Hyaluronic acid cloaked oleic acid nanoparticle inhibits MAPK signaling with sub-cellular DNA damage in colon cancer
RAS-RAF-MEK-ERK cascade in mitogen activated protein kinase (MAPK) signaling has been highjacked in colon cancer. However, selective targeting of MAPK signaling components in colon cancer cells remained a surmountable challenge. To address these, we have engineered hyaluronic acid cloaked 154 nm diameter oleic acid nanoparticles (HA-OA-NPs) comprising ERK inhibitor (AZD6244) and DNA damaging drug (cisplatin) simultaneously. Dual drugs were slowly released from the HA-OA-NPs at acidic pH (pH = 5.5) over 72 h. HCT-116 colon cancer cells engulfed these HA-OA-NPs by CD44 receptor and clathrin dependent endocytosis pathways followed by accumulating into lysosomes over 6 h. These HA-OA-NPs inhibited phosphorylation of extracellular signal-regulated kinases (ERK1 and ERK2) and damaged sub-cellular DNA to induce remarkable colon cancer cell (HCT-116 and DLD-1) death in contrast to free drug cocktail at 24 h post incubation. Due to the biocompatibility and biodegradability of the nanoparticle components, HA-OA-NPs could be translated into clinics as platform for synchronized inhibition of multiple targets for improved therapeutic efficacy in colon cancer patients.