Pluronics: Triblock Surfactant Polymers for Use in Drug Delivery

Rebecca Williams 15 March 2005

Presentation Outline

Background Current Problems in Drug Delivery Hyrdogels in Drug Delivery Introduction to Pluronics Poly(propylene oxide) Poly(ethylene oxide) Pluronics in Drug Delivery Pluronics as Micelles Pluronics as Hydrogels Problems with Pluronics Innovations in Pluronic Technology Use of Pluronics in Cancer Therapy

Current Problems in Drug Delivery

High initial release (burst) Loss of bioactivity

2,3 1

Thermodynamic fragility of proteins (temperature, pH, agitation) 2 Aggregation Adsorption

Delivery to incorrect sites

Hydrogels in Drug Delivery

Water-swollen cross-linked homopolymers or 10 copolymers Release of drug can be controlled chemically, by diffusion, by solvent, or can be induced 10 external forces 4 Bioerodable Cleavage of backbone, crosslinks, or sidechains Chemical degradation

Hydrolysis Varies with tissue and individual

Enzymatic degradation

Hydrogels in Drug Delivery

Reservoir Devices

Matrix Devices

Hydrogels in Drug Delivery

Bulk Erosion:

Surface Erosion:
Rate of hydrolysis > rate of water in
Time

Rate of water in > rate of hydrolysis

Degree of Degradation

BEH 462/3.962J. Molecular Principles of Biomaterials.

Hydrogels in Drug Delivery

Rate of erosion affected by :

Hydrophobicity

Amount of CH2, CH3

Crystalline < Amorphous glassy < Amorphous rubbery Amide < Ester < Anhydride

Morphology

Chemical stability of backbone

Molecular weight Catalysts, plasticizers, geometry, fabrication

Introduction to Pluronics

Trade name (BASF) Poloxamers, Tetronics 8 FDA approved for use of drug delivery in vivo Symmetrical hydrophobically associating 2,5 triblock copolymers Poly(propylene oxide) and poly(ethylene oxide)

(PEO)b(PPO)a(PEO)b

Introduction to Pluronics
CH3 HO(CH2-CH2-0)n(CH2-CH2-O)m(CH2-CH2-0)nH

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

3
3

Hydrophobic interactions Decrease Gibbs free energy Increase stability of native conformation

Poly(ethylene oxide)
Hydrophilic Soluble in water

Hydrogen bonding interaction 4 More PEO in Pluronic , easier to dissolve

Moves freely in aqueous solution High entropy low protein adsorption

Protein Protein S < 0

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

2
2,6

Micelles Hydrogels

Pluronics as Micelles

Form after passing critical micelle concentration (CMC) or critical micelle 5,7 temperature (CMT) Suspensions can encapsulate drugs
Pluronic Encapsulated Drug Aqueous Solution

Drug

Pluronic
Aqueous Solution

Pluronics as Micelles
Pluronic Encapsulated Drug

Pluronic Micelle
Drug

Pluronics as Micelles

Enhance membrane permeability

2 2

Promote transfer across plasma membrane

3

Keep drugs biologically active

2,3,4,5,8

Stabilize native protein conformation

2

Sustain drug release Better targeting to specific sites Decrease adsorption

Pluronics as Hydrogels

Formed by the aggregation of micelles

Micelles remain intact Crystal-like structure

Reverse gelatinous behavior

6,7

Increasing temperature increases micelle aggregations and viscosity 3 Viscous at body temperature and above

Allow gradual, quantifiable diffusion of drugs at significant concentrations

Problems with Pluronics

PPO sometimes elicits mild immunogenic response Big PPO, small PEO chains lead to waxlike properties Can adsorb to solid surfaces Influence of drug-Pluronic complex on drug uptake by cells in vivo not well quantified

4,9
4 4 2

Innovations in Pluronic Technology

Polymer chains with individual segments that respond to pH, temperature, ionic strength, 6 UV irradiation, and electric fields Modifications of polymer chains to increase 8 circulation time or drug release profile 9 Introduction of targeting moieties 6 Alteration of pharmokinetic properties

Environmentally responsive behavior Response to cytokines, inflammatory response

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

2 2

Example: Photosensitizers (PDT)

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 10s of nanometers

6 4

Examples: Taxol and Doxorubacin

Acknowledgements
Dr.

Joseph McGuire Deborah Gale Katie Weigandt

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.

Works Cited

6. Alaron, 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).

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): 147148 (2001). 10. Peppas, Nikolaos A. Ed. Hydrogels in Medicine and Pharmacy: Volume 1, Fundamentals. Florida: CRC Press, Inc. 1986.

Questions?

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

Use of Pluronics in Device Coatings

Hydrophobic backbone of Pluronic preferentially adsorbs to device surface

Adsorbed Pluronic

Pluronic

Surface of Device

Surface of Device

Use of Pluronics in Device Coatings

Proteins in solution see Pluronic as energetically equivalent to bulk Pluronic does not gain energetically from protein adsorbtion

Protein Protein S < 0

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 cant cover surface adequately

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