(351d) Hydrogels Decorated with Hydrophobic Nanoparticles for the Oral Delivery of Chemotherapeutics | AIChE

(351d) Hydrogels Decorated with Hydrophobic Nanoparticles for the Oral Delivery of Chemotherapeutics

Authors 

Schoener, C. A. - Presenter, University of Texas at Austin
Hutson, H. - Presenter, University of Texas at Austin
Peppas, N. - Presenter, The University of Texas at Austin


Introduction: Intravenous
(I.V.) administration of chemotherapeutics is adjunct to patients who underwent
surgical removal of tumors. Intravenous delivery involves the systemic flow of
harmful drugs throughout the body which destroy both cancerous cells and
healthy cells non-discriminately. This non-targeted treatment often causes
patients to experience side effects too burdensome for continued treatment
resulting in the reduction or termination of chemotherapeutic administration
before the drug can effectively diminish or oblate remaining tumor cells. A new
set of biopolymer carriers may show promising results for the oral delivery of
chemotherapeutic agents and may reduce patient side effects to anticancer
agents; however, a host of obstacles and challenges must be overcome including
protecting the therapeutic agent from the low pH and degradative enzymes of the
stomach, absorption and transport across the lumen wall to desired cancerous
location, and loading hydrophobic chemotherapeutics in conventional hydrophilic
polymer carriers. Recently, we have developed hydrophobic nanoparticles
composed of poly(methyl methacrylate) (PMMA) photoencapsulated within a
pH-responsive hydrophilic poly(methacrylic acid ? grafted ? ethylene glycol)
(P(MAA-g-EG)) hydrogel. In this way, individual characteristics of each polymer
network can be uniquely combined to give rise to a new set of physical
properties appropriate for oral delivery of chemotherapeutics.

Materials and Methods: Using the
following methods, a biopolymer composed of hydrophobic and hydrophilic
properties was synthesized. First, nanoparticles were synthesized using a
surfactant-free emulsion polymerization by combining methyl methacrylate
(hydrophobic monomer), benzoyl peroxide (thermal catalyst), tetraethylene
glycol dimethacrylate (TEGDMA; crosslinker), and water into a small round
bottom flask and reacting for 3 h at 75 ºC. The resulting nanoparticles were
dialyzed and freeze dried to remove unreacted components. Second, methacrylic
acid, poly(ethylene glycol methyl methacrylate) (PEGMMA; MW ~1000g/mol), TEGDMA,
and 1-hydroxycyclohexylbenzophenone (Irgacure 184, photocatalyst), and either 1%,
2.5%, or 5% nanoparticles (by weight of hydrophilic monomer) were dissolved in
ethanol and water and exposed to UV light for 30 min between glass slides. The
resulting hydrogel was washed and dried in vacuum.

Swelling experiments were carried out in
0.1 M 3, 3-Dimethylglutaric Acid buffers between pH 3.2 and 7.6. Scanning
electron microscopy (SEM) was used to determine the size of hydrophobic
nanoparticles. Fluorescein, a cancer drug analogue, was loaded into crushed
hydrogel particles (75 ? 500 mm)
by imbibing in 2% (v/v) Dimethyl Sulfoxide in 1X PBS (pH ~ 7.4).

Results and
Discussion:
SEM
imaging (Figure 1) indicated nanoparticles were 200 nm in diameter and
monodisperse. As the percentage of nanoparticles increased in the hydrogel the
ability to swell decreased. This illustrates the molecular influence
nanoparticles may have on the hydrogel including increased hydrogen bonding
between both polymer networks, reduction in free volume necessary for polymer
chain motion, or decreased wetting due to hydrophobic properties of PMMA. All
nanoparticle encapsulated hydrogels showed collapsed states at low pH's
indicating protection from the stomach during oral transit. The loading
efficiency was 41 ± 3%, 47 ± 4%, 51 ± 1%, and 38% ± 2% for the 5%,
2.5%, 1% nanoparticle hydrogel and pure P(MAA-g-EG) (control) hydrogel,
respectively.

 

Conclusions: The PMMA
nanoparticles encapsulated in the P(MAA-g-EG) hydrogel can provide the
necessary protection during oral transit while still preferentially loading
hydrophobic drugs. Current and future investigations include release studies of
loaded hybrid materials in both constant pH (7.4) and variable pH (2 to 7) to
mimic gastrointestinal conditions. We are also developing protocols for the loading
and unloading of Fluorouracil, a cancer drug. Finally, we will be testing the cytotoxicity
of these materials against Caco-2 cell lines.