Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery

Abstract

A novel amphiphilic triblock pH-sensitive poly( β -amino ester)- g -poly(ethylene glycol) methyl ether-cholesterol (PAE- g -MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation–deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX) was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE- g -MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy.

pH-sensitive micelles self-assembled from polymer brush (PAE-<em>g</em>-cholesterol)-<em>b</em>-PEG-<em>b</em>-(PAE-<em>g</em>-cholesterol) for anticancer drug delivery and controlled release

“…40,41 The pK b values of PAE were about 6.0~6.5 as reported, indicating the beneficial pH-sensitive range. 42,43 The hydrophilic PEG was selected as a hydrophilic segment to form the shell, maintaining stability of the system during long-time biological circulation. 44,45 The pH-sensitive PAE segment was conjugated on the two terminals of PEG, resulting in triblock polymer PAE-b-PEG-b-PAE.…”

“…Anhydrous dichloromethane (DCM), anhydrous triethylamine (TEA), and other materials were prepared as described in previous work. 42,44 All other reagents were used as received except additional description.…”

“…42 In brief, BD (1 mol) was dissolved in anhydrous DCM and immersed in an ice bath. AP (0.9 mol) was added dropwise slowly into the flask.…”

Poly(2-(diethylamino)ethyl methacrylate)-based, pH-responsive, copolymeric mixed micelles for targeting anticancer drug control release

“…The base dissociation constant (pK b ) buffering region of the mixed copolymers was measured. This method was reported in our previous works, 21,32 and the details are shown in the Supplementary materials.…”

Preparation, characterization, in vivo pharmacokinetics, and biodistribution of polymeric micellar dimethoxycurcumin for tumor targeting

“…31,32 In brief, 100 μL of pyrene solution (0.1 mg/mL in benzene) was aliquoted into a series of 10 mL test tubes, and the solvent benzene was evaporated under nitrogen stream at room temperature for 5 hours. A series of aqueous polymeric solutions (concentrations ranging from 10 ng/mL to 1 mg/mL) were added separately to obtain the final concentration of pyrene of 1 μg/mL, and then were sonicated for 20 minutes at room temperature, and finally were incubated at 45°C for 4 hours.…”