Grafted Polymeric Nanoscale Hydrogels for the Oral Delivery of Chemotherapeutics

Grafted Polymeric Nanoscale Hydrogels for the Oral Delivery of Chemotherapeutics                                           

Amey S. Puranik¹ and Nicholas A. Peppas^1,2,3                                                                                           

 Department of Chemical Engineering¹, Department of Biomedical Engineering² and Division of Pharmaceutics³, The University of Texas at Austin, Austin, TX , 78712

Introduction: Intravenous administration of hydrophobic chemotherapeutics can result in potentially toxic systemic concentrations of therapeutics, causing several deleterious side effects and deterioration of patient quality of life. To remedy these shortcomings, we seek to investigate carriers that can enhance the therapeutic effect of hydrophobic chemotherapeutics, while minimizing side effects and be delivered orally. However, oral delivery of hydrophobic therapeutic agents involves a number of challenges that must be circumvented such as loading hydrophobic chemotherapeutics in conventional hydrophilic polymer carriers, protecting the therapeutic agent from the low pH and degradative enzymes of the stomach, and finally, absorption and transport across the lumen wall to desired cancerous location. In this work, we report the development of grafted polymeric nanoparticles that exhibit increased loading and release of the hydrophobic chemotherapeutic doxorubicin. These nanoscale hydrogels are composed of a pH-responsive hydrophilic poly(methacrylic acid – grafted – ethylene glycol) (P(MAA-g-EG)) hydrogel copolymerized with the hydrophobic monomer tert-butyl methacrylate that can associate with hydrophobic therapeutics.   

Materials and Methods: Synthesis of the nanoparticles was achieved using an emulsion polymerization technique by combining methacrylic acid, tert-butyl methacrylate, poly(ethylene glycol methyl ether methacrylate) (PEGMMA; MW ~2080g/mol), tetraethylene glycol dimethacrylate (TEGDMA), 4-(2-hydroxyethoxy)phenyl-(2-hydroxy-2-propyl)ketone (Irgacure 2959) and water into a small round bottom flask, followed by probe sonication, nitrogen purging and UV-initiated free radical polymerization for 2.5 h. The resulting nanoparticles were dialyzed and lyophilized. Doxorubicin, an intravenously administered drug for a wide range of cancers, was chosen to be a model hydrophobic chemotherapeutic to evaluate the loading and release capabilities of these nanoparticles.               

Results: A set of polymers with varying cross-linking density and core hydrophobicity was synthesized. Nanoparticles demonstrated reversible, pH-responsive swelling with a swollen diameter in the range of 105-125 nm at pH 7.4. In addition, SEM imaging (Figure 1A &1C) was also used to determine the dry diameters of the particles which were in the range of 50-70nm. As the crosslinking density of the nanoparticles was increased, their ability to swell decreased (Figure 1B).

Particles with the lowest degree of cross-linking demonstrated the highest loading of doxorubicin at an overall efficiency of 55% in 2 hours at pH 7.4 (Figure 1D). Release studies of the loaded particles were carried at pH values maintained constant (at 2 as well as 7.4), in addition to varying the pH values from 2 to 7, to better emulate the passage of the nanoparticles through the gastrointestinal tract. The physically encapsulated doxorubicin was completely released at pH 7.4 while still being retained at pH values representative of conditions in the stomach. The physically encapsulated doxorubicin was completely released at pH 7.4 while still being retained at pH values representative of conditions in the stomach. Particles with lower cross-linking displayed the fastest release kinetics with doxorubicin.                                                                  

Conclusions: Our findings suggest that the P(MAA-co-tBMA-g-PEG) nanoscale hydrogels are suitable candidates as carriers that prevent release of chemotherapeutics at the low pH of the stomach during transit in the gastrointestinal tract, while still being able to preferentially load hydrophobic chemotherapeutics. Ongoing and future studies include determining the cytotoxicity of these nanoscale hydrogels against Caco-2 cell lines in addition to evaluating their mucoadhesion capacity.                 

Acknowledgement: This work was supported by the NIH/NCI Center for Oncophysics (CTO PSOC U54-CA-143837).