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Hyaluronic Acid and Cyclodextrin Derivatives

Hyaluronic Acid and Cyclodextrin Derivatives. Scott Zawko Group Meeting 02.21.07. n. HA Hydrogels – Tissue Engineering. Hydrogels resemble natural tissues with respect to mechanical properties, porosity and water content (Peppas NA et al. 2000 Eur J Pharm Biopharm). Biocompatibility.

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Hyaluronic Acid and Cyclodextrin Derivatives

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  1. Hyaluronic Acid and Cyclodextrin Derivatives Scott Zawko Group Meeting 02.21.07

  2. n HA Hydrogels – Tissue Engineering Hydrogels resemble natural tissues with respect to mechanical properties, porosity and water content(Peppas NA et al. 2000 Eur J Pharm Biopharm) Biocompatibility Biodegradability

  3. n HA Hydrogels - Drug Delivery HA-Drug Interactions Ionic Interactions Hydrogen Bonding Hydrophobic Interactions Viscosity Porosity Goal: Make HA hydrogel appropriate for a dual tissue engineering and drug delivery application.

  4. HA – Drug Release: Covalent linkage Ester Linkage - HA-methylprednisolone ester(Payan E et al. 1995 J Control Release) Amide Linkage - HA-mitomycin C(Li H et al 2004 Biomacromolecules)

  5. Soln % Release Heparin Complex Mixture FGF (Cai S. et al. 2005 Biomaterials) Complex FGF (Liu L. et al. 2002 JBMR) VEGF, FGF (Pike DB et al. 2006 Biomaterials) Time (min) HA – Drug Release: Non-covalent linkage Ionic Complex Lidocaine(Doherty MM et al. 1995 Anesth Analg) Bupivacaine(Dollo G et al. 2004 Int J Pharm)

  6. BSA in Gel Half BSA in Gel BSA in Microspheres HA – Drug Release: Microspheres PLGA Microsphere – Bovine Serum Albumin(Leach JB et al 2005 Biomaterials)

  7. HA – Drug Release: Cyclodextrin Conjugate Ibuprofen Ibuprofen – CD: Ka = 10700 M-1 Ibuprofen – HACD: Ka = 3500 M-1

  8. Drug Gel Uptake Release Increased Loading Hydrogel material that binds drug molecules Prolonged Release Matrix: Hyaluronic Acid Functionalities: Cyclodextrin

  9. n O H Cyclodextrin O O • Host-Guest Inclusion Complexes • Increase solubilization • Decrease crystallization • Increase stability H O O H Composite Hydrogel Material Hyaluronic Acid High molecular weight High water content High porosity Biocompatible Biodegradable 7 MW = 5x105 – 2x106

  10. Ka ~ 105 M-1 b-cyclodextrin (n=7) a-cyclodextrin (n=6) HO + HO OH Adamantane I.D. ~ 6Å Cyclodextrin’s Structure Hydrophobic Interior Hydrophilic Exterior

  11. Ka ~ 103 M-1 + Hydrocortisone Cyclodextrin’s Structure Hydrocortisone Solubility (mM) b-Cyclodextrin (mM)

  12. + GMHA + Triethylamine Photoinitiator UV Light Leach, J.B. et al. (2003) Biotechnol Bioeng Methacryloyl Hyaluronic Acid Methacryloyl Cyclodextrin Photocrosslinked Hydrogels

  13. Methacryloyl Cyclodextrin Possible steric hindrance

  14. 3 MAbCD DS = 3.2 2 4 5 1 No unpolymerizable CD Low average DS Comparable DS 6 3 4 2 MAaCD DS = 3.6 5 1 Methacryloyl Cyclodextrin

  15. Hydrocortisone CD (mM): 0 1 3 5 Quantitation of MAbCD-Hydrocortisone Binding MAbCD: 1400 M-1 MAaCD: 180 M-1 aCD: 92 M-1 bCD: 5380 M-1 [Cyclodextrin] (mM)

  16. + I2959, UV Light bCD / HA aCD / HA 20% CD / 80% HA 0.5% w/v 33% CD / 67% HA 1.0% w/v 43% CD / 57% HA 1.5% w/v Swelling Ratio (PBS) 20 HA 33 43 Cyclodextrin (%w/w) Swelling of Hyaluronic Acid – Cyclodextrin Hydrogels Cyclodextrin Hyaluronic Acid CD / HA Hydrogel 2% w/v

  17. Drug Gel Uptake Release Hyaluronic Acid – Cyclodextrin Drug Release HA-Drug Interactions Ionic Interactions Hydrogen Bonding Hydrophobic Interactions Viscosity Porosity Inclusion Complexation Hydrocortisone

  18. Drug Drug Drug HA Gel HA-bCD Gel HA-aCD Gel Uptake Uptake Uptake Release Release Release

  19. 43% bCD Hydrocortisone Gel Uptake Release 33% bCD Hydrocortisone Release (mg) 20% bCD 43% aCD 20% aCD HA Time (h) Hyaluronic Acid-Cyclodextrin Hydrogels: Hydrocortisone Uptake and Release

  20. Hydrocortisone Gel Uptake Release 1 HC : 8 MAbCD Hydrocortisone Release (mmol) 1 HC : 21 MAaCD Cyclodextrin (mmol) Hyaluronic Acid-Cyclodextrin Hydrogels: Hydrocortisone Uptake and Release

  21. Drug Drug HA Gel HA-bCD Gel Uptake Uptake Release Release HA-bCD Gel + Adamantane Drug Uptake Release

  22. HA 43% bCD 43% bCD Adamantane Hyaluronic Acid-Cyclodextrin Hydrogels: Hydrocortisone Uptake and Release Pre-incubation with Adamantane Carboxylic Acid Hydrocortisone Release (mg)

  23. 24% 37% Non-Inclusion 76% 63% Inclusion aCD Adamantane Hyaluronic Acid-Cyclodextrin Hydrogels: Hydrocortisone Uptake and Release

  24. HA Hydrogels - Drug Delivery Goal: Make HA hydrogel appropriate for a dual tissue engineering and drug delivery application. HA-CD Hydrogel exhibitsincreased loading of hydrocortisone Current Work: Prolonged Release Future Work: Tissue Engineering Context Does delivery of peptides or proteins benefit from HA-CD hydrogel? Which specific tissues could benefit from a HA-CD hydrogel?

  25. Acknowledgements Schmidt Lab: Quan Truong Funding Agencies NSF BES – 021744 NSF BES – 0500969 http://www.bme.utexas.edu/faculty/schmidt

  26. C A B Super-absorbent Hyaluronic Acid Hydrogels Unswollen Saline Swollen Water Swollen

  27. Photocured Hydrogel Film SEM of Hydrogel Film Patterned with Ridges 100 mm

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