Characterization and Evaluation of a Folic Acid Receptor-Targeted Norcantharidin/Tetrandrine Dual-Drug Loaded Delivery System

Abstract

The objective of this study was to construct norcantharidin (NCTD)/tetrandrine (Tet) dual-drug loaded lipid nanoparticles (FA-LP@Tet/(MSNs@NCTD)) based on mesoporous silica nanoparticles (MSNs) for controlling drug release and lowering their systemic toxicity. In this study, MSNs were prepared and used for encapsulating anticancer drug NCTD; then MSNs@NCTD and Tet were loaded into liposomes to construct dual-drug loaded lipid nanoparticles with folic acid (FA) as the targeting moiety. The prepared dual-drug loaded lipid nanoparticles with a uniform particle size distribution of 153.17±4.17 nm (PDI 0.191±0.017, zeta potential -20.93±1.75 mV), had a visible core-shell structure under transmission electron microscopy; the encapsulation efficiency of NCTD and Tet was 86.62% and 79.19%, respectively, with obvious in vitro sustained release characteristics. The cellular uptake results suggested that FA modification could enhance intracellular distribution of FA-LP@Tet/(MSNs@NCTD). Furthermore, cell apoptosis assays showed FA-LP@Tet/(MSNs@NCTD) had better antitumor ability via reversing multidrug resistance. Therefore, FA-LP@Tet/(MSNs@NCTD) was a promising drug delivery system for combination cancer therapy.

Review targeted drug delivery systems for norcantharidin in cancer therapy

“…, 3 times a week for 5 consecutive weeks), reduce β-catenin level and its nuclear localization, increase E-cadherin expression [ 135 ], 2019 Folate acid (FA)-conjugated NCTD-loaded stealth niosomes FA FA receptor FA-PEG-chol, F127-chol, Span-80, 3.8 mg NCTD, 0.15 mL absolute ethanol, 0.05 mL ethyl acetate, 5 mL PBS Hela cells: cellular uptake ↑; IC 50 (12 h): FA-conjugated NCTD-loaded stealth niosomes (46 µg/mL) < FA + FA-conjugated NCTD-loaded stealth niosomes (91 µg/mL) < NCTD-loaded stealth niosomes (148 µg/mL) < NCTD (261 µg/mL) [ 137 ], 2013 Diacid metabolite (DM)-NCTD-loaded, FA-modified, polyethylene glycolated (DM-NCTD/FA-PEG) liposomes FA FA receptor DSPC, cholesterol, DSPE-PEG2000, DSPE-PEG2000-FA = 2: 1: 0.11: 0.017 (molar ratio), DM-NCTD H22 cells: IC 50 (48 h): DM-NCTD (30.0 ± 1.73) µg/mL < DM-NCTD/FA-PEG liposomes (50.1 ± 1.04) µg/mL < DM-NCTD/PEG liposomes (92.5 ± 1.31) µg/mL; tumor-targeting efficiency: DM-NCTD/PEG liposomes [relative intake rate 4.86, tissue/tumor-targeting efficacy 12.81%, relative targeting efficiency 2.36, peak concentration ratio 4.78] < DM-NCTD/FA-PEG liposomes (9.25, 24.44%, 4.50, and 9.24); H22 tumor inhibition rate ( iv. , once daily, 9 days, 2.0 mg/kg): DM-NCTD = 30.14% < DM-NCTD/PEG liposomes = 40.41% < DM-NCTD/FA-PEG liposomes = 67.81%; tumor-cell apoptosis ↑ [ 138 ], 2016 FA receptor-targeted NCTD/tetrandrine (Tet) dual-drug loaded lipid nanoparticles [(FA-LP@Tet/(MSNs@NCTD)] FA FA receptor FA-DSPE-PEG2000 (0.18 mg), DSPE-PEG2000 (0.72 mg), DSPC (6.3 mg), cholesterol (2.8 mg), Tet (2 mg), 5 mL dichloro- methane, 10 mL anhydrous ethanol, PBS buffer (10 mL, pH 7.4) containing 2 mg of MSNs@NCTD HepG2 cells: cellular uptake ↑; IC 50 (HepG2, HepG2/Adr, MCF-7, LO2 cells): FA-LP@Tet/(MSNs@NCTD) < LP@Tet/(MSNs@NCTD) < LP/(MSNs@NCTD) < NCTD; induce cell apoptosis: HepG2 cells < HepG2/Adr cells; inhibit P-gp expression [ 182 ], 2019 FA-LB(ABT-737)-(DM-NCTD@CHMSN) FA FA receptor DSPC, cholesterol, DSPE-PEG2000, DSPE-PEG2000-FA = 2: 1: 0.11: 0.017 (molar ratio), CHMSN/DM-NCTD = 2.5: 1 (weight ratio), ABT-737/ DM-NCTD = 1: 10 (mol ratio), DM-NCTD@CHMSN/lipid = 0.02: 1 (weight ratio) In vitro cytotoxicity, cell apoptosis (H22 cells): DM-NCTD < ABT-737 < DM-NCTD + ABT-737 < LB(ABT-737)-(DM-NCTD@CHMSN) < FA-LB(ABT-737)-(DM-NCTD@CHMSN); mitochondrial membrane p...…”

“…In addition to its own antitumor activity, TET is also a reversal agent for MDR of tumors [ 180 ]. Xiong et al [ 182 ] constructed a FA receptor-targeted NCTD/Tet dual-drug loaded lipid nanoparticles [(FA-LP@Tet/(MSNs@NCTD)] based on MSNs, with an average size of (153.17 ± 3.17) nm (Fig. 9 ).…”

“…9 The synthetic route of FA-LP@Tet/(MSNs@NCTD). Reproduced with permission from reference [ 182 ]. Copyright 2019, HINDAWI …”