Intelligent Nanogels for the Concurrent Delivery of Hydrophilic and Hydrophobic Chemotherapeutic Agents
Angela M. Wagner1 and Nicholas A. Peppas1,2,3,4
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
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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.