Mixed PEG–PE/vitamin E tumor-targeted immunomicelles as carriers for poorly soluble anti-cancer drugs: Improved drug solubilization and enhanced in vitro cytotoxicity

Abstract

Two poorly soluble, potent anticancer drugs, paclitaxel and camptothecin, were successfully solubilized by mixed micelles of polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) and vitamin E. Drug containing micelles were additionally modified with anti-nucleosome monoclonal antibody 2C5 (mAb 2C5), which can specifically bring micelles to tumor cells in vitro. The optimized micelles had an average size of about 13-to-22 nm and the immuno-modification of micelles did not significantly change it. The solubilization of both drugs by the mixed micelles was more efficient than by micelles made of PEG-PE alone. Solubilization of camptothecin in micelles prevented also the hydrolysis of active lactone form of the drug to inactive carboxylate form. Drug loaded mixed micelles and mAb 2C5-immunomicelles demonstrated significantly higher in vitro cytotoxicity than free drug against various cancer cell lines.

Development and evaluation of vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate-mixed polymeric phospholipid micelles of berberine as an anticancer nanopharmaceutical

“…This can be explained by possible additional hydrophobic interactions of Brb alkaloid molecules with the aromatic chromane structure in nonpolar region of TPGS. 22,27,28,32 The Brb release from our PEG-PE/TPGS micelles, presented in Figure 3, generally shows an initial burst of ~20% of drug within the first 4 hours, followed by a slow-release phase over the remaining 24-or 48-hourperiods, irrespective of the pH or composition of the test release media. This overall in vitro release behavior of Brb from mMic reflects the drug incorporation stability and can be explained through the localization of Brb within the micelles.…”

“…Substances with intermediate polarity -such as our active alkaloid, Brb HCl -are typically distributed mostly surrounding the core and along the surfactant molecules in certain intermediate positions within the micelle's corona. 27,28,32 The addition of the PEGylated vitamin E, TPGS, was thus intended to enhance the Brb drug loading due to the hydrophobic fragment in its molecules. This should increase both the core and corona volumes and the overall micellar capacity (Figure 1).…”

“…CMC values corresponding to the concentration of the polymer at which a sharp increase in fluorescence is observed. 22,28 In vitro release of Brb from micelles at "sink" conditions and modeled physiological media…”

“…[23][24][25] Here, mixed micelle (mMic) formulation of Brb is investigated in order to enhance the solubilization efficacy of PEG-PE micellar carriers, by including d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as an additional component -a PEGylated derivative of natural Vitamin E (VE), (α-tocopherol) commonly utilized as a pharmaceutical solubilizer, absorption enhancer, and a vehicle for lipidic drug formulations (Figure 1). [25][26][27][28][29] Such a mixed micellar system would not only improve Brb solubilization capacity, owing to increased core volume of mMics, created by the planar chromane moiety of VE, but would also provide better protection for the active isoquinolone structure of Brb (Figure 1), effectively enhancing both Brb encapsulation and stability. 30 Based on recent reports, TPGS has shown notable proapoptotic activity as well as a strong ability to overcome drug resistance by inhibiting Pgp efflux pumps.…”

Micelles: Chemotherapeutic Drug Delivery

“…Uptake was modulated by increasing or decreasing the density of the ligands on the nanoparticle surface [22]. Micelles modified with anti-nucleosome monoclonal antibody 2C5 demonstrated higher cytotoxicity in tumor cells than free drug against the B16 (murine melanoma) and 4T1 (murine mammary carcinoma) cell lines [23]. AS1411 is a DNA aptamer that specifically binds nucleolin, which is highly expressed in cancer cells and endothelial cells lining angiogenic blood vessels.…”