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A novel pH-sensitive polymer, poly( l -histidine)–poly(lactide- co -glycolide)–tocopheryl polyethylene glycol succinate (PLH–PLGA–TPGS), was synthesized to design a biocompatible drug delivery system for cancer chemotherapy. The structure of the PLH–PLGA–TPGS copolymer was confirmed by 1 H-NMR, FTIR and GPC. The apparent p K a of the PLH–PLGA–TPGS copolymer was calculated to be 6.33 according to the acid–base titration curve. The doxorubicin (DOX)-loaded nanoparticles (PLH–PLGA–TPGS nanoparticles and PLGA–TPGS nanoparticles) and corresponding blank nanoparticles were prepared by a co-solvent evaporation method. The blank PLH–PLGA–TPGS nanoparticles showed an acidic pH-induced increase in particle size. The DOX-loaded nanoparticles based on PLH–PLGA–TPGS showed a pH-triggered drug-release behavior under acidic conditions. The results of in vitro cytotoxicity experiment on MCF-7 and MCF-7/ADR cells showed that the DOX-loaded PLH–PLGA–TPGS nanoparticles resulted in lower cell viability versus the PLGA–TPGS nanoparticles and free DOX solution. Confocal laser scanning microscopy images showed that DOX-loaded PLH–PLGA–TPGS nanoparticles were internalized by MCF-7/ADR cells after 1 and 4 h incubation and most of them accumulated in lysosomes to accelerate DOX release under acidic conditions. In summary, the PLH–PLGA–TPGS nanoparticles have great potential to be used as carriers for anti-tumor drug delivery. [ABSTRACT FROM AUTHOR]

[Display omitted] The aim of this investigation is to clarify the effect of D-α-tocopheryl succinate (vitamin E succinate, VES) and distearoylphosphatidyl ethanolamine-poly(ethylene glycol) (DSPE-PEG) on the encapsulation and controlled release of doxorubicin (DOX) in nano-assemblies and their consequences on the anti-tumor efficacy of DOX. DOX molecules were successfully loaded into the hybrid micelles with VES and DSPE-PEG (VDPM) via thin-film hydration method, exhibiting a small hydrodynamic particle size (~30 nm) and a weak negative zeta potential of around −5 mv. The obtained DOX-loaded VDPM2 displayed retarded DOX release at pH of 7.4, while substantially accelerated drug release at acidic pH of 5.0. Furthermore, the DOX-loaded VDPM2 exhibited substantially slower drug release rate at pH 7.4 compared with the drug-loaded VDPM1 or DPM preparation, benefiting for decreasing the premature DOX release during blood circulation. In vitro cell experiment indicated that DOX-loaded micelles (DPM, VDPM1 and VDPM2) improved the cellular uptake of DOX in 4T1 and MDA-MB-231 cells. The existence of VES component in the structure of DOX-loaded micelles had no obvious influence on the subcellular distribution of the encapsulated DOX molecules. Furthermore, the DOX-loaded VDPM2 exhibited more pronounced cytotoxicity to 4T1 and MDA-MB-231 cancerous cells compared with DOX-loaded DPM and free DOX solution. The hybrid nanocarriers including VES and DSPE-PEG selectively induced intracellular ROS accumulation and increased level of cytoplasmic calcium ion in cancerous cells by interacting with mitochondria and endoplasmic reticulum, bringing about the improved cytotoxicity of DOX. In vivo antitumor efficacy investigation of DOX-loaded VDPM2 against 4T1 xenograft-bearing mice displayed satisfied therapeutic activity with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The proposed DOX-loaded VDPM preparation, as a mulifunctional chemotherapeutic nanomedicine system, holds great potential and bright prospect for clinical tumor therapy. [ABSTRACT FROM AUTHOR]