pluronics : triblock surfactant polymers for use in drug delivery

1. Pluronics®: Triblock Surfactant Polymers for Use in Drug Delivery Rebecca Williams 15 March 2005

3. Current Problems in Drug Delivery High initial release (burst) Loss of bioactivity Thermodynamic fragility of proteins (temperature, pH, agitation) Aggregation Adsorption Delivery to incorrect sites Burst: Each time a person takes a drug, drug concentration in blood rises, peak then declines. If dosage schedule is not followed, plasma levels of drugs are not constantBurst: Each time a person takes a drug, drug concentration in blood rises, peak then declines. If dosage schedule is not followed, plasma levels of drugs are not constant

4. Hydrogels in Drug Delivery Water-swollen cross-linked homopolymers or copolymers Release of drug can be controlled chemically, by diffusion, by solvent, or can be induced external forces Bioerodable Cleavage of backbone, crosslinks, or sidechains Chemical degradation Hydrolysis Enzymatic degradation Varies with tissue and individual Diffusion Controlled: Most common mechanism of drug release Chemically Controlled: As polymer around drug erodes, drug escapes Solvent-Controlled: Glass transition temperature is lowered from that of the original environment OR drug is dissolved and then released from a semi-permiable membrane Release by External Forces: Drug and small magnetic beads dispersed in polymer matrix, exposure to oscillating magnetic field leads to higher rates of drug release Ultrasonic energy (again modulates release of substance) Bioerodable: Conversion of material from one that is insoluble in water to one that is soluble in waterDiffusion Controlled: Most common mechanism of drug release Chemically Controlled: As polymer around drug erodes, drug escapes Solvent-Controlled: Glass transition temperature is lowered from that of the original environment OR drug is dissolved and then released from a semi-permiable membrane Release by External Forces: Drug and small magnetic beads dispersed in polymer matrix, exposure to oscillating magnetic field leads to higher rates of drug release Ultrasonic energy (again modulates release of substance) Bioerodable: Conversion of material from one that is insoluble in water to one that is soluble in water

5. Hydrogels in Drug Delivery Reservoir Devices Matrix Devices Reservoir devices: Drug dispersed or dissolved through hydrogel Released by diffusion Diffusion through polymer matrix is the rate-limiting step Matrix devices: Drug covalently linked to polymer scaffold Drug released as polymer is hydrolyzed (or enzymatically cleaved)Reservoir devices: Drug dispersed or dissolved through hydrogel Released by diffusion Diffusion through polymer matrix is the rate-limiting step Matrix devices: Drug covalently linked to polymer scaffold Drug released as polymer is hydrolyzed (or enzymatically cleaved)

6. Hydrogels in Drug Delivery Bulk Erosion: Rate of water in > rate of hydrolysis Surface Erosion: Rate of hydrolysis > rate of water in Bulk Erosion: Like a sugar cube dropped in water Surface Erosion: Maintains shape but shrinks Bulk Erosion: Like a sugar cube dropped in water Surface Erosion: Maintains shape but shrinks

7. Hydrogels in Drug Delivery Rate of erosion affected by : Hydrophobicity Amount of CH2, CH3 Morphology Crystalline < Amorphous glassy < Amorphous rubbery Chemical stability of backbone Amide < Ester < Anhydride Molecular weight Catalysts, plasticizers, geometry, fabrication Increased Hydrophobility: increases rate of erosion Morphology (rate of erosion): Crystalline < Amorphous glassy < Amorphous rubbery Backbone (rate of erosion): Amide < Ester < Anhydride Higher molecular weight: Slower rate of erosionIncreased Hydrophobility: increases rate of erosion Morphology (rate of erosion): Crystalline < Amorphous glassy < Amorphous rubbery Backbone (rate of erosion): Amide < Ester < Anhydride Higher molecular weight: Slower rate of erosion

8. Introduction to Pluronics® Trade name (BASF) Poloxamers, Tetronics FDA approved for use of drug delivery in vivo Symmetrical hydrophobically associating triblock copolymers Poly(propylene oxide) and poly(ethylene oxide)

9. Introduction to Pluronics®

10. Poly(propylene oxide) Central hydrophobic core Folds in aqueous solution CH3 groups interact by Van der Waals Binds hydrophobic proteins Decreases PE of adsorbed proteins Hydrophobic interactions Decrease Gibbs free energy Increase stability of native conformation

11. Poly(ethylene oxide) Hydrophilic Soluble in water Hydrogen bonding interaction More PEO in Pluronic®, easier to dissolve Moves freely in aqueous solution High entropy ? low protein adsorption

12. Pluronics® in Drug Delivery Readily soluble in aqueous solutions, polar and non-polar organic solvents Applications in emulsification, solubilization, dispersion, thickening, and in coating and wetting agents Two distinct forms Micelles Hydrogels

13. Pluronics® as Micelles Form after passing critical micelle concentration (CMC) or critical micelle temperature (CMT) Suspensions can encapsulate drugs

14. Pluronics® as Micelles

15. Pluronics® as Micelles Enhance membrane permeability Promote transfer across plasma membrane Keep drugs biologically active Stabilize native protein conformation Sustain drug release Better targeting to specific sites Decrease adsorption

16. Pluronics® as Hydrogels Formed by the aggregation of micelles Micelles remain intact Crystal-like structure “Reverse gelatinous” behavior Increasing temperature increases micelle aggregations and viscosity Viscous at body temperature and above Allow gradual, quantifiable diffusion of drugs at significant concentrations

17. Problems with Pluronics® PPO sometimes elicits mild immunogenic response Big PPO, small PEO chains lead to wax-like properties Can adsorb to solid surfaces Influence of drug-Pluronic® complex on drug uptake by cells in vivo not well quantified

18. Innovations in Pluronic® Technology Polymer chains with individual segments that respond to pH, temperature, ionic strength, UV irradiation, and electric fields Modifications of polymer chains to increase circulation time or drug release profile Introduction of targeting moieties Alteration of pharmokinetic properties Environmentally responsive behavior Response to cytokines, inflammatory response Modification of polymer chains is only about 50% effective [4] and can be very difficult because the ends are very inert Modification of polymer chains is only about 50% effective [4] and can be very difficult because the ends are very inert

19. Use of Pluronics® in Cancer Therapy Tissues undergoing rapid proliferation express high levels of LDL receptors Lipoprotein mediated delivery of drugs can increase selective accumulation of drugs in these tissues Pre-association of drugs with LDLs in Pluronics® improves efficacy in vivo Example: Photosensitizers (PDT) Photodynamic therapy (PDT) is a treatment that uses a drug, called a photosensitizer or photosensitizing agent, and a particular type of light. When photosensitizers are exposed to a specific wavelength of light, they produce a form of oxygen that kills nearby cells Photodynamic therapy (PDT) is a treatment that uses a drug, called a photosensitizer or photosensitizing agent, and a particular type of light. When photosensitizers are exposed to a specific wavelength of light, they produce a form of oxygen that kills nearby cells

20. Use of Pluronics® in Cancer Therapy Rapidly proliferating tissues have increased vasculature Particles of 10-200nm can be selectively taken up by tumor cells because of their increased permeability compared to normal tissue cells Pluronic® micelles form on the order of 10’s of nanometers Examples: Taxol® and Doxorubacin

21. Acknowledgements Dr. Joseph McGuire Deborah Gale Katie Weigandt

22. Works Cited 1. University of Illinois at Urbana-Champaign, Office of Technology Management. “Controlled release drug delivery through injectable polymer blends.” www.otm.uiuc.edu/technology.htm. 2. Chowdhary, Rubinah, Isha Sharif, Namarata Chansarkar, David Dolphin, Leslie Ratkay, Sean Delaney and Howard Meadows. “Correlation of photosensitizer delivery to lipoproteins and efficacy in tumor and arthritis mouse models; comparison of lipid-based Pluronic® P123 formulations.” J Parm Parmaceut Sci. 6(2):198-204, 2003. 3. England, Jeremy L. “Stabilization and release effects of Pluronic® F127 in Protein Drug Delivery.” JUS 5(2):17-24, 1999. 4. McGuire, Joseph. BIOE 451 Class Notes. Oregon State University. 26 January 2005. 5. BEH 462/3.962J. Molecular Principles of Biomaterials.

23. Works Cited 6. Alarcon, Carolina de las Heras, Sivanand Pennadam and Cameron Alzexander. “Stimuli response polymers for biomedical applications.” Chem. Soc. Rev. 34: 276-285, 2003. 7. Alexandaridis, Paschalis, T. Alan Hatton. “Poly(ethylene oxide)—poly(propylene oxide)—poly(ethylene oxide) block copolymer surfactants in aqueous solutions and at interfaces: thermodynamics, structure, dynamics, and modeling.” Colloids and Surfaces A: Physiochemical and Engineering Aspects. 96: 1-46 (1995). 8. Adams, Monica L., Afsaneh Lavasanifar, Glen S. Kwon. “Amphiphilic block copolymers for drug delivery.” Journal of Pharmaceutical Sciences. 92(7): 1343-1355 (2003).

24. Works Cited 9. Huang Kui, Bruce Lee and Philip B. Messersmith. “Synthesis and Characterization of self-assembling block copolymers containing adhesive moieties.” Polymer Preprints. 42(2): 147-148 (2001). 10. Peppas, Nikolaos A. Ed. “Hydrogels in Medicine and Pharmacy: Volume 1, Fundamentals.” Florida: CRC Press, Inc. 1986.

25. Questions?

26. Use of Pluronics® in Device Coatings Biofilm formation is a problem Proteins want to adsorb to surfaces Unfolding is energy favorable but leads to loss of activity Healing can be delayed Bacteria also adsorb to surfaces Can cause infections when released Toxins can be released by bacteria

27. Use of Pluronics® in Device Coatings Hydrophobic backbone of Pluronic® preferentially adsorbs to device surface

28. Use of Pluronics® in Device Coatings Proteins in solution see Pluronic® as energetically equivalent to bulk Pluronic® does not gain energetically from protein adsorbtion

29. Problems with Pluronic® Coatings Turbidity in body environment is high ~30% Pluronic® lost Presence of Pluronic® affects protein behavior Pluronics® are synthetic and can be seen by the body as foreign Cell healing is not promoted Cells can’t cover surface adequately

30. Innovations in Pluronic® Coatings Covalent linkage of Pluronic® to device UV, ?-irradiation Create multifunctional surfaces Create surfaces that change with time Create degradable surface coatings