1. Porous-Wall Hollow Glass Microsphere as novel potential nanocarriers for biomedical applications Shuyi Li, M.D., Ph.D. NIH Nanomedicine Center for Nucleoprotein Machines Institute of Molecular Medicine and Genetics Medical College of Georgia, USA 3rd Annual Unither Nanomedical & Telemedical Technology Conference, Orford, Canada February 23 -26, 2010

2. Background information 1.History: two decades, one million patients. 2.Applications: dental, orthopedic, and tissue engineering. 3.Recent example: tumor treatments (solid glass microsphere + Yttrium ( 90 Y) radio isotope). 4.Current strategy: bonding to organic polymers or the deposition of chemical substances directly into the glass matrix. 5.Our strategy: development of a more general approach for drug delivery Porous-Wall Hollow Glass Microsphere (PW-HGMs)

3. Background information Biomed Imaging Interv J 2006; 2(3):e43 Example: liver cancer treatment with 90 Y glass microsphere

4. Our Goal and Strategy Our Goal: To develop a novel drug carrier Higher dose delivery of bioactive agents Prolonged or controlled release Versatile drug delivery capability (chemot drugs, antibodies, siRNA, radio isotope or other macromolecules individually or in combination) Our Strategy: Glass microsphere, not regular glass

5. Introduction to PW-HGMs Safe: same as bioglass PW-HGMs have higher delivery capacity than solid glass microsphere. Porous wall allows controlled release of biological molecules such as antibody proteins, and siRNA Able to delivery different reagents.

6. PW-HGMs and its Shell Shuyi Li, et al., Nanomedicine 6:127–136 (2010)

7. Interaction of dextrans, nucleic acids, and proteins with PW-HGMs Shuyi Li, et al., Nanomedicine 6:127–136 (2010)

8. What is size exclusion limit of PW- HGMs? FITC-Dextran:200  g/ml Shuyi Li, et al., Nanomedicine 6:127–136 (2010) Size exclusion limit: 8.5 ~14.4 nm

9. Can PW-HGMs be a carrier for nucleic acids? Shuyi Li, et al., Nanomedicine 6:127–136 (2010) Both DNA oligonucleotide and siRNA can enter interior cavity. 70-kDa dextran can be used to “gate” siRNA. Internalized siRNA shows controlled release.

10. Can PW-HGMs be a carrier for protein? Shuyi Li, et al., Nanomedicine 6:127–136 (2010) PW-HGMs can be used as carries for proteins, antibodies, and antibody fragments. Antibody shows controlled release. Delivered antibody fragments are functional.

11. Can PW-HGMs be a carrier for intratumoral injection? Shuyi Li, et al., Nanomedicine 6:127–136 (2010) Quantitative image analysis revealed a linear relationship between the amount of material loaded and the corresponding photon counts. PW-HGMs are retained at the site of intratumoral injection and thus could be used for localized delivery of antitumor antibodies or siRNA.

12. CONCLUSIONS 1. PW-HGMs are a novel form of glass material consisting of a hollow central cavity with 1 micron-thick wall, which has tortuous network of nanometer-scale channels. 2. The porous walls of PW-HGMs promote size-dependent uptake and controlled release of biological molecules in the 3-8 nm range. This includes antibodies and a modified single-chain antibody fragment which are released functional. 3. The 70 kDa dextran can be used to gate the porous walls, facilitating controlled release of an internalized siRNA. 4. Dextran loaded with PW-HGMs remained in place after mouse intratumoral injection, suggesting a possible application for drug delivery of anti-cancer drugs. 5. The results suggest that PW-HGMs have potential as novel nanocarriers for antibodies, recombinant antibody derivatives, and small oligonucleotides.

13. Acknowledgement Medical College of Georgia William S. Dynan Hairong Xiong Tom Hu Jin-Xiong She Savannah River National Laboratory George G. Wicks Steven M. Serkiz

14. Something colorful Augusta, GA, USA

15. Thank you Augusta, GA, USA Institute of Molecular Medicine and Genetics