The development of a "magic bullet" that could carry a therapeutic dose of drug to a target organ or tumor with high specificity is the ideal goal of targeted drug delivery. The development of such a vehicle could improve therapeutic efficacy while reducing side effects. This is of particular interest for chemotherapy administration, where the drugs have high systemic toxicity. In this proposal, novel microfluidic technology is utilized to precision engineer acoustically-active drug delivery vehicles. Currently, liposomes are utilized as one of the most effective drug carriers, although their in-vivo accumulation is relatively non-specific. We propose that by making acoustically-active liposome-like vehicles, we can overcome this nonspecificity by utilizing ultrasound to "steer" the vehicles using acoustic radiation force and then disrupt the vehicle shells to release the contents preferentially at the target site. Acoustically active drug carriers must possess a layer with drug-carrying capacity, similar as a liposome, yet at the same time, they must have a core with significantly different density and compressibility than the surrounding media - such as a gas. Vehicles with this unique multi-layer composition can be created with microfluidics. Additionally, microfluidics provides a precise way to engineer vehicles with exactly the same size, drug payload, and shell characteristics. The uniform acoustic properties of precision engineered vehicles will allow specific tuning of the ultrasound frequency for optimized acoustically-mediated delivery, and will enhance the ability of these vehicles to be used for simultaneous imaging. This proposal describes a multi step process for the development, improvement, and exploration of acoustically-active drug delivery vehicles for site-specific drug delivery. The first step in this proposal is the precision engineering of acoustically active drug delivery vehicles through the application of novel microfluidic technology. The second component consists of testing and optimizing the stability, acoustic properties, and drug release characteristics of these new vehicles, as well as examining the safety of ultrasound parameters optimized to concentrate and disrupt the vehicles. Finally, the delivery potential and biodistribution of the new vehicles will be examined with optical imaging and ultrasound. This collaboration between the principal investigators at the UNC- NCSU Joint Department of Biomedical Engineering, the UNC School of Pharmacy, and the University of California Irvine provide a unique and qualified research group with expertise in ultrasound, microbubbles, drug delivery vehicles and their drug loading and release characteristics, and microfluidics required to achieve these goals.

Public Health Relevance

PROJECT NARRATIVE Our research proposes to create and test new acoustically-active delivery vehicles for site specific delivery of chemotherapeutics. These vehicles have the potential for local delivery of chemotherapy or other drugs while minimizing systemic toxicity. The success of an acoustically localized delivery system would improve therapeutic methods, reduce side effects, and improve public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB008733-04
Application #
8225204
Study Section
Instrumentation and Systems Development Study Section (ISD)
Program Officer
Lopez, Hector
Project Start
2009-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$316,715
Indirect Cost
$102,608
Name
North Carolina State University Raleigh
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Doinikov, Alexander A; Sheeran, Paul S; Bouakaz, Ayache et al. (2014) Vaporization dynamics of volatile perfluorocarbon droplets: a theoretical model and in vitro validation. Med Phys 41:102901
Bardin, David; Lee, Abraham P (2014) Low-cost experimentation for the study of droplet microfluidics. Lab Chip 14:3978-86
Martin, K Heath; Dayton, Paul A (2013) Current status and prospects for microbubbles in ultrasound theranostics. Wiley Interdiscip Rev Nanomed Nanobiotechnol 5:329-45
Sheeran, Paul S; Matsunaga, Terry O; Dayton, Paul A (2013) Phase-transition thresholds and vaporization phenomena for ultrasound phase-change nanoemulsions assessed via high-speed optical microscopy. Phys Med Biol 58:4513-34
Mullin, Lee B; Phillips, Linsey C; Dayton, Paul A (2013) Nanoparticle delivery enhancement with acoustically activated microbubbles. IEEE Trans Ultrason Ferroelectr Freq Control 60:65-77
Shih, Roger; Bardin, David; Martz, Thomas D et al. (2013) Flow-focusing regimes for accelerated production of monodisperse drug-loadable microbubbles toward clinical-scale applications. Lab Chip 13:4816-26
Gessner, Ryan C; Streeter, Jason E; Kothadia, Roshni et al. (2012) An inýývivo validation of the application of acoustic radiation force to enhance the diagnostic utility of molecular imaging using 3-d ultrasound. Ultrasound Med Biol 38:651-60
Sheeran, Paul S; Dayton, Paul A (2012) Phase-change contrast agents for imaging and therapy. Curr Pharm Des 18:2152-65
Johnson, Kennita; Cianciolo, Rachel; Gessner, Ryan C et al. (2012) A pilot study to assess markers of renal damage in the rodent kidney after exposure to 7 MHz ultrasound pulse sequences designed to cause microbubble translation and disruption. Ultrasound Med Biol 38:168-72
Bardin, David; Martz, Thomas D; Sheeran, Paul S et al. (2011) High-speed, clinical-scale microfluidic generation of stable phase-change droplets for gas embolotherapy. Lab Chip 11:3990-8

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