Effect of Periodate-Induced Cross-linking on Dual Anticancer Drug Release from Poly(2-isopropyl-2-oxazoline)/Tannic Acid-Based Layer-by-Layer Microparticles.

This study reports, first, on the preparation and cross-linking of multilayers composed of poly(2-isopropyl-2-oxazoline--ethyleneimine) (PiPOX-PEI) and tannic acid (TA). PiPOX was synthesized by cationic ring-opening polymerization (CROP) and partially hydrolyzed, yielding a random copolymer PiPOX-PEI. It was then coassembled at the surface with TA using the layer-by-layer (LbL) technique. Multilayers were exposed to NaIO solution to induce covalent bond formation between PEI units of PiPOX-PEI and TA. Cross-linking with NaIO enhanced the stability of the multilayers, especially under basic conditions. Second, the potential of PiPOX-PEI and TA multilayers as a stimuli-responsive dual drug-releasing platform was examined using curcumin (CUR) and doxorubicin (DOX) as model drugs. These drugs were chosen as they can act in a combinatorial manner to increase cell death. The surface of CUR-containing CaCO microparticles was modified with PiPOX-PEI and TA multilayers and postloaded with DOX. We found that LbL particles could release DOX in a pH-responsive manner, whereas temperature-induced release was observed only when the temperature was raised above 40 °C. The DOX and CUR released from the LbL particles could act synergistically on HCT-116 cells. Cross-linking increased the DOX release from LbL particles but decreased the CUR release from the core. Corroborating the release data, the synergy observed with the non-cross-linked particles was lost with the cross-linked particles, and the decrease in the viability of HCT-116 cells was attributed mainly to the release of DOX. Overall, we describe here NaIO-induced cross-linking of PiPOX-PEI/TA LbL films, the effects of pH, temperature, and cross-linking on DOX and CUR release from multilayers, and comparison of the combinatorial effect of DOX and CUR for cross-linked and non-cross-linked LbL microparticles through cell viability assays.