Polyacrylamide-b-copolypeptide hybrid copolymer as pH-responsive carrier for delivery of paclitaxel: Effects of copolymer composition on nanomicelles properties, loading efficiency and hemocompatibility

In the current study, a series of pH-responsive di/tri-block copolymers of poly N-(2-hydroxypropyl) methacrylamide-b-poly histidine/poly leucine (pHPMA-pHis/pLeu) were developed through sequential RAFT and ring-opening polymerization. Chemical structure of the synthesized copolymers was studied by FT-IR and 1H NMR spectroscopy and their molecular weight was characterized by size exclusion chromatography (SEC). The study of dynamic light scattering (DLS) revealed that copolymers could self-assemble into nanomicelles with particle size (PS) of 96-233 nm which increased in acidic media. Higher fpLeu and fpLeu/fpHis led to significantly smaller PS and CMC values, respectively. Higher CMC values, together with zeta potential reversal at acidic pH and having buffering activity at pH range of about 6-8 were indications of protonation of imidazole groups of histidine residues and pH-sensitiveness of hybrid copolymers. Atomic force microscopy also proved the DLS data. Hemocompatibility assay demonstrated that while only tri-block copolymers caused hemolysis at neutral pH, all copolymers caused significant hemolysis at low concentrations at pH 5.2 and pLeu had opposite effects on hemolysis percent at different pH values. Paclitaxel was efficiently loaded in nanomicelles with highest loading efficiency (LE) of 75% which was influenced by the composition of the copolypeptide block. PTX-loaded micelles of tri-block copolymer 5-5-3 showed accelerated PTX release in endosomal pH. In conclusion, the optimum designed copolymer can be considered as a good pH-sensitive candidate for drug delivery to solid tumors.

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