Based on our work during past grant periods, low-frequency sonophoresis (LFS) is now clinically used, but its application is limited to only certain low-molecular weight drugs. To broaden the application of LFS, we aim to improve the treatment regimen of skin using a combination of LFS and the surfactant sodium lauryl sulfate (SLS), as well as to design nano-scale delivery vehicles to be used after LFS/SLS treatment to increase the transdermal delivery of high-molecular weight permeants, such as proteins and vaccines, to therapeutic levels. The proposed studies involve: 1) Understanding the mechanisms of heterogenous skin perturbation with LFS and the observed synergism between LFS/SLS on skin permeability enhancement. These mechanisms will be investigated by studying the cavitation field that develops in the coupling medium between the ultrasound horn and the skin. The synergistic mechanism of LFS/SLS-enhanced transdermal penetration may be identified by correlating the extent of enhanced skin permeability with the partitioning of novel "fluorescent surfactants" (which allow for molecular-level imaging of surfactant behavior using two-photon fluorescence microscopy) between major skin structural components. Upon determination of these mechanisms, the LFS application and topical formulation may be improved to more effectively deliver drugs through a treated skin area;2) Promoting the formation of "localized transport regions" (LTRs, highly permeabilized regions that form on the surface of the skin as a result of LFS application) by controlling the nucleation of LFS-induced cavitation events, in order to reduce skin treatment areas, minimize variability between skin treatment sites, and decrease ultrasonic power input requirements;3) Designing polymeric micelle delivery vehicles to enhance the transdermal delivery of permeants through skin pre-treated with LFS/SLS by utilizing functionalized nanoparticles (quantum dots and biomimetic gold nanoparticles) to identify optimal permeant properties for passive transdermal delivery of permeants through skin pre-treated with LFS/SLS;4) Transport modeling of the permeant diffusion pathways through the skin, which will aid in proper clinical drug dosing by predicting the lag time to reach steady state and the steady state permeability of a drug;and 5) Investigating the safety of the LFS/SLS skin treatment by determining the reversibility of the LTRs and their biological effects. Overall, the studies proposed here aim to expand the clinical utility and efficacy of LFS/SLS as a painless and non-invasive method of transdermal drug delivery for a broad class of drugs.

Public Health Relevance

Ultrasound-assisted transdermal drug delivery provides an alternative to oral delivery and injections, circumventing issues related to absorption in the gastrointestinal tract, liver metabolism, and poor patient compliance. The proposed research aims to design a more effective ultrasound-assisted skin treatment regimen in order to deliver a broader class of drugs at therapeutic levels than is currently possible.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000351-19
Application #
8217204
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Krosnick, Steven
Project Start
1991-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
19
Fiscal Year
2012
Total Cost
$337,789
Indirect Cost
$121,519
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Schoellhammer, Carl M; Blankschtein, Daniel; Langer, Robert (2014) Skin permeabilization for transdermal drug delivery: recent advances and future prospects. Expert Opin Drug Deliv 11:393-407
Sharei, Armon; Zoldan, Janet; Adamo, Andrea et al. (2013) A vector-free microfluidic platform for intracellular delivery. Proc Natl Acad Sci U S A 110:2082-7
Chertok, Beata; Webber, Matthew J; Succi, Marc D et al. (2013) Drug delivery interfaces in the 21st century: from science fiction ideas to viable technologies. Mol Pharm 10:3531-43
Seto, Jennifer E; Polat, Baris E; VanVeller, Brett et al. (2012) Fluorescent penetration enhancers for transdermal applications. J Control Release 158:85-92
Polat, Baris E; Deen, William M; Langer, Robert et al. (2012) A physical mechanism to explain the delivery of chemical penetration enhancers into skin during transdermal sonophoresis - Insight into the observed synergism. J Control Release 158:250-60
Polat, Baris E; Figueroa, Pedro L; Blankschtein, Daniel et al. (2011) Transport pathways and enhancement mechanisms within localized and non-localized transport regions in skin treated with low-frequency sonophoresis and sodium lauryl sulfate. J Pharm Sci 100:512-29
Ciolino, Joseph B; Hudson, Sarah P; Mobbs, Ashley N et al. (2011) A prototype antifungal contact lens. Invest Ophthalmol Vis Sci 52:6286-91
Polat, Baris E; Lin, Shangchao; Mendenhall, Jonathan D et al. (2011) Experimental and molecular dynamics investigation into the amphiphilic nature of sulforhodamine B. J Phys Chem B 115:1394-402
Lopez, Renata F V; Seto, Jennifer E; Blankschtein, Daniel et al. (2011) Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate. Biomaterials 32:933-41
Polat, Baris E; Hart, Douglas; Langer, Robert et al. (2011) Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J Control Release 152:330-48

Showing the most recent 10 out of 18 publications