1. CHeM 442 – BIomaterIals Ultrasound responsIVE materIals FOR DRUG DELIVERY
ARZU ANGI
Spring 2012

2. Outline Stimuli-responsive materials in drug delivery
Requirements
Ultrasound responsive materials
Acoustic cavitation
Drug delivery
An example
Release mechanisms
Advantages / Disadvantages
Conclusions

3. Stimuli-responsive materials in drug delivery
“Smart” materials which have the ability to undergo rapid change their micro or macro structure as a response to small changes in the environment.
Temperature pH
Light
Magnetic field
Electric field
Ultrasound
Permeability
Surface properties
Optical properties
Shape - size change
Phase seperation
Reversible or not
Priya Bawa, Viness Pillay1, Yahya E Choonara and Lisa C du Toit, Stimuli-responsive polymers and their applications in drug delivery, 2009, Biomedical Meterials Volume 4, Number 2.

4. Requirements Non toxic Biocompatible
Temporal control - Sensitive to the sitimuli
Optimal size to accumulatation and escape from immune system
Optimal circulation time
Site specific drug targeting
No harm to healthy cells – non spesific uptake
Reversible or not
Priya Bawa, Viness Pillay1, Yahya E Choonara and Lisa C du Toit, Stimuli-responsive polymers and their applications in drug delivery, 2009, Biomedical Meterials Volume 4, Number 2.

5. Ultrasound
Ultrasound which traditionally was used as a diagnostic tool is recently found to be a potential system for gene transfer and drug delivery.
Ultrasound assisted nanotherapy can be utilized in :
Ovarian, breast and pancreatic cancerous tumors - chemotheraphy
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.
Zhang, Hesheng Xia, Jie Wang, Yongwen Li, High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles, Journal of Controlled Release, 2009,Volume 139, Issue 1, 31–39

6. Ultrasound
Ultrasound consists of acoustic waves with frequecies 20kHz or greater.
Acoustic cavitation – Main phenomena :
“Continuous formation, growth and sudden collapse of vapor filled micro bubbles formed by acoustical wave-induced compression.
Extreme local high temperature (>5000 K) and
high pressure (>500 atm)
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.
Zhang, Hesheng Xia, Jie Wang, Yongwen Li, High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles, Journal of Controlled Release, 2009,Volume 139, Issue 1, 31–39

7. Drug Delivery
The most employed drug carrier : Amphiphilic copolymer micelles
Advantages :
Longer circulation times when their corona contains PEO chains
Longer shelf life – polymers do not degrade
Appropriate size to escape renal excretion (15-30 nm), and for extravasation and accumlation at a tumor site.
Delivery of hydrophobic drugs : Doxorubicin (Dox), Ruboxyl, Paclitaxel
Significant decrease in tumor volume was achived in studies on animals.
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.
Zhang, Hesheng Xia, Jie Wang, Yongwen Li, High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles, Journal of Controlled Release, 2009,Volume 139, Issue 1, 31–39

8. Drug Delivery Pluronic Micelles : ABA type copolymers - Pluronic ®
A – Hydrophilic PEO B – Slightly hydrophobic PPO
Advantages :
Reversing drug resistence
Low concentrations of Pluronic ® can overcome multi drug resistence developed by
cancer cells that had been repeatedly exposed to chemotheraphy .
Protecting healthy cells from toxic drug & On demand release with ultrasound
At high concentrations less accumulation of Dox in the cellular compartments is
observed : Reducing effective drug concentration in systematic circulation.
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.
Zhang, Hesheng Xia, Jie Wang, Yongwen Li, High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles, Journal of Controlled Release, 2009,Volume 139, Issue 1, 31–39

9. Drug Delivery
Example  Amphiphilic copolymer : PLA-b-PEG containing Nile Red
Biodegradibility
Biocompatibility
Synthesized by polycondensation
Triggered by high intensity frequency ultrasound (HIFU) : 1.1 MHz
Observed with fluorescence emission spectra
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.
Zhang, Hesheng Xia, Jie Wang, Yongwen Li, High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles, Journal of Controlled Release, 2009,Volume 139, Issue 1, 31–39

10. Drug Delivery To confirm the role of ultrasonic cavitation :
 Thermal effect : Micelles are heated to 95 °C, very low release without HIFU
 Possibility of NR degredation :
Nile red is dissolved in THF and HIFU applied,
no change in fluorescence emission.
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.
Zhang, Hesheng Xia, Jie Wang, Yongwen Li, High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles, Journal of Controlled Release, 2009,Volume 139, Issue 1, 31–39

11. Release Mechanisms
Release mechanism of hydrophobic drug from PLA-b-PEG micelle :
Distruption of the micelle due to degradation of block copolymer
Chemical process
Irreversible
Release profile depends on :
Intensity
Time
The location of reactor cuvette
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.

12. Release Mechanisms
Ultrasound assisted release mechanism of drug delivery vehicles and transport through cell membrane are not well understood.
Ultrasonic release of the drug from micelles is followed by normal transport into the cell
Ultrasound upregulates edoctyosis of the micelles into the cell
Ultrasound perturbs the cell membrane which increases passive but direct transport of the drug into the cell cytosol.
Sonoporation : Reversible pore formation up to 100 nm effective diameter with a half life of a few seconds.
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.

13. Release Mechanisms
Ultrasound assisted release mechanism of drug delivery vehicles and transport through cell membrane are not well understood.
Ultrasonic release of the drug from micelles is followed by normal transport into the cell
Ultrasound upregulates edoctyosis of the micelles into the cell
Ultrasound perturbs the cell membrane which increases passive but direct transport of the drug into the cell cytosol.
Sonoporation : Reversible pore formation up to 100 nm effective diameter with a half life of a few seconds.
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.

14. Advantages Non-invasive, no surgery is needed
Extra ordinary safety record
Deep tissue penetration – better than light
Precise targeting and focus (High frequency ultrasound -HFU)
Bioeffects – Sonoporation
Possibility of combination of diagnostics with therapy
Simplicity and cost efficiency
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.
Zhang, Hesheng Xia, Jie Wang, Yongwen Li, High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles, Journal of Controlled Release, 2009,Volume 139, Issue 1, 31–39
Natalya Y. Rapoport, Anne M. Kennedyb, Jill E. Sheac, Courtney L. Scaife, Kweon-Ho Nam, Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/ microbubbles, Journal of Controlled Release, 2009, Volume 138, Issue 3, 268–276
C. M. H. Newman, T Bettinger, Gene therapy progress and prospects: Ultrasound for gene transfer, Gene Therapy 14, 2007, 465–475.

15. Disadvantages Trade off between cavitation power and focus.
Cavitation is weaker with HFU, but it is focusable. Low frequency ultrasound (LFU) is difficult to focus, but cavitation is stronger
Demage to cells due to excessive shear force, radical formation
Time, frequency and dose
Tumor reccurrence or drug resistivity in some cases
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.
Zhang, Hesheng Xia, Jie Wang, Yongwen Li, High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles, Journal of Controlled Release, 2009,Volume 139, Issue 1, 31–39
Natalya Y. Rapoport, Anne M. Kennedyb, Jill E. Sheac, Courtney L. Scaife, Kweon-Ho Nam, Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/ microbubbles, Journal of Controlled Release, 2009, Volume 138, Issue 3, 268–276
C. M. H. Newman, T Bettinger, Gene therapy progress and prospects: Ultrasound for gene transfer, Gene Therapy 14, 2007, 465–475.

16. Conclusions – Future prospects
Ultrasound mediated chemotherapy is found to be very effective in regression in ovarian and pancreatic cancer models
Development of supressing the drug resistance is needed
Hydrophobic cargo ( anti cancer drugs ) can be transported with amphiphilic micelles
More studies are needed to answer the questions regarding the release and transport mechanisms
To overcome the trade off between power of cavitation and focusability, fast responsive micelles are needed
Reversible or not
Ghaleb A. Husseini,William G. Pitt, Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery, Advanced in Drug Delivery, 2008, 1137–1152.
Zhang, Hesheng Xia, Jie Wang, Yongwen Li, High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles, Journal of Controlled Release, 2009,Volume 139, Issue 1, 31–39
Natalya Y. Rapoport, Anne M. Kennedyb, Jill E. Sheac, Courtney L. Scaife, Kweon-Ho Nam, Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/ microbubbles, Journal of Controlled Release, 2009, Volume 138, Issue 3, 268–276
C. M. H. Newman, T Bettinger, Gene therapy progress and prospects: Ultrasound for gene transfer, Gene Therapy 14, 2007, 465–475.

17. Conclusions – Future prospects
Progress towards clinical application requires the development of standardized reporting of ultrasound exposure conditions to facilitate comparisons.
C. M. H. Newman, T Bettinger, Gene therapy progress and prospects: Ultrasound for gene transfer, Gene Therapy 14, 2007, 465–475.

18. Thank you

19. Questions ?