Wang Liping, Jang Grace, Ban Deependra Kumar, Sant Vrinda, Seth Jay, Kazmi Sami, Patel Nirav, Yang Qingqing, Lee Joon, Janetanakit Woraphong, Wang Shanshan, Head Brian P, Glinsky Gennadi, Lal Ratneshwar
School of Biomedical Engineering, Shanghai Jiaotong Univerity, Shanghai, China.
Department of Mechanical and Aerospace Engineering, La Jolla, CA, USA.
Bone Res. 2017 Dec 20;5:17051. doi: 10.1038/boneres.2017.51. eCollection 2017.
Multi-functional nanoshuttles for remotely targeted and on-demand delivery of therapeutic molecules and imaging to defined tissues and organs hold great potentials in personalized medicine, including precise early diagnosis, efficient prevention and therapy without toxicity. Yet, in spite of 25 years of research, there are still no such shuttles available. To this end, we have designed magnetic and gold nanoparticles (NP)-embedded silica nanoshuttles (MGNSs) with nanopores on their surface. Fluorescently labeled Doxorubicin (DOX), a cancer drug, was loaded in the MGNSs as a payload. DOX loaded MGNSs were encapsulated in heat and pH sensitive polymer P(NIPAM-co-MAA) to enable controlled release of the payload. Magnetically-guided transport of MGNSs was examined in: (a) a glass capillary tube to simulate their delivery via blood vessels; and (b) porous hydrogels to simulate their transport in composite human tissues, including bone, cartilage, tendon, muscles and blood-brain barrier (BBB). The viscoelastic properties of hydrogels were examined by atomic force microscopy (AFM). Cellular uptake of DOX-loaded MGNSs and the subsequent pH and temperature-mediated release were demonstrated in differentiated human neurons derived from induced pluripotent stem cells (iPSCs) as well as epithelial HeLa cells. The presence of embedded iron and gold NPs in silica shells and polymer-coating are supported by SEM and TEM. Fluorescence spectroscopy and microscopy documented DOX loading in the MGNSs. Time-dependent transport of MGNSs guided by an external magnetic field was observed in both glass capillary tubes and in the porous hydrogel. AFM results affirmed that the stiffness of the hydrogels model the rigidity range from soft tissues to bone. pH and temperature-dependent drug release analysis showed stimuli responsive and gradual drug release. Cells' viability MTT assays showed that MGNSs are non-toxic. The cell death from on-demand DOX release was observed in both neurons and epithelial cells even though the drug release efficiency was higher in neurons. Therefore, development of smart nanoshuttles have significant translational potential for controlled delivery of theranostics' payloads and precisely guided transport in specified tissues and organs (for example, bone, cartilage, tendon, bone marrow, heart, lung, liver, kidney, and brain) for highly efficient personalized medicine applications.
用于将治疗分子和成像物质远程靶向并按需递送至特定组织和器官的多功能纳米穿梭体在个性化医疗中具有巨大潜力，包括精确的早期诊断、高效的预防和无毒治疗。然而，尽管经过了25年的研究，目前仍没有此类穿梭体可用。为此，我们设计了表面带有纳米孔的磁性和金纳米颗粒（NP）嵌入的二氧化硅纳米穿梭体（MGNSs）。将荧光标记的阿霉素（DOX），一种癌症药物，作为有效载荷加载到MGNSs中。载有DOX的MGNSs被封装在对热和pH敏感的聚合物P（NIPAM-co-MAA）中，以实现有效载荷的控释。在以下方面研究了MGNSs的磁引导运输：（a）玻璃毛细管，以模拟它们通过血管的递送；（b）多孔水凝胶，以模拟它们在包括骨、软骨、肌腱、肌肉和血脑屏障（BBB）在内的复合人体组织中的运输。通过原子力显微镜（AFM）检查水凝胶的粘弹性。在源自诱导多能干细胞（iPSC）的分化人神经元以及上皮HeLa细胞中证明了载有DOX的MGNSs的细胞摄取以及随后的pH和温度介导的释放。扫描电子显微镜（SEM）和透射电子显微镜（TEM）证实了二氧化硅壳和聚合物涂层中嵌入的铁和金NP的存在。荧光光谱和显微镜记录了MGNSs中的DOX负载。在玻璃毛细管和多孔水凝胶中均观察到了由外部磁场引导的MGNSs的时间依赖性运输。AFM结果证实，水凝胶的硬度模拟了从软组织到骨骼的刚性范围。pH和温度依赖性药物释放分析表明了刺激响应性和药物的逐渐释放。细胞活力MTT测定表明MGNSs无毒。即使在神经元中药物释放效率更高，在神经元和上皮细胞中均观察到了按需释放DOX导致的细胞死亡。因此，智能纳米穿梭体的开发对于治疗诊断有效载荷的控释以及在特定组织和器官（例如骨、软骨、肌腱、骨髓、心脏、肺、肝脏、肾脏和大脑）中的精确引导运输具有重大的转化潜力，可用于高效的个性化医疗应用。
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