Temperature sensitive nanogels for drug delivery and methods to improve nanoparticle recovery

Sarah Hutchinson, Jonathan T. Peters, and Nicholas A. PeppasDepartment of Chemical Engineering, Department of Biomedical Engineering

Biomaterials, Drug Delivery and Regenerative Medicine The University of Texas at Austin, Austin, TX 78712

Targeted Drug Delivery

Solubility of fluorescein and PNIPMAAm/PPhMA Challenges/Future Work

Introduction and Scope of WorkThermoresponsive nanogelsTemperature sensitive polymers improve drug efficiency by facilitating delivery to targeted area within a desired concentration and time interval. Nanogels such as Poly(N-isoproyl acrylamide) (PNIPAAm) entrap drugs and act as nanocarriers.PNIPAAm encapsulates and carry drug to target tumor cells.EPR facilitates retention of encapsulated drug in tumor vasculature. Surface modifications increase LCST ≈ 40 °CAfter reaching target tumor cells, an external stimulus:

Heats PNIPMAAm above LCST Collapses nanogel network Forces drug out

ObjectiveThe current challenge is determining a reproducible and convenient methods for drug loading that will achieve high entrapment and nanoparticle recovery.

EtOH has shown high solvent volumes to dissolve PNIPMAAm/PPhMA

DMF dissolves polymer moderately but current dialysis bags (Spectra/Por Regenerated Cellulose) have limited exposure.

Future work is to measure the effectiveness of dialysis to load therapeutic drugs.

Determine drug loading efficiency of fluorescein in the PNIPMAAm/PPhMA (per solven)

Determine the nanopartical yield

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2. Lyon, A. L. (n.d.). “Smart Nanoparticles” stimuli sensitive hydrogel particles. Lecture presented at Georgia Institute of Technology.

3. Zhang, Z., & Feng, S.-S. (2006). Self-assembled nanoparticles of poly(lactide)-Vitamin E TPGS copolymers for oral chemotherapy. International Journal of Pharmaceutics, 324, 191-198. 

4. Sanson, C., Christophe, C., Le Meins, J., Soum, A., Thevenot, J., Garanger, E., & Lecommandoux, S. (2010). A simple method to achieve high doxorubicin loading in biodegradable polymersomes. Journal of Controlled Release. http://10.1016/j.jconrel.2010.07.123 

Acknowledgements I want to thank my research mentor Jonathan Peters for teaching me about his research and encouraging me to ask questions that would help me design my own experiment.

References

Stimulus

PEG

Tumor cells

PNIPMAAm gel network

Drug

T>LCST

Problematic Drug Release

Toxic Level

Desirable – Controlled Release

Minimum effective level

TimeStimulus

Solvent TestingExperimentCompare the drug loading efficiency and nanoparticle recovery between three solvents via dialysis. Dialysis is a drug loading technique that is simpler than other methods because it avoids stabilizers and emulsifiers. Fluorescein was substituted for the doxorubicin and PNIPMAAm/PPhMA (core/linker) was used for nanoparticle

EtOH DMSO DMF

Methods1) Test solubility of

fluorescein in solvents by adding solvent to known amount of fluorescein.

EtOH DMSO DMF

EtOH DMSO DMF

1:100 NP:fluroescein

1:10 NP:fluroescein

1:1 NP:fluroescein

2) For each solvent test three ratios of NP to fluorescein

3) Dialyze each homogenous solution against filtered water

Synthesis of Thermo-responsive nanoparticles

Ammonium Persulfate (APS)

Initiator

NIPAAm N’N’-Methylene-bis-acrylamide

(MBAAm)

Sodium dodecyl sulfate (SDS)

Monomer SurfactantCrosslinker

Inject APS/water solutionand react for 6 hours

Dialysis against water for 3 weeks

Dissolve NIPMAAm MBAAm, SDS in filtered water in round bottom flask

Heat solution to 70 °C in an oil bath and N2 purge for 30 min(presence of O2 stops reaction)