1) Thermoresponsive nanogels made of polymers like PNIPAAm can encapsulate and deliver drugs to targeted tumor cells. When heated above a threshold, the nanogels collapse and release the drug.
2) The objective is to determine a reproducible method for high drug loading and nanoparticle recovery during drug loading. Different solvents will be tested for dissolving the polymer and drug, including ethanol, DMSO and DMF.
3) An experiment will compare the drug loading efficiency and nanoparticle recovery of fluorescein-loaded PNIPAAm/PPhMA nanoparticles prepared using the three solvents via dialysis against water. Solubility and different polymer to drug ratios
1. Temperature sensitive nanogels for drug delivery and
methods to improve nanoparticle recovery
Sarah Hutchinson, Jonathan T. Peters, and Nicholas A. Peppas
Department 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 Work
Thermoresponsive nanogels
Temperature 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 °C
After reaching target tumor cells, an external stimulus:
Heats PNIPMAAm above LCST
Collapses nanogel network
Forces drug out
Objective
The 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
1. Na, K., Hee Lee, K., Haeng Lee, D., & Han Bae, Y. (2006). Biodegradable thermo-sensitive
nanoparticles from poly(lactic acid)/poly(ethylene glycol) alternating multi-block copolymer for
potential anti-cancer drug carrier. European Journal of Pharmaceutical Sciences, 27, 115-122.
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 Testing
Experiment
Compare 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
Methods
1) 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
solution
and 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)
Editor's Notes
For Cancer section if summary/intro needed:
Advances in detection, imaging, and surgical procedures has resulted in a downward trend for deaths associated with many cancer types. However, delivery of chemotherapeutics still relies heavily on intravenous treatment (IV). IV treatment often results in poor patient compliance, significant discomfort, and steep financial costs. Recent developments in polymeric drug delivery systems (DDS) may have the ability to orally deliver a host of traditional hydrophobic cancer drugs. These systems can be fabricated and tailored to deliver drugs in a highly targeted, effective matter based upon cancer drug properties and cancer types. The final goal of this research is that patients be able to orally self administer drug treatment and thus improve patient compliance and quality of life.
To help increase uptake and delivery of hydrophobic agents, we have developed two hybrid anionic pH-responsive hydrogels composed of both hydrophobic and hydrophillic components.