title: Redox-sensitive self-assembled nanoparticles based on alpha-tocopherol succinate-modified heparin for intracellular delivery of paclitaxel.
abstract: To remedy the problems riddled in cancer chemotherapy, such as poor solubility, low selectivity, and insufficient intra-cellular release of drugs, novel heparin-based redox-sensitive polymeric nanoparticles were developed. The amphiphilic polymer, heparin-alpha-tocopherol succinate (Hep-cys-TOS) was synthesized by grafting hydrophobic TOS to heparin using cystamine as the redox-sensitive linker, which could self-assemble into nanoparticles in phosphate buffer saline (PBS) with low critical aggregation concentration (CAC) values ranging from 0.026 to 0.093mg/mL. Paclitaxel (PTX)-loaded Hep-cys-TOS nanoparticles were prepared via a dialysis method, exhibiting a high drug-loading efficiency of 18.99%. Physicochemical properties of the optimized formulation were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM) and differential scanning calorimetry (DSC). Subsequently, the redox-sensitivity of Hep-cys-TOS nanoparticles was confirmed by the changes in size distribution, morphology and appearance after dithiothreitol (DTT) treatment. Besides, the in vitro release of PTX from Hep-cys-TOS nanoparticles also exhibited a redox-triggered profile. Also, the uptake behavior and pathways of coumarin 6-loaded Hep-cys-TOS nanoparticles were investigated, suggesting the nanoparticles could be taken into MCF-7 cells in energy-dependent, caveolae-mediated and cholesterol-dependent endocytosis manners. Later, MTT assays of different PTX-free and PTX-loaded formulations revealed the desirable safety of PTX-free nanoparticles and the enhanced anti-cancer activity of PTX-loaded Hep-cys-TOS nanoparticles (IC50=0.79μg/mL). Apoptosis study indicated the redox-sensitive formulation could induce more apoptosis of MCF-7 cells than insensitive one (55.2% vs. 41.7%), showing the importance of intracellular burst release of PTX. Subsequently, the hemolytic toxicity confirmed the safety of the nanoparticles for intravenous administration. The results indicated the developed redox-sensitive nanoparticles were promising as intracellular drug delivery vehicles for cancer treatment.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China. Electronic address: professorgxzhai@126.com.
authors.forename: Guangxi
authors.initials: G
authors.lastname: Zhai
mesh_terms: D000272:Adipates / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006493:Heparin / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D053758:Nanoparticles / Q000737:chemistry*; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D024502:alpha-Tocopherol / Q000737:chemistry*
chemical_list: D000272:Adipates; D000970:Antineoplastic Agents; D011108:Polymers; D006493:Heparin; D024502:alpha-Tocopherol; D017239:Paclitaxel; C010011:adipic dihydrazide
keywords: Alpha-tocopherol succinate; Heparin; Paclitaxel; Polymeric nanoparticles; Redox-sensitive