(617e) 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).