pH‐Responsive H‐Type PMAA₂‐b‐HTPBN‐b‐PMAA₂ Four‐Arm Star Block Copolymer Micelles for PTX Drug Release

Abstract

pH-Responsive H-type poly(methylacrylic acid-block-four hydroxyl terminated poly(butadiene-acrylobitrile)-block-poly(methylacrylic acid (PMAA2 -b-HTPBN-b-PMAA2 ) block copolymers were synthesized via atom transfer radical polymerization and the follow-up hydrolysis, and characterized by (1) H NMR, FT-IR and SEC. The block copolymers could self-assemble into nanoscale spherical core-shell micelle aggregates in aqueous solution, and the physicochemical properties depended on the system composition and pH media, with pH phase transition at 5.7-6.1. The copolymer micelle aggregates exhibited pH-triggered drug release and cytotoxicity, and could potentially be used as drug targeting release carriers.

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“…The faster release of PTX triggered by the destabilization of the micelles at acidic pH environments as a result of the protonation of the PMAA moieties was reported previously elsewhere. 38,39 Moreover, the transition from the hydrophilicity of deprotonated PMAA chains at pH 7.4 to the protonated hydrophobicity at low pH would also lead to the rapid release of the entrapped PTX. 40 In addition, the secondary amine groups in PTX molecules possess a positive charge in PBS solution of pH 7.4, which would lead to an electrostatic attraction with negatively charged polymers due to deprotonated carboxylic groups, thus forming a hindrance layer for PTX release, and producing low PTX release percentage.…”

“…The agglomeration nanoparticles are more unstable, and the entrapped drug PTX is swiftly and dramatically dislodged from the cores of the destabilized micelles, the release of PTX accelerate, as expected. 38,39 The more reduced interparticle spacing caused by agglomeration and more intense hydrophilic-hydrophobic transition of the PMAA blocks also results in faster PTX release. With increasing the length of PMAA chains, the protonation of more PMAA chains further weakens the electrostatic attraction between PMAA and PTX, significantly enhancing PTX release percentage.…”

“…the concentration of the drug that inhibits cell growth by 50%, of about 11.52 µg mL −1 , lower than that of free PTX (18.25 µg mL −1 ). This is attributed to a synergistic effect of the target-specific selectivity and pH-sensitivity provided by CNTs- g -PMAA 14 carriers 39 ; the swift and targeted release of PTX from the drug preparation at acidic cancer cell environments leads to higher toxicity to cancer cells and hence achieves good therapeutic efficiency. It should be pointed out that despite about 37% PTX drug release in vitro at pH 7.4 within 48 h, the concentration of the drug formulation in MTT assays or drug concentrations is far lower than that in release experiments, and moreover the LC of PTX@P1 is only about 29%.…”

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“…Abraxane significantly increases the compliance of patients (Yardley, ) However, Abraxane may also cause neurotoxicity (Sahoo & Kumar, ). In order to obtain better clinical use of PTX, many PTX delivery systems have been developed and investigated, including micelles (Han et al, ; Luo, Han, Xu, Chen, & Zhang, ), nanoparticles (Jiang et al, ; Wang et al, ; Xiang et al, ; Xin et al, ), liposomes (Hong et al, ; Monteiro et al, ; Wang et al, ), PTX prodrugs (Han et al, ; Jiang et al, ; Jiang et al, ; Luo et al, ; Tam, Gao, & Kwon, ), and so on. Among these PTX delivery systems, PTX prodrugs, especially targeting peptide‐PTX conjugates (Bianchi et al, ; Colombo et al, ; Dal Corso et al, ; Zanella et al, ), achieved great attention because conjugating targeting peptide onto PTX can not only increase the water solubility of PTX, but also endow the conjugate with the capability of targeting tumor cells by ligand–receptor interactions.…”