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Self‐Assembled Oleic Acid Nanoparticle Mediated Inhibition of Mitogen‐Activated Protein Kinase Signaling in Combination with DNA Damage in Cancer Cells
Author(s) -
Palvai Sandeep,
More Piyush,
Mapara Nikunj,
Nagraj Jyothi,
Chowdhury Rajdeep,
Basu Sudipta
Publication year - 2016
Publication title -
chemnanomat
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.947
H-Index - 32
ISSN - 2199-692X
DOI - 10.1002/cnma.201500195
Subject(s) - hela , cisplatin , mapk/erk pathway , cancer cell , chemistry , protein kinase a , cytotoxicity , kinase , cancer research , dna damage , apoptosis , signal transduction , cancer , microbiology and biotechnology , pharmacology , in vitro , biochemistry , biology , medicine , dna , chemotherapy
Mitogen‐activated protein kinase (MAPK) signaling has been dysregulated in different types of cancers. However, targeting MAPK signaling with small molecules leads to severe toxic side effects to the patients as well as manifestation of drug resistance. To address these, we have developed 120 nm sized self‐assembled, biocompatible, biodegradable oleic acid nanoparticles (OA‐NPs) which can simultaneously contain AZD6244 (MAPK inhibitor) and cisplatin (DNA damaging drug). These OA‐NPs released AZD6244 and cisplatin in increased amount in pH 5.5 compared to pH 7.4 in a slow and sustained manner over 4 days with excellent stability at 4 °C for 2 months in water and in blood circulation mimic for 6 days. Moreover, these OA‐NPs showed much improved in vitro cytotoxicity in cervical cancer (HeLa) and triple negative breast cancer (MDA‐MB‐231) cells at 48 h and in hepatocellular carcinoma (Hep3B) and cisplatin‐resistant hepatocellular carcinoma (Hep3B‐R) cells at 24 h. In HeLa cells, these OA‐NPs induced apoptosis through inhibiting MAPK signaling and damaging DNA after being internalized through macropinocytosis and homed into the acidic lysosomal compartments. These OA‐NPs have the potential to be translated into the clinic for targeting multiple oncogenic signaling pathways and damaging DNA concurrently for augmented efficacy, reduced toxicity, and overcoming drug resistance in next‐generation cancer treatment.