RCEES OpenIR  > 环境化学与生态毒理学国家重点实验室
功能纳米材料抑制肿瘤转移及 促进 组织 修复 的机制研究
Alternative TitleMechanism of F unctional N anomaterials for I nhibiting T umor M etastasis and Accelerating T issue R epair
汪顺浩
Subtype博士
Thesis Advisor刘思金
2019-12
Degree Grantor中国科学院生态环境研究中心
Place of Conferral北京
Degree Name理学博士
Degree Discipline有机化学
Keyword黑磷量子点 钯纳米片 纳米全氟化碳 乳腺癌转移 组织修复 Black p Hosphorus q Uantum d Ots, Palladium n Ano Plate s, nAno Perfluorocarbons, b Reas t c Ancer Metastasis, Tissue Repair
Abstract

      随着人口老龄化社会的来临,癌症、糖尿病以及骨折等慢性疾病已成为影响病人生活质量的主要因素。与之相关的高致死率的转移性肿瘤、久治不愈的糖尿病溃疡以及骨不连是目前临床医学领域面临的严峻挑战。所以,亟待开发选择性靶向药物降低转移性肿瘤风险,促进 慢性疾病的 组织修复。最近, 人工纳米材料Engineered nanomaterials ENMs )在纳米医学领域得到了广泛地关注 。 但 仍存在 作用 机制 不明 、靶向效率 较低、生物相容性较差 等挑战。因此, 揭示 ENMs对 癌症 、组织损伤等慢性疾病的 作用机制 进而开发新型低毒纳米药物 已经 成为迫切需求 。
      针对上述科学问题,我们选择目前严重危害女性身体健康的转移性乳腺癌作为研究对象。此外, 为了 探究 ENMs 对转移性乳腺癌的选择性靶向能力以及治疗机制,我们制备了具有良好生物相容性的二维( 2 D )纳米材料:黑磷量子点BPQDs )和 钯 纳米片 Pd NP 。
      首先,我们开发了基于 BPQDs 的多模式纳米 治疗剂用于治疗转移性乳腺癌 。为改善 BPQDs 的稳定性以及治疗效率,我们使用美国食品和药物管理局( FDA批准的可降解聚乳酸 乙醇酸共聚物( PLGA )作为载体实现 BPQDs 和化疗药多烯紫杉醇( DTX BP/ DTX@PLGA )的高效共载。此纳米复合材料不仅保留了 BPQDs 优异的光热特性 也实现了化疗药的有效靶向和 近红外( NIR )触发
的 可控释放 。体内结果显示, BP/DTX@PLGA 可以高效精准 地靶向 原位瘤和肺转移瘤 。在 NIR 辐照下, BP/DTX@PLGA 表现 出 优异 的可控化疗和光热疗组合疗效 极大的改善了肿瘤 治疗 效率 。 机制 研究发现,光热效应触发 DTX 的加速释放 协同光热本身 可 诱导肿瘤细胞的凋亡性死亡,进而抑制和消除肺转移。此外,我们也证实了 BP/DTX@PLGA 具有良好的生物相容性,为其进一步 临床 转化提供了潜力。
      同时,我们 制备了 目前应用广泛的钯 纳米片 Pd NP 并对其抵抗乳腺癌及其肺转移的分子机制进行 细致 研究 。我们所制备的 Pd NP 具有均一和可控的尺寸,并且在 NIR 光区具有强吸收, 可以实现高效的 N IR 光热转化效率 。体内分布显示,在 原位以及 肺转移 肿瘤 模型上, Pd NP 可以有效靶向 原位 肿瘤和肺转移 瘤 。并且, 单独 Pd NP 以及协同光热治疗 均 可以有效抑制 乳腺癌 肺 转移 。通过转录组测序和生物信息学分析 ,我们 揭示了在非毒性暴露剂量下, Pd NP 通过阻断 TGF β所驱动的 上皮 间充质转化 信号通路来抑制乳腺癌肺转移。综上所述,我们的发现为 揭示 ENM s 的 肿瘤 治疗 机制和转移性乳腺癌的治疗 提供了新的 策略 与依据。

       此外,为改善组织修复进程,我们选择具有代表性的慢性愈合伤口糖尿病足溃疡( D UF s )和骨折作为研究对象。 考虑到纳米材料在生物医学方面所面临的毒理学以及生物相容性方面的风险,我们进一步开发了基于 FDA 批准的具有高氧亲和力的 纳米 全氟化碳( PFC Nano PFC )。 值得注意的是, 纳米化的 PFC保留了优异的氧亲和力和良好生物相容性。在放散式体外冲击波( rESW )的触发下, Nano PFC 可以实现 载氧 的可控 、高效 释放。借助于 rESW 改善的局部微循环,载氧 Nano PFC 有效促进了 DFUs 的愈合。 并且,在兔桡骨骨折模型上,Nano PFC 可通过促进成骨细胞的增生与活化,进而加速骨折愈合。 此研究为新型纳米药物载体的构建以及 慢性组织修复 提供了一种全新的 治疗 策略。
      综上所述,本论文为 转移性乳腺癌以及难愈合组织损伤的治疗提供了高效、靶向纳米治疗剂,并对其治疗机制进行了细致探究。这将可能为此类疾病的临床治疗提供替代性方法,并为新型功能化 ENMs 的设计提供全新的认识和理论依据。

Other Abstract

      With the advent of an aging society, chronic diseases such as cancer, diabetes and fractures have become major factors for affec ting the quality of life of patients. Related high fatal metastatic tumors, therapy resistant diabetic foot ulcers ( DFUs), and bone nonunion are currently serious challenges in the clinical medicine field. Therefore, it is urgent to develop selective targeted drugs to reduce the risk of metastatic tumors and promote tissue repair. Recently, engineered nanomaterials (ENMs) have attracted extensive attention in nanomedicine. However, there are still challenges such as unclear therapeutic mechanism, low t argeting efficiency, and poor biocompatibility. Thus , it has become a pressing need to reveal the therapeutic mechanism of ENMs on chronic diseases such as cancer and tissue damage, and develop new low toxic nano drugs.
      Focusing on the above scientific pro blems, we selected metastatic breast cancer that seriously harms women's health as a research object. In addition, for explor ing the selective targeting ability and therapeutic mechanism of ENMs for metastatic breast cancer, we prepared two dimensional (2D ) nanomaterials with good biocompatibility including black phosphorus quantum dots (BPQDs) and palladium nanoplates(PDNP)

      First, we developed BPQDs based multimodal nanotherapeutic agent against metastatic breast cancer. To improve the stability and therapeutic efficiency of BPQDs, we used the US Food and Drug Administration (FDA) approved degradable polylactic acid glycolic acid copolymer (PLGA) as a carrier to co load BPQDs and docetaxel (DTX , a chemotherapeutic drug ) (BP/DTX@PLGA). Th e nanocomposite s not only retain ed the excellent photothermal propert y of BPQDs, but also achieved effective targeting of chemotherapeutic drugs and near infrared (NIR) mediated controllable release. In vivo result s show ed that BP/DTX@PLGA c ould efficiently and accurately target orthotopic tumors and lung metastases. Under NIR irradiation, BP/DTX@PLGA showed excellent combination of controll able chemotherapy and phototherm al therapy, which greatly improved the effic iency of tumor treatment. Mechanism studies have found that the photothermal effect mediated the accelerated release of DTX and the photothermal therapy itself could induce apoptotic death of tumor cells, thereby inhibiting and eliminating lung metastasis. In addition, we have confirmed that BP/DTX@PLGA has great biocompatibility and provided enormous potential for further clinical transformation.
      At the same time, we have prepared a widely used PdNP, and studied the molecular mechanism against breast cancer and lung metastasis. The obtained PdNP have uniform and controllable sizes and strong absorption in the NIR region, enabling efficient NIR photothermal conversion efficiency. In vivo distribution show ed that PdNP c ould effectively target in situ tumors and lung metastases. In orthotopic and lung metastasis tumor models, PdNP alone and synergistic photothermal therapy could effectively inhibit lung metastasis in breast cancer. Through transcriptome sequencing and bioinformatics analysis, we re vealed that PdNP inhibit ted breast cancer lung metastasis by blocking TGF β driven epithelial mesenchymal transition signaling pathway at non toxic exposure doses . In summary, our findings provide d a new strateg y and evidence for revealing the therapeutic mechanisms of ENMs and the treatment of metastatic breast cancer. 
      In addition, in order to improve the process of tissue repair, we selected representative chronic healing wounds including DUFs and fractures as subjects.Considering the toxicological and b iocompatib le risks of ENMs in biomedical fields ,we have further developed nano perfluorocarbon ( Nano PFC) with high oxygen affinity based on FDA approved PFC . It is worth noting that the nanosized PFC retain ed the excellent oxygen affinity and good biocompatibility. And the controlled release of oxygen could be achieved under the trigger of a clinical radial
extracorporeal shock wave (rESW) rESW). With the improvement of the local microcirculation by rESW, oxygen saturate d Nano PFC effectively promoted the healing of DFUs. Moreover, Nano PFC could accelerate fracture healing bypromoting the proliferation and activation of osteoblasts in rabbit radial fractures model . This study provide d a new therapeutic strategy for the construction of novel nanodrug carriers and chronic tissue repair.

      In summary, this paper provides a highly effective, targeted nanotherapeutic agent against metastatic breast cancer and refractory tissue damage, and explores related therapeutic mechanism which will likely provide an alternative approach for the clinical treatment of such diseases and offer a new understanding and rationale for
the design of new functionalized ENMs.

Pages163
Language中文
Document Type学位论文
Identifierhttp://ir.rcees.ac.cn/handle/311016/42295
Collection环境化学与生态毒理学国家重点实验室
Recommended Citation
GB/T 7714
汪顺浩. 功能纳米材料抑制肿瘤转移及 促进 组织 修复 的机制研究[D]. 北京. 中国科学院生态环境研究中心,2019.
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