Hyaluronic Acid Engineered Nanomicelles Loaded with 3,4-Difluorobenzylidene Curcumin for Targeted Killing of CD44+ Stem-Like Pancreatic Cancer Cells

Abstract

Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenotypes. 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 copoly(styrene maleic acid) (HA-SMA) that could be engineered to form nanomicelles with a potent anticancer agent, 3,4-difluorobenzylidene curcumin (CDF). The anticancer activity of CDF loaded nanomicelles 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 nanomicelles 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 anticancer response toward 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 nanomicelles may have great implications in treating pancreatic cancers including the more aggressive pancreatic CSLCs.

Hyaluronic acid-conjugated polyamidoamine dendrimers for targeted delivery of 3,4-difluorobenzylidene curcumin to CD44 overexpressing pancreatic cancer cells

“…The observed results may be attributed to overexpression of comparatively more CD44 receptors in MiaPaCa-2 cells, which allow more amount of CDF delivered by the HA conjugated formulation (HA-PAMAM-CDF) within the cells and displayed better cell killing. Our results are in agreement with reported literature[5,26].…”

L-Ferritin targets breast cancer stem cells and delivers therapeutic and imaging agents

“…Its anti-cancer activity is operated through modulation or inhibition of multiple molecular pathways [37]. Furthermore, during the past few years, a number of studies have suggested that Curcumin may have direct or indirect influence on CSC self-renewal pathways, including Wnt/b-catenin, sonic hedgehog, and Notch [38–40]. Another important property is that, unlike other known chemotherapeutic compounds, Curcumin does not cause any damage to normal cells [41].…”

Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy

“…These combined data suggest that micelles utilize the interaction of HA with CD44 receptors to enter the cytosol via receptor-mediated endocytosis [50]. Similar HA blockade studies by other groups have repeatedly confirmed this finding [51–53]. …”

“…Free CDF showed a high level of toxicity to pancreatic cancer cells in a MTT assay, and this potency was further increased by targeted delivery in the HA nanomicelle formulation. By comparing targeted HA-SMA-CDF micelles with nontargeted SMA-CDF micelles, the authors found that there was an increased cellular uptake and in vitro carcinoma toxicity resulting from conjugation with HA [53]. Their results indicate a potential for targeted treatment of CD44-expressing pancreatic CSCs, which are known to contribute to the resistance of a tumor to conventional cancer therapy [53,70,71].…”

“…By comparing targeted HA-SMA-CDF micelles with nontargeted SMA-CDF micelles, the authors found that there was an increased cellular uptake and in vitro carcinoma toxicity resulting from conjugation with HA [53]. Their results indicate a potential for targeted treatment of CD44-expressing pancreatic CSCs, which are known to contribute to the resistance of a tumor to conventional cancer therapy [53,70,71]. Therefore, pancreatic cancer stem cells are an ideal target for effective therapy, and their overexpression of the CD44 receptor renders them responsive to treatment with HA-conjugated micelles.…”