Hyaluronic acid engineered nano-micelles loaded with 3, 4-difluorobenzylidene curcumin for targeted killing of CD44+ stem-like pancreatic cancer cells.
Biomacromolecules. 2015 Aug 24;
Authors: Kesharwani P, Banerjee S, Padhye S, Sarkar FH, Iyer AK
Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenotype. It has been established that pancreatic cancers overexpressing CD44 receptors (a target of hyaluronic acid; HA) is one of the major contributors for causing MDR. Therefore, targeted killing of CD44 expressing tumor cells using HA based active targeting strategies may be beneficial for eradicating MDR-pancreatic cancers. Here, we report the synthesis of a new HA conjugate of co-poly(styrene maleic acid) (HA-SMA) that could be engineered to form nano-micelles with a potent anticancer agent, 3, 4-difluorobenzylidene curcumin (CDF). The anticancer activity of CDF loaded nano-micelles against MiaPaCa-2 and AsPC-1 human pancreatic cancer cells revealed dose-dependent cell killing. Results of cellular internalization further confirmed better uptake of HA engineered nano-micelles in triple-marker positive (CD44+/CD133+/EpCAM+) pancreatic CSLCs compared with triple-marker negative (CD44-/CD133-/EpCAM-) counterparts. More importantly, HA-SMA-CDF exhibited superior anti-cancer response towards CD44+ pancreatic CSLCs. Results further confirmed that triple-marker positive cells treated with HA-SMA-CDF caused significant reduction in CD44 expression and marked inhibition of NF-κB that in-turn can mitigate their proliferative and invasive behavior. Conclusively, these results suggest that the newly developed CD44 targeted nano-micelles may have great implications in treating pancreatic cancers including the more aggressive pancreatic CSLCs.
PMID: 26302089 [PubMed - as supplied by publisher]