Lin Cheng-Wei, Lu Kun-Ying, Wang Sin-Yu, Sung Hsing-Wen, Mi Fwu-Long
Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Acta Biomater. 2016 Apr 15;35:280-92. doi: 10.1016/j.actbio.2016.02.005. Epub 2016 Feb 4.
CD44-specific and redox-responsive nanoparticles were prepared by coating a bioreducible chitosan-based nanoparticles with hyaluronic acid for intracellular glutathione-triggered reactive oxygen species (ROS) production and doxorubicin (DOX) release. Chitosan (CS) was conjugated with a copper chelator, D-penicillamine (D-pen), to obtain a CS-SS-D-pen conjugate through the formation of a disulfide bond. D-pen release from the conjugate was triggered by intracellular glutathione (GSH) via reducing biologically reversible disulfide bonds. Self-assembled CS-SS-D-pen nanoparticles were prepared through ionotropic gelation with tripolyphosphate and subsequently coated with hyaluronic acid (HA). The HA-coated CS-SS-D-pen NPs were reduced by GSH to release free D-pen and trigger ROS production via a series of reactions involving Cu(II)-catalyzed D-pen oxidation and H2O2 generation. DOX was loaded into the HA-coated CS-SS-D-pen NPs by a method involving the complexation of DOX with Cu(II) ions. The Cu(II)-DOX complex-loaded NPs exhibited redox-responsive release properties which accelerated DOX release at a higher glutathione level (10mM). Confocal fluorescence microscopy demonstrated that the Cu(II)-DOX-loaded NPs effectively delivered DOX to human colon adenocarcinoma cells (HT-29) by active targeting via HA-CD44 interactions. Intracellular ROS generated from the HA-coated CS-SS-D-pen NPs sensitized cancer cells to DOX-induced cytotoxicity. In vitro cytotoxicity assays revealed that Cu(II)-DOX-loaded NPs sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells compared to CD44 low-expressing HCT-15 cells.
In this manuscript, we develop a CD44-targetable loaded with nanoparticles Cu(II)-DOX complex. The nanoparticles exhibited redox-responsive properties, which triggered reactive oxygen species (ROS) production and accelerated DOX release. The Cu(II)-DOX-loaded nanoparticle sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells. To our knowledge, this is the first report showing the combination of CD44-targeting and redox-responsive property for triggering ROS production and subsequent drug release. We believe our findings would appeal to the readership of Acta Biomaterialia because the study bring new and interesting ideals in the development of specific and stimuli-responsive nanoparticles as drug carrier for cancer therapy.
通过用透明质酸包被基于生物可还原壳聚糖的纳米颗粒来制备CD44特异性且对氧化还原有响应的纳米颗粒，用于细胞内谷胱甘肽触发的活性氧（ROS）生成和阿霉素（DOX）释放。壳聚糖（CS）与铜螯合剂D-青霉胺（D-pen）共轭，通过形成二硫键获得CS-SS-D-pen共轭物。细胞内谷胱甘肽（GSH）通过还原生物可逆二硫键触发共轭物中D-pen的释放。通过与三聚磷酸进行离子凝胶化制备自组装的CS-SS-D-pen纳米颗粒，随后用透明质酸（HA）包被。HA包被的CS-SS-D-pen纳米颗粒被GSH还原以释放游离的D-pen，并通过一系列涉及Cu（II）催化的D-pen氧化和H2O2生成的反应触发ROS生成。通过DOX与Cu（II）离子络合的方法将DOX负载到HA包被的CS-SS-D-pen纳米颗粒中。负载Cu（II）-DOX络合物的纳米颗粒表现出氧化还原响应释放特性，在较高谷胱甘肽水平（10mM）下加速DOX释放。共聚焦荧光显微镜表明，负载Cu（II）-DOX的纳米颗粒通过HA-CD44相互作用的主动靶向有效地将DOX递送至人结肠腺癌细胞（HT-29）。HA包被的CS-SS-D-pen纳米颗粒产生的细胞内ROS使癌细胞对DOX诱导的细胞毒性敏感。体外细胞毒性试验表明，与CD44低表达的HCT-15细胞相比，负载Cu（II）-DOX的纳米颗粒使CD44高表达HT-29细胞对DOX诱导的细胞毒性敏感。
在本手稿中，我们开发了一种负载有纳米颗粒Cu（II）-DOX络合物的可靶向CD44的物质。这些纳米颗粒表现出氧化还原响应特性，可触发活性氧（ROS）生成并加速DOX释放。负载Cu（II）-DOX的纳米颗粒使CD44高表达的HT-29细胞对DOX诱导的细胞毒性敏感。据我们所知，这是第一份显示CD44靶向与氧化还原响应特性相结合以触发ROS生成和随后药物释放的报告。我们相信我们的发现会吸引《生物材料学报》的读者，因为该研究为开发用于癌症治疗的特异性和刺激响应性纳米颗粒作为药物载体带来了新的有趣理念。
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