- Pluronics

Pluronics®: Triblock Surfactant Polymers for Use in Drug Delivery

Rebecca Williams15 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

Thermodynamic fragility of proteins (temperature, pH, agitation)

AggregationAdsorption

Delivery to incorrect sites

1

2,3

2

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

BioerodableCleavage of backbone, crosslinks, or

sidechainsChemical degradation

HydrolysisEnzymatic degradation

Varies with tissue and individual

4

10

10


Reservoir Devices

Matrix Devices

Degree ofDegradation


Bulk Erosion: Rate of water in >

rate of hydrolysis

Surface Erosion: Rate of hydrolysis >

rate of water in

BEH 462/3.962J. Molecular Principles of Biomaterials.

Time


Rate of erosion affected by :Hydrophobicity

Amount of CH2, CH3

MorphologyCrystalline < Amorphous glassy < Amorphous

rubberyChemical stability of backbone

Amide < Ester < AnhydrideMolecular weightCatalysts, plasticizers, geometry, fabrication

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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)

(PEO)b—(PPO)a—(PEO)b

2,5

8


HO—(CH2-CH2-0)n—(CH2-CH2-O)m—(CH2-CH2-0)n—H

CH3

HO—(CH2-CH2-0)n—(CH2-CH2-O)m—(CH2-CH2-0)n—H

CH3

Poly(propylene oxide)

Central hydrophobic coreFolds in aqueous solution CH3 groups interact by Van der WaalsBinds hydrophobic proteinsDecreases PE of adsorbed proteins

Hydrophobic interactionsDecrease Gibbs free energy Increase stability of native conformation

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3

3

Poly(ethylene oxide)HydrophilicSoluble in water

Hydrogen bonding interactionMore PEO in Pluronic®, easier to dissolve

Moves freely in aqueous solutionHigh entropy → low protein adsorption

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4

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ProteinProtein

ΔS < 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 formsMicellesHydrogels

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2,6

Pluronics® as Micelles

Form after passing critical micelle concentration (CMC) or critical micelle temperature (CMT)

Suspensions can encapsulate drugs

Drug

Pluronic®

AqueousSolution

AqueousSolution

Pluronic® Encapsulated Drug

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Pluronic® Micelle

Drug

Pluronic® Encapsulated Drug


Enhance membrane permeabilityPromote transfer across plasma membrane

Keep drugs biologically activeStabilize native protein conformation

Sustain drug releaseBetter targeting to specific sitesDecrease adsorption

2

2

3

2,3,4,5,8

2

Pluronics® as Hydrogels

Formed by the aggregation of micellesMicelles remain intactCrystal-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

6,7

7

3

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

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4

4

2

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

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9

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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 vivoExample: Photosensitizers (PDT)

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2

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 nanometersExamples: Taxol® and Doxorubacin

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4

Acknowledgements

Dr. Joseph McGuireDeborah GaleKatie Weigandt

Works Cited1. 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 Cited6. Alarćon, 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): 147-148 (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 problemProteins want to adsorb to surfaces Unfolding is energy favorable but leads to

loss of activityHealing can be delayed

Bacteria also adsorb to surfacesCan cause infections when releasedToxins can be released by bacteria


Hydrophobic backbone of Pluronic® preferentially adsorbs to device surface

Pluronic®

Surface of Device Surface of Device

Adsorbed Pluronic®


Proteins in solution see Pluronic® as energetically equivalent to bulk

Pluronic® does not gain energetically from protein adsorbtion

ProteinProtein

ΔS < 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 promotedCells can’t cover surface adequately

Innovations in Pluronic® Coatings

Covalent linkage of Pluronic® to deviceUV, γ-irradiation

Create multifunctional surfacesCreate surfaces that change with timeCreate degradable surface coatings

- Pluronics

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