BADERC-Apostolos Doukas

Apostolos Doukas, Ph.D

Transdermal Delivery of Insulin and Protein Drugs

In clinical drug therapies, topical application allows localized drug delivery to the site of interest. This enhances the therapeutic effect of the drug while minimizing systemic side effects. Furthermore, topical application of drugs bypasses systemic deactivation or degradation and minimizes gastrointestinal incompatibility and potential toxicological risk.

Pressure waves (high amplitude pressure transients) generated by lasers is one of the latest platforms for drug delivery. A pressure wave was first shown to permeabilize the cell plasma membrane and allow macromolecules to diffuse through it into the cytoplasm. Pressure waves have been used to permeabilize the stratum corneum and facilitate the transport of macromolecules, such as insulin, into the viable skin. They have also been shown to facilitate drug delivery into microbial biofilms. Last, we have recently demonstrated that pressure waves can permeabilize the nuclear envelope and facilitate the delivery of macromolecules into the cell nucleus. The many diverse applications of pressure waves exemplify the potential of this platform for drug delivery in many different biological systems. Furthermore, different pressure-wave parameters are required for each of these applications. Therefore, it is conceivable to apply one type of pressure waves to permeabilize the stratum corneum for transdermal delivery and follow with a second pressure wave of different characteristics for delivery into the cytoplasm or even into the cell nucleus. Large particles, 100 nm in diameter, have been delivered with this method into the viable skin in vivo. On the other hand, macromolecules, 2 MDa molecular weight, have been delivered into the cytoplasm in cell cultures.

References:

1. S Lee, N Kollias, DJ McAuliffe, TJ Flotte, AG Doukas. Topical drug delivery in humans with a single photomechanical wave. Pharm. Res. 16, 1717-1721 (1999).

2. NS Soukos, SS Socransky, S. Mulholland, S Lee, AG Doukas. Photomechanical drug delivery into bacterial bofilms. Pharm. Res. 17, 405-409 (2000).

3. T Kodama, MR Hamblin, AG Doukas. Cytoplasmic molecular delivery with shock waves: Importance of impulse. Biophys. J. 79, 1821-1832 (2000).

4. S Lee, DJ McAuliffe, SE Mulholland, AG Doukas. Photomechanical transdermal delivery of insulin in vivo. Lasers Surg. Med. 28, 282-285 (2001).

5. S González, S Lee, E González, AG Doukas. Rapid antigen delivery with photomechanical waves for inducing allergic skin reaction in the DNCB-sensitized hairless guinea pig animal model. Am. J. Contact Dermatitis 12, 162-165 (2001).

6. T Kodama, AG Doukas, MR Hamblin. Shock wave-mediated molecular delivery into cells. Biochim. Biophys. Acta 1542, 186-194 (2002).

7. S Lee, DJ McAuliffe, N Kollias, TJ Flotte, AG Doukas. Photomechanical delivery of 100-nm microspheres through the stratum corneum: Implications for transdermal drug delivery. Lasers Surg. Med. 31, 207-210 (2002).

8. T Kodama, AG Doukas, MR Hamblin. Delivery of ribosome-inactivating protein toxin into cancer cells with shock waves. Cancer Letters 189, 69-75 (2003).

9. T-Y D Lin, DJ Mcauliffe, N Michaud, H Zhang, S Lee, AG Doukas, TJ Flotte. Nuclear transport by laser-induced pressure transients. Pharm Res (in press).






			Apostolos Doukas, Ph.D Transdermal Delivery of Insulin and Protein Drugs In clinical drug therapies, topical application allows localized drug delivery to the site of interest. This enhances the therapeutic effect of the drug while minimizing systemic side effects. Furthermore, topical application of drugs bypasses systemic deactivation or degradation and minimizes gastrointestinal incompatibility and potential toxicological risk. Pressure waves (high amplitude pressure transients) generated by lasers is one of the latest platforms for drug delivery. A pressure wave was first shown to permeabilize the cell plasma membrane and allow macromolecules to diffuse through it into the cytoplasm. Pressure waves have been used to permeabilize the stratum corneum and facilitate the transport of macromolecules, such as insulin, into the viable skin. They have also been shown to facilitate drug delivery into microbial biofilms. Last, we have recently demonstrated that pressure waves can permeabilize the nuclear envelope and facilitate the delivery of macromolecules into the cell nucleus. The many diverse applications of pressure waves exemplify the potential of this platform for drug delivery in many different biological systems. Furthermore, different pressure-wave parameters are required for each of these applications. Therefore, it is conceivable to apply one type of pressure waves to permeabilize the stratum corneum for transdermal delivery and follow with a second pressure wave of different characteristics for delivery into the cytoplasm or even into the cell nucleus. Large particles, 100 nm in diameter, have been delivered with this method into the viable skin in vivo. On the other hand, macromolecules, 2 MDa molecular weight, have been delivered into the cytoplasm in cell cultures. References: 1. S Lee, N Kollias, DJ McAuliffe, TJ Flotte, AG Doukas. Topical drug delivery in humans with a single photomechanical wave. Pharm. Res. 16, 1717-1721 (1999). 2. NS Soukos, SS Socransky, S. Mulholland, S Lee, AG Doukas. Photomechanical drug delivery into bacterial bofilms. Pharm. Res. 17, 405-409 (2000). 3. T Kodama, MR Hamblin, AG Doukas. Cytoplasmic molecular delivery with shock waves: Importance of impulse. Biophys. J. 79, 1821-1832 (2000). 4. S Lee, DJ McAuliffe, SE Mulholland, AG Doukas. Photomechanical transdermal delivery of insulin in vivo. Lasers Surg. Med. 28, 282-285 (2001). 5. S González, S Lee, E González, AG Doukas. Rapid antigen delivery with photomechanical waves for inducing allergic skin reaction in the DNCB-sensitized hairless guinea pig animal model. Am. J. Contact Dermatitis 12, 162-165 (2001). 6. T Kodama, AG Doukas, MR Hamblin. Shock wave-mediated molecular delivery into cells. Biochim. Biophys. Acta 1542, 186-194 (2002). 7. S Lee, DJ McAuliffe, N Kollias, TJ Flotte, AG Doukas. Photomechanical delivery of 100-nm microspheres through the stratum corneum: Implications for transdermal drug delivery. Lasers Surg. Med. 31, 207-210 (2002). 8. T Kodama, AG Doukas, MR Hamblin. Delivery of ribosome-inactivating protein toxin into cancer cells with shock waves. Cancer Letters 189, 69-75 (2003). 9. T-Y D Lin, DJ Mcauliffe, N Michaud, H Zhang, S Lee, AG Doukas, TJ Flotte. Nuclear transport by laser-induced pressure transients. Pharm Res (in press).