Facile synthesis of aquo-cisplatin arsenite multidrug nanocomposites for overcoming drug resistance and efficient combination therapy.

Cisplatin (CDDP) and arsenic trioxide (ATO), two representative inorganic anticancer drugs, have been successful in the treatment against several kinds of malignancies. However, combination therapy with these two drugs in clinical application suffers from poor pharmacokinetics, serious side effects, and drug resistance of the tumor. Herein, we report a carrier-free aquo-cisplatin arsenite multidrug nanocomposite loaded with cisplatin and arsenic trioxide prodrugs simultaneously. This nanocomposite achieves a high loading capacity and pH-dependent controlled release of the drugs. Because of these features, this nanocomposite shows better in vitro toxicity against various carcinoma cell lines than either the single drug or free drug combination, promotes the synergistic effect of cisplatin and arsenic trioxide, and significantly inhibits the growth of tumors in vivo. Furthermore, cisplatin and arsenic trioxide in this nanocomposite can realize a coordination of both enhanced DNA damage and DNA repair interference within cisplatin-resistant cells, which results in overcoming the drug resistance effectively. Gene expression profiles demonstrate the reduced expression of proto-oncogenes and DNA damage repair related genes MYC, MET, and MSH2, along with the increase of tumor suppressor genes PTEN, VHL, and FAS after the nanocomposite treatment. This type of multidrug nanocomposite offers an alternative and promising strategy for combination therapy and overcoming drug resistance.

Synthesis and characterisation of arsenic nanoparticles and its interaction with DNA and cytotoxic potential on breast cancer cells.

Therapeutic applications of arsenic trioxide (ATO) are limited due to their severe adverse effects. However, nanoparticles of ATO might possess inimitable biologic effects based on their structure and size which differ from their parent molecules. Based on this conception, AsNPs were synthesized from ATO and comparatively analysed for their interaction mechanism with DNA using spectroscopic & electrochemical techniques. Finally, anti-proliferative activity was assessed against different breast cancer cells (MDA-MB-231 & MCF-7) and normal non-cancerous cells (HEK-293). The DNA interaction study revealed that AsNPs and ATO exhibit binding constant values in the order of 106 which indicates strong binding interaction. Binding of AsNPs did not disturb the structural integrity of DNA, on the other hand an opposing effect was observed with ATO through biophysical techniques. Further, in vitro study, confirms cytotoxicity of ATO and AsNPs against different cells, however at particular concentration ATO exhibits more cytotoxicity than that of AsNPs. Furthermore, cytotoxicity was confirmed through acridine orange and comet assay. In conclusion, AsNPs are safer than ATO with comparable efficacy and might be a suitable candidate for the development of novel therapeutic agent against breast cancer and other solid tumours.