Drug-loaded pH-responsive polymeric micelles: Simulations and experiments of micelle formation, drug loading and drug release

• Published in: Colloids and surfaces, B, Biointerfaces B, Biointerfaces, 2017-10, Vol.158, p.709-716
• Main Authors: Li, Qiu, Yao, Weishang, Yu, Xiang, Zhang, Baolei, Dong, Junxing, Jin, Yiguang
• Format: Article
• Language: English
• Subjects: Block copolymer; Coarse grain; Computer Simulation; Dissipative particle dynamics; Drug Liberation; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Micelles; Molecular dynamics; Paclitaxel; Paclitaxel - chemistry; pH-responsive; Polyesters - chemistry; Polymeric micelles; Polymers - chemistry
• ISSN: 0927-7765; 1873-4367
• DOI: 10.1016/j.colsurfb.2017.07.063

[Display omitted] •A pH-responsive polymeric micelle of mPEG-PDEA-PCL (PDC).•Mechanistic details of micelle formation, drug loading and drug release.•More drug release from the micelles at acidic than neutral environments.•Higher cytotoxicity of PTX PDC micelles at acidic than neutral environments. pH-responsive drug nanocarriers are widely applied for cancer treatment. However, the mechanistic details of drug loading and drug release from these micelles are unknown. Here, we reveal the mechanistic details of micelle formation, drug loading and drug release from pH-responsive polymeric micelles using computer simulations and experiments. A triblock amphiphilic copolymer, methoxy-poly(ethylene glycol) 2000-poly(2-(N,N-diethylamino)ethyl methacrylate)-polycaprolactone (mPEG-PDEA-PCL, PDC), was used to load paclitaxel (PTX), a hydrophobic anticancer agent, using an injection method. The micelles showed strong pH-responsive behavior, where the sizes and zeta potentials ranged from 51nm and 19mV at pH 4.5, respectively, to 22nm and −5.5mV at pH 8, respectively, with greater PTX release at pH 6.5 than that at pH 7.4. Furthermore, the PTX-loaded PDC micelles showed higher cytotoxicity to MCF-7 cells at pH 6.5 than that at pH 7.4 due to differential drug release. Molecular dynamics and the coarse-grained dissipative particle dynamic method were used to mimic micelle formation, drug loading and drug release. The pH-responsive segment, PDEA, transforms to its protonated form, PDEAH+, in an acidic environment. PTX and PDC form micelles based on hydrophobic interactions, where PTX inserts into the hydrophobic PDEA-PCL core in a neutral environment. An acidic transition of the environment leads to rapid PTX release from the micelles due to the hydrophobic-hydrophilic transition of PDEA to PDEAH+, though some PTX molecules still remain in the PCL core. The pH-responsive PDC micelles are suitable for triggered drug release in an acidic tumor microenvironment. The PDC micelle is, therefore, a promising nanocarrier of anticancer agents for cancer treatment.