Dimethylcurcumin

Polymer-based nanoparticles with tumor-targeting ability, controlled-release properties and good biocompatibility are of great interest for anticancer drug delivery.Herein, two amphiphilic reduction-responsive copolymers self-assembled nanoparticles (mPEG-Cys-PCL and mPEG-Ami-PCL) along with their inert counterpart (mPEG-Hex-PCL) were prepared and evaluated.These three copolymers were synthesized by conjugating mPEG and PCL with different linkers and characterized by proton NMR spectrometry, flourier transform IR spectrometry and gel permeation chromatog.Nile red (NR) was loaded into the prepared nanoparticles as a model drug to study the in vitro drug release, cellular uptake amount and biodistribution.Dimethylcurcumin (DMC) was loaded into the prepared nanoparticles to study the in vitro antitumor effect.The results show that NR@mPEG-Cys-PCL and NR@mPEG-Ami-PCL nanoparticles exhibit glutathione (GSH)-triggered drug release and NR@mPEG-Ami-PCL nanoparticles display enhanced GSH-responsiveness as compared to NR@mPEG-Cys-PCL.Moreover, NR@mPEG-Ami-PCL nanoparticles possess enhanced cellular uptake amount as compared to NR@mPEG-Hex-PCL and NR@mPEG-Cys-PCL nanoparticles.DMC@mPEG-Ami-PCL nanoparticles possess the highest in vitro antitumor effect.In biodistribution study, both NR@mPEG-Cys-PCL and NR@mPEG-Ami-PCL nanoparticles show reduced organ distribution and similar tumor accumulation as compared to NR@mPEG-Hex-PCL nanoparticles.The mPEG-Ami-PCL nanoparticles developed in this work show great potential for anticancer drug delivery.

A panel of ferrocenyl-substituted curcumin derivatives has been designed and synthesized as protein tyrosine phosphatase proto-oncogene SHP-2 inhibitors. Antiproliferative activities of the synthesized compounds were tested against colorectal cancer cell lines (including RKO, SW480, and CT26). Compound 3f showed excellent activities against the tested cell lines with IC₅₀ values of 5.72, 3.71, and 1.42 μM. The cytotoxicity of compound 3f was investigated on human normal colon epithelial cell line NCM460 with IC₅₀ values of 929 μM compared to curcumin with IC₅₀ values of 431 μM. The Western blot analysis approved that the expression level of SHP-2 in the CT26 and SW480 cell lines after being treated with 3f was decreased, meanwhile it also affected the SHP-2 in tumor-associated macrophages (THP-1 and RAW264.7), which may support the suggested mechanism of 3f as an SHP-2 inhibitor. Besides, 3f could also inhibit the activation of the PI3K-Akt pathway in SW480 and CT26 cell lines and the tumor microenvironment (TME) by reducing the expression of PI3K and Akt proteins. Some cytokines (Arg-1, TGF-β, and IL-10) and chemokines (chemokine receptors and CC and CXC chemokine subfamilies) in the TME were also inhibited by 3f. Finally, 3f could increase the expression level of cell cycle-related and mitophagy-related proteins p27, PINK1, and Parkin and decrease the expression level of CDK1 and Cyclin-D1 proteins in CT26 and SW480 cells, which proved that 3f could inhibit the proliferation of CRC cells through multiple pathways. Molecular docking studies against ALDH1 (PDB ID: 5ABM) revealed the good binding modes of the newly synthesized compounds.