Cholesterol and vitamin E-conjugated PEGylated polymeric micelles for efficient delivery and enhanced anticancer activity of curcumin: evaluation in 2D monolayers and 3D spheroids

Abstract

A newly synthesized PEGylated cholesterol/α-tocopheryl succinate (α-TOS) linked polymer (CV) was self-assembled and loaded with curcumin to form a micellar system (C-CVM). The tri-functionalized amphiphilic polymer was constituted of hydrophobic cholesterol and α-TOS connected to hydrophilic PEG via a lysine linker. The synthesized polymer and the micelles were characterized by H NMR, DLS, zeta potentiometer, TEM, CMC determination and hemolysis studies. CVM displayed low CMC value of 15 µM with extent of hemolysis as less than 4%. The stable C-CVM with optimum % drug loading (14.2 ± 0.24) displayed Z average of 175.8 ± 0.68 nm with PDI (0.248 ± 0.075) and released curcumin in sustained manner in the in vitro drug release study. C-CVM demonstrated dose-dependent cellular uptake and cytotoxicity in murine melanoma, B16F10 and human breast cancer, MDA-MB-231 cell lines. CV exhibited marked reversal of drug resistance as indicated by significantly higher retention of P-glycoprotein substrate, rhodamine-123 in the resistant B16F10 cell line compared to standard P-glycoprotein inhibitor, verapamil. C-CVM demonstrated significantly higher spheroidal growth inhibition compared to C-PPM. The results provide strong evidence for CVM as promising drug delivery system and confirm the potential of C-CVM as chemotherapy in cancer.

The Efficacy of Cholesterol-Based Carriers in Drug Delivery

“…α-TOS induce apoptosis in various cancer cells via membrane destabilization and it is a potential multi-drug resistance inhibitor in cancer therapy. Muddineti et al developed a drug delivery system composed of vitamin E, a lipophilic core of cholesterol and a hydrophilic corona of polyethylene glycol (PEG), covalently bonded by a trifunctional linker, lysine ( Scheme 1 ) ( 2 ), which was loaded with curcumin [ 37 ]. Micelles 2 loaded with curcumin (C-CVM) had a bigger hydrophobic compartment size varying in the range of 162.2–175.8 nm compared to polyethylene glycol amine phosphatidyl ethanolamine micelles (PPM) (20.4–24.4 nm).…”

“…Micelles 2 loaded with curcumin (C-CVM) had a bigger hydrophobic compartment size varying in the range of 162.2–175.8 nm compared to polyethylene glycol amine phosphatidyl ethanolamine micelles (PPM) (20.4–24.4 nm). Micelles 2 displayed high drug encapsulation efficiencies of between 97.2% and 98.6% [ 37 ].…”

“…A low hemolysis activity between 1.10% and 2.81%, which is below the acceptable range of less than 5%, was reported in the cholesterol vitamin E-based polymer, indicating the safe use of the formulation for in vivo studies. Cellular uptake studies showed that the micelles, 2 and C-PPM were taken up in dose- and time-dependent manner as the fluorescence was brighter after 4 h when compared to an hour after administration of the formulation [ 37 ]. Both micelles, 2 and C-PPM, showed no significant difference in the cellular uptake which is due to the presence of PEG-based polymeric corona.…”

“…In vitro cytotoxicity evaluation on the free curcumin, CVM, PPM and micelles 2 and C-PPM in B16F10 and MDA-MB-231 cell lines revealed that PPM showed no cytotoxic effect on both cell lines with nearly 100% cell survival. However, the presence of α-TOS led to CVM showing significant cytotoxic effect [ 37 ].…”

Improved oral bioavailability of magnolol by using a binary mixed micelle system

“…TPGS is a water-soluble derivative of natural vitamin E, and is composed of PEG and tocopherol succinate to form an amphiphilic structure. Additionally, it is very stable and does not hydrolyze under normal conditions [29,30]. As a result, it has been used as a component in mixed micelles to increase micelle stability, achieve controlled drug delivery and increase drug encapsulation efficiency [31].…”