Polymer carriers with amphiphilic properties for the oral delivery of therapeutic agents for cancer treatment
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Polymer carriers composed of poly(methacrylic acid – grafted – ethylene glycol) (P(MAA-g-EG)) hydrogels modified with poly(butyl acrylate) (PBA) to form IPNs or photopolymerized in the presence of poly(methyl methacrylate) (PMMA) nanoparticles were investigated for their use in the oral delivery of therapeutic agents for cancer treatment. The P(MAA-g-EG) hydrogel provided pH-responsive and hydrophilic properties while PBA or PMMA polymers provided hydrophobic properties. An inulin- doxorubicin conjugate was also synthesized to provide local, direct targeting for the treatment of colon cancer. The pH-responsive behavior of these polymer systems was investigated using equilibrium and dynamic swelling experiments. In gastric conditions (low pH) all materials were in a collapsed state and in intestinal conditions (neutral pH) these material were swollen. The equilibrium swelling ratios decreased with increasing hydrophobic content for both IPNs and compositions of P(MAA-g-EG) containing nanoparticles. The loading efficiencies of doxorubicin, a chemotherapeutic drug, were as high as 56% for IPNs and the IPN structure and hydrophobicity influenced the loading efficiency values. The loading efficiency of doxorubicin using P(MAA-g-EG) containing nanoparticles was as high as 64% and increased with increasing weight percent of PMMA nanoparticles in the P(MAA-g-EG) hydrogel. In gastric conditions (low pH), IPNs released a majority of the encapsulated doxorubicin (up to 70%) as compared to the P(MAA-g-EG) containing nanoparticles (up to 27%). P(MAA-g-EG) containing nanoparticles was used to load and release the inulin-doxorubicin conjugate. Loading efficiency was 54% and release profiles behaved similarly as doxorubicin. Both polymer systems were biocompatible with Caco-2, HT29-MTX, and SW620 cell models over concentration ranging from 1 mg/mL to 5 mg/mL and exposure times lasting from 2 hr to 24 hr. The 75/25 IPN exhibited the highest degree of mucoadhesion and the P(MAA-g-EG)-5.0NP the lowest. Using the same cell lines and cytotoxicity assays, the inulin-doxorubicin conjugate was determined to be more toxic than free doxorubicin at equal doxorubicin concentrations. Doxorobuicin and inulin-doxorubicin conjugate were tested for transport across Caco-2/HT29-MTX cell monolayers with and without the presence of unmodified P(MAA-g-EG) or P(MAA-g-EG)-5.0NP microparticles. The presence of the microparticles did not increase transport across the cell monolayer which is advantageous for local, direct delivery to the colon.