene delivery currently relies on invasive intracerebral injection to transit the blood-brain barrier. Non-viral gene delivery via systematic transvascular route is an attractive alternative because it is non-invasive, but a high-yield and targeted gene-expressed method is still lacking. In this study, we propose a novel non-viral gene delivery approach to achieve targeted gene transfection. Cationic microbubbles as gene carriers were developed to allow the stable formation of a bubble-GDNF gene complex, and transcranial focused ultrasound (FUS) exposure concurrently interacting with the bubble-gene complex allowed transient gene permeation and induced local GDNF expression. We demonstrate that the focused ultrasound-triggered GDNFp-loaded cationic microbubbles platform can achieve non-viral targeted gene delivery via a noninvasive administration route, outperform intracerebral injection in terms of targeted GDNF delivery of high-titer GDNF genes, and has a neuroprotection effect in Parkinson's disease (PD) animal models to successfully block PD syndrome progression and to restore behavioral function. This study explores the potential of using FUS and bubble-gene complexes to achieve noninvasive and targeted gene delivery for the treatment of neurodegenerative disease.

Biomimicking Platelet–Monocyte Interactions as a Novel Targeting Strategy for Heart Healing

Abstract: In patients who survive myocardial infarction, many go on to develop congestive heart failure (CHF). Despite ongoing efforts to develop new approaches for postinfarction therapy, there are still no effective therapeutic options available to CHF patients. Currently, the delivery of cardioprotective drugs relies entirely on passive uptake via the enhanced permeability and retention (EPR) effect which occurs in proximity to the infarction site. However, in ischemic disease, unlike in cancer, the EPR effect only exists for a short duration postinfarction and thus insufficient for meaningful cardioprotection. Splenic monocytes are recruited to the heart in large numbers postinfarction, and are known to interact with platelets during circulation. Therefore, the strategy is to exploit this interaction by developing platelet-like proteoliposomes (PLPs), biomimicking platelet interactions with circulating monocytes. PLPs show strong binding affinity for monocytes but not for endothelial cells in vitro, mimicking normal platelet activity. Furthermore, intravital multiphoton imaging shows that comparing to plain liposomes, PLPs do not aggregate on uninjured endothelium but do accumulate at the injury site 72 h postinfarction. Importantly, PLPs enhance the targeting of anti-inflammatory drug, cobalt protoporphyrin, to the heart in an EPR-independent manner, which result in better therapeutic outcome.

Hollow Cone Electron Imaging for Single Particle 3D Reconstruction of Proteins

Abstract: The main bottlenecks for high-resolution biological imaging in electron microscopy are radiation sensitivity and low contrast. The phase contrast at low spatial frequencies can be enhanced by using a large defocus but this strongly reduces the resolution. Recently, phase plates have been developed to enhance the contrast at small defocus but electrical charging remains a problem. Single particle cryo-electron microscopy is mostly used to minimize the radiation damage and to enhance the resolution of the 3D reconstructions but it requires averaging images of a massive number of individual particles. Here we present a new route to achieve the same goals by hollow cone dark field imaging using thermal diffuse scattered electrons giving about a 4 times contrast increase as compared to bright field imaging. We demonstrate the 3D reconstruction of a stained GroEL particle can yield about 13.5 A resolution but using a strongly reduced number of images.