(512f) Intelligent Nanogels for the Concurrent Delivery of Hydrophilic and Hydrophobic Chemotherapeutic Agents

Intelligent Nanogels for the Concurrent
Delivery of Hydrophilic and Hydrophobic Chemotherapeutic Agents

Angela M. Wagner¹ and
Nicholas A. Peppas^1,2,3,4

¹Department of Chemical
Engineering, ²Department of Biomedical Engineering, ³College
of Pharmacy, and ⁴Institute for Biomaterials, Drug Delivery, and
Regenerative Medicine, The University of Texas at Austin, Austin, TX 78712

Author Correspondence: angelamwagner@utexas.edu,
peppas@che.utexas.edu

The
lack of specificity in traditional chemotherapeutic administration typically
leads to significant systemic toxicity and requires patients to wait for long
periods between treatments.  During this
time, cancerous cells have an opportunity to recover from the treatment.  One method to improve treatment efficiency is
to use nanoparticle systems as carriers for chemotherapeutic agents.  Hydrogel nanocarriers have demonstrated their
suitability as a customizable multicomponent system for the intracellular delivery
of therapeutic agents, and the physical properties of these carriers can be
designed to take advantage of passive targeting (via the enhanced permeability
and retention effect).  Our current work
aims to develop a responsive hydrogel platform to enhance treatment efficiency through
the synchronous delivery of hydrophilic and hydrophobic anticancer agents for
combination therapy. 

Our
lab has previously shown success using cationic hydrogels to deliver
hydrophilic therapeutics such as insulin and siRNA.  Here, poly(2-(diethylamino)ethyl methacrylate)-g-poly(ethylene
glycol methyl methacrylate) nanogels have been developed for the intravenous delivery
of multiple chemotherapeutic agents.  The
nanogels entrap anticancer agents at physiological conditions and release the
therapeutic agents in response to the intracellular environment.  To improve hydrophobic drug-polymer
interactions, we modified the P(DEAEMA)-g-PEGMA nanogel via copolymerization
with a series of n-alkyl methacrylate hydrophobic monomers and investigated the
impact of nanogels physical characteristics. 

Nanogels
were synthesized using an oil-in-water emulsion UV-initiated polymerization
using tetra ethylene glycol dimethacrylate (TEGDMA) as a crosslinking agent
with a crosslinking density of 2.5 mole %. 
The impact of n-alkyl methacrylate monomer inclusion was investigated
through systematic variation of monomer functionality and chain length.  Monomers included methyl methacrylate, ethyl
methacrylate, isopropyl methacrylate, tert-butyl methacrylate, phenyl
methacrylate, n-hexyl methacrylate, and 2-ethylhexyl methacrylate.  The physical properties of the resulting nanogels
were then compared, utilizing dynamic light scattering, zeta potential,
titration, pyrene fluorescence, and hemolysis assays to understand the
influence of polymer composition on swelling ratio, surface charge, pKa,
relative hydrophobicity and hydrophile-hydrophobe phase transition, and
membrane disruption capabilities.  Varying
the type and ratio of n-alkyl methacrylate monomer allows for precise control
over the nanogel pKa.  Loading and
release experiments were performed to determine the improvement of loading
efficiency and simultaneous release of hydrophilic (Cisplatin) and hydrophobic
(Paclitaxel) chemotherapeutic agents.  The
rational design and characterization of P(DEAEMA)-g-PEGMA networks was
necessary for tailoring the cationic nanogel system as a platform for the synchronous
delivery of multiple chemotherapeutic agents. 

Acknowledgements:  This work was supported by a grant from the
National Institutes of Health (R01-EB-000246-22). We also acknowledge the
assistance of Rishabh Shah and Balark Chetan.