Hydrogels Decorated with Hydrophobic Nanoparticles for the Oral Delivery of Chemotherapeutics

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 șC. 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.