Quercetin Covalently Linked Lipid Nanoparticles: Multifaceted Killing Effect on Tumor Cells.

The encapsulation of hydrophobic drugs is a problem that many researchers are working on. The goal of this study is to achieve the delivery of hydrophobic drugs by means of prodrugs and nanoformulations for a stronger tumor cell-killing effect and explore related killing mechanisms. Lipophilic quercetin (Qu) was covalently linked to glyceryl caprylate-caprate (Gcc) via disulfide bonds-containing 3,3'-dithiodipropionic acid (DTPA) to synthesize novel lipid Qu-SS-Gcc. Qu-SS-Gcc lipid nanoparticles (Qu-SS-Gcc LNPs) were fabricated using the solvent diffusion technique. The intracellular release of Qu by cleavage of nanocarriers was determined by liquid chromatography and compared with the uptake of free Qu. Detection methods, such as fluorescent quantitation, flow cytometry, and western blot were applied to explore the action mechanism induced by Qu. It was revealed that Qu-SS-Gcc LNPs could be cleaved by the high concentrations of reduction molecules in MCF-7/ADR (human multidrug-resistant breast cancer) cells, followed by the release of Qu. The intracellular Qu content produced by dissociation of Qu-SS-Gcc LNPs was higher than that produced by internalization of free Qu. The resulting release of Qu exerted superior cell-killing effects on MCF-7/ADR cells, such as P-gp inhibition by binding to P-gp binding sites, blocking the cell cycle in the G2 phase, and causing cell apoptosis and autophagy. Moreover, it was revealed autophagy triggered by a low concentration of Qu-SS-Gcc LNPs was beneficial to cell survival, while at a higher concentration, it acted as a cell killer. Qu-SS-Gcc LNPs can realize massive accumulation of Qu in tumor cells and exert a multifaceted killing effect on tumor cells, which is a reference for the delivery of hydrophobic drugs.

Chitosan-modified lipid nanodrug delivery system for the targeted and responsive treatment of ulcerative colitis.

Targeted and sensitive drug release at the colitis site is critical for the effective therapy of ulcerative colitis and reduction of side effects from the drug. Herein, we used 3,3'-dithiodipropionic acid (DTPA) to covalently link quercetin (Qu) and glyceryl caprylate-caprate (Gcc) via ester bonds to prepare Qu-SS-Gcc lipid nanoparticles (Qu-SS-Gcc LNPs). Dexamethasone (Dex) was used as a model drug, and chitosan (CSO) was modified on the surface of Qu-SS-Gcc LNPs to obtain CSO-modified Dex-loaded Qu-SS-Gcc LNPs (CSO/Dex/LNPs). The encapsulation efficiency and drug loading of CSO/Dex/LNPs were 93.1 % and 8.1 %, respectively. The in vitro release results showed that CSO/Dex/LNPs had esterase-responsive characteristics and could release the drug rapidly in esterase-containing artificial intestinal fluid. A human colorectal adenocarcinoma cell (Caco-2) monolayer was used as the intestinal cell barrier model. Transmembrane resistance measurements and permeation experiments showed that CSO/Dex/LNPs had a protective effect on the lipopolysaccharide (LPS)-stimulated Caco-2 cell monolayer and increased the expression of E-cadherin in LPS-stimulated Caco-2 cells. Moreover, CSO/Dex/LNPs could significantly reduce the expression of the inflammatory factors TNF-α, IL-6 and NO in LPS-stimulated RAW 264.7 cells. The ulcerative colitis mouse model was constructed by using C57BL/6 mice. The in vivo distribution results showed that CSO/Dex/LNPs had colon-targeting effects and strong retention ability in the colons of mice with colitis. The results also showed that CSO/Dex/LNPs had better anti-inflammatory effects than free Dex, which could reduce colonic atrophy, reduce histomorphological changes and increase the expression of E-cadherin in the colon. Furthermore, the expression levels of TNF-α, IL-6 and NO in the CSO/Dex/LNP-treated group were 37.4 %, 35.5 % and 33.2 % of those in mice with colitis, respectively.

A novel biocompatible, simvastatin-loaded, bone-targeting lipid nanocarrier for treating osteoporosis more effectively.

An insufficient drug concentration at the target site and drug efflux resulting in poor efficacy are recognized as important obstacles in osteoporosis treatment. Simvastatin (SIM), which can treat osteoporosis by promoting osteoblast differentiation and mineralization through the bone morphogenetic proteins (BMP)-Smad signaling pathway, has lower bioavailability, and less bone tissue distribution. Herein, novel lipid nanoparticles (LNPs) delivering SIM (SIM/LNPs) for osteoporosis therapy were developed with aspartic oligopeptide (ASP n , here ASP6)-based bone-targeting moieties grafted to the nanoparticles (SIM/ASP6-LNPs) in an attempt to increase the concentration of SIM in bones with a relatively low dose to minimize adverse effects. In vivo experiments indicated that the ASP6-LNPs exhibited ideal bone-targeting characteristics, and in vitro cell evaluation experiments showed LNPs have good biocompatibility with MC3T3-E1 cells. The cell mineralization experiment revealed that the SIM-loaded LNPs induced osteoblast differentiation and the formation of mineralized nodules in MC3T3-E1 cells, achieving the same efficacy as that of SIM. Pharmacodynamic experiments revealed that SIM/ASP6-LNPs improved the efficacy of SIM on the recovery of bone mineral density when compared to SIM/LNPs or to SIM alone. Therefore, SIM/ASP6-LNPs may represent a potential bone-targeting drug delivery system (DDS) that contributes to the development of a novel osteoporosis treatment.

Correction: A novel biocompatible, simvastatin-loaded, bone-targeting lipid nanocarrier for treating osteoporosis more effectively.

[This corrects the article DOI: 10.1039/D0RA00685H.].