Abstract ：

Imaging-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer treatment are beneficial for precise localization of the malignant lesions and combination of multiple cell killing mechanisms in eradicating stubborn thermal-resistant cancer cells. However, overcoming the adverse impact of tumor hypoxia on PDT efficacy remains a challenge. Here, carrier-free nano-theranostic agents are developed (AIBME@IR780-APM NPs) for magnetic resonance imaging (MRI)-guided synergistic PTT/thermodynamic therapy (TDT). Two IR780 derivatives are synthesized as the subject of nanomedicine to confer the advantages for the nanomedicine, which are by feat of amphiphilic IR780-PEG to enhance the sterical stability and reduce the risk from reticuloendothelial system uptake, and IR780-ATU to chelate Mn2+ for T-1-weighted MRI. Dimethyl 2,2 '-azobis(2-methylpropionate) (AIBME), acting as thermally decomposable radical initiators, are further introduced into nanosystems with the purpose of generating highly cytotoxic alkyl radicals upon PTT launched by IR780 under 808 nm laser irradiation. Therefore, the sequentially generated heat and alkyl radicals synergistically induce cell death via synergistic PTT/TDT, ignoring tumor hypoxia. Moreover, these carrier-free nano-theranostic agents present satisfactory biocompatibility, which could be employed as a powerful weapon to hit hypoxic tumors via MRI-guided oxygen-independent PTT and photonic TDT.

Keyword ：

carrier-free nanomedicine magnetic resonance imaging photothermal therapy thermodynamic therapy tumor hypoxia

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Abstract ：

Chemotherapy is one of conventional treatment methods for breast cancer, but drug toxicity and side effects have severely limited its clinical applications. Photothermal therapy has emerged as a promising method that, upon combination with chemotherapy, can better treat breast cancer. In this context, a biodegradable mesoporous silica nanoparticle (bMSN NPs) system was developed for loading doxorubicin (DOX) and IR780, to be potentially applied in the treatment of breast cancer. IR780 is encapsulated in the pores of bMSN NPs by hydrophobic adsorption, while DOX is adsorbed on the surface of the bMSN NPs by hyaluronic acid electrostatically, to form the bMID NPs. Transmission electron microscopy, fluorescence spectrum and UV absorption spectrum are used to prove the successful encapsulation of IR780 and the loading of DOX. In vitro experiments have shown bMID NPs present an excellent therapeutic effect on breast cancer cells. In vivo fluorescence imaging results have indicated that bMID NPs can accumulate in tumor sites gradually and achieve in vivo long-term circulation and continuous drug release. Furthermore, bMID NPs have provided obvious antitumor effects in breast cancer mouse models, thus evolving as an efficient platform for breast cancer therapy.

Keyword ：

biodegradable mesoporous silica nanoparticles breast cancer chemotherapy doxorubicin IR780 photothermal therapy

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At present, the clinical diagnosis of and treatment methods for hepatic carcinoma still fail to fully meet the needs of patients. The integrated theranostic system, in which functional materials are used to load different active molecules, created a new developmental direction for the combination treatment of hepatic carcinoma, realizing the synchronization of diagnosis and treatment. In this study, polydopamine (PDA), which has the functions of self-assembly, encapsulation, photothermal conversion, and photoacoustic interaction, was used as the carrier material. The IR780, a near-infrared fluorescence imaging (NIFI), photoacoustic imaging (PAI), and photothermal therapy (PTT) agent, and paclitaxel (PTX), a broad-spectrum chemotherapy drug, were selected to build the NIF/PA dual-mode imaging and PTT/chemo synergistic theranostic nanoparticles (DIST NPs). The DIST NPs have a 103.4 +/- 13.3 nm particle size, a weak negative charge on the surface, good colloidal stability, slow and controlled drug release, and high photothermal conversion ability. The experiments results showed that the DIST NPs have a long circulation in vivo, high bioavailability, high biocompatibility, and low effective dose. DIST NPs showed an excellent NIFI/PAI dual-mode imaging and significant synergistic antitumor effect in hepatic carcinoma models. DIST NPs met the initial design requirements. A set of fast and low-cost preparation methods was established. This study provides an experimental basis for the development of new clinical theranostic methods for hepatic carcinoma.

Keyword ：

dual-mode imaging hepatic carcinoma nanocarrier synergistic therapy theranostic

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A novel strategy called "two-stage dual-synergistic tumor therapy (TDTT)," which combines photothermal therapy with infinite coordination polymers (ICPs) chemotherapy at the first stage in the short term and two drugs of ICPs synergistic chemotherapy (coordinated dual drugs chemotherapy) at the second stage in the long term, is proposed. This strategy is achieved by preparing IR780-loaded hyaluronic acid (HA) encapsulated gossypol-Fe(III)-epigallocatechin gallate (EGCG) ICP nanoparticles (HA@IRGFE ICP NPs), which have IR780 inclusions, a natural gossypol, and EGCG coordinated with Fe3+ framework, and a HA shell. It is found that the HA@IRGFE ICP NPs' diameter is 120.0 +/- 39.5 nm and has tumor-targeting ability and can be rapidly released in tumor environment. Their photothermal conversion efficiency is greatly improved to 47.8%, and the total combination index of TDTT is 0.38, which indicates an excellent synergistic therapy result. These HA@IRGFE ICP NPs show low toxicity with a high tolerated dose (30.0 mg kg(-1)), a high tumor inhibition rate of 98.7%, and a very low tumor recurrence rate over 60 days (12.5%) with TDTT strategy, indicating their great potential applications in the field of tumor therapy.

Keyword ：

infinite coordination polymers IR780 photothermal therapy synergistic therapy tumors

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Abstract ：

目的 探索光热转换剂IR-780对于耐药性乳腺癌细胞的光热干预效果.方法 通过MTT法检测IR-780对于人乳腺癌细胞多药耐药株MCF-7/ADR的抑制率,设置不同的浓度及光照时长,以判断对细胞的光热干预差异.结果 在无辐照条件下,IR-780对细胞无明显毒性;在光辐照条件下,则呈现出明显的细胞杀伤效果.抑制效果与光热转换剂浓度及照射时间有明显的量效关系.结论 IR-780可有效杀伤耐药性乳腺癌细胞,可为进一步开发耐药性乳腺癌治疗的新方法提供理论依据.

Keyword ：

IR-780 光热治疗 耐药性三阴乳腺癌

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本发明公开了一种ROS响应型纳米颗粒及其在声动力介导的肿瘤精准治疗中的应用，利用ROS敏感分子TL连接抗肿瘤药物PTX及亲水片段NH2‑PEG1K‑NH2，得到两亲性ROS敏感片段PTX‑TL‑PEG1K‑NH2，随后利用超声乳化法得到负载敏化剂IR780的ROS响应型纳米颗粒；制备得到的纳米颗粒可以在外界超声的作用下产生ROS，不仅杀伤肿瘤细胞，而且可以使纳米颗粒释放PTX杀伤肿瘤细胞，从而在声动力治疗肿瘤中形成级联放大协同效应，实现肿瘤精准治疗。

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惯性空化是介导或增效聚焦超声热消融、机械毁损、声动力、药物释放、基因转染 等治疗手段的核心机制，高效且可控的惯性空化有利于进一步提高治疗效率和安全性。获得高效惯性空化活动最为直接有效的手段是，向治疗区域引入人工制备的外源性空化核从而降低空化发生阈值。纳米尺度的氟碳相变液滴作为人工空化核具备无生物毒性、体内循环时间长、可透过肿瘤新生血管间隙实现在瘤内富集等突出应用优势。在超声作用下，液滴可在体内原位发生液气相变形成微气泡，继而引发惯性空化实现辅助治疗的目的。虽然相变液滴辅助的聚焦超声治疗研究已被大量报道，但现存文献中对聚焦超声场中纳米相变液滴惯性空化空间分布特征研究还不够系统深入，而空化的空间分布是影响超声治疗安全性的关键因素。因此，本论文首先利用声致发光揭示了聚焦声场中纳米相变液滴惯性空化强度和空间分布特征，发现并提出了一种十微秒级脉宽的短脉冲聚焦超声序列，其能够激发高效且可控的惯性空化。进一步，针对现有聚焦超声热消融和声动力治疗研究在惯性空化利用上的不足，本论文将该种短脉冲序列和纳米相变液滴引入了热消融和声动力治疗研究，借由高效且可控的惯性空化行为辅助实现了高效且安全可靠的热消融和声动力治疗。 针对上述内容本论文分别从以下三个方面开展了研究： 1）利用声致发光揭示了全氟戊烷和全氟己烷纳米液滴在聚焦声场中的惯性空化行 为。并探究了超声作用方式、脉冲宽度、脉冲间隔、声强等关键声参数，以及液滴内核材料、浓度、混合比例等液滴参数对惯性空化活动的影响。研究结果显示：相比于连续波，脉冲式的超声辐照方式更有利于产生强度更强且分布集中的惯性空化；5~10 μs 的脉冲宽度和80~100 μs 脉冲间隔能够在声场焦域内产生最强的惯性空化；空化的强度会随着焦点声强的增高而变强直至进入平台期；过低和过高的液滴浓度都会减弱惯性空化强度；等比例混合使用两种内核的液滴可进一步增强惯性空化。由以上结果可知，针对不同的应用环境，合适的短脉冲超声参数联合纳米相变液滴能够最大化地利用惯性空化，实现增效治疗和调控治疗区域的目的。该研究结果也为后续的应用研究提供了合理的参数选择范畴和实验基础。 2）利用短脉宽（10 μs）高脉冲重复频率（10 kHz）的聚焦超声序列联合纳米相变 液滴，在透明牛血清白蛋白仿体内实现了高效可控的热消融。高速摄影记录显示，在纳米相变液滴的辅助下热消融治疗的重复性变得更优。相同功率下，热消融效率可增高6倍。形成特定体积热损伤所需声功率和辐照剂量均显著降低，提高了治疗的安全性。增强的惯性空化效应所带来的加快组织热沉积的效果，使得热消融过程中焦域温度的上升速度也明显变快。对热消融过程中惯性空化的检测结果表明，热损伤区域的每次扩展都是在空化微泡群出现之后，惯性空化的分布区域和面积大小与热损伤的形状和横截面积保持了很好的一致性，证实了短脉冲聚焦超声热消融中惯性空化对热损伤形成的关键作用。上述研究结果为通过合理利用惯性空化实现高效和安全的热消融提供了新的治疗策略。 3）利用疏水性声敏剂IR780 碘化物与牛血清白蛋白的疏水结合，成功将声敏剂负 载于全氟己烷纳米相变液滴内，为声敏剂在体内的选择性分布提供了基础。借助于短脉冲聚焦超声序列高效激发惯性空化的能力和全氟己烷纳米液滴规律可控的惯性空化行为，在HeLa 宫颈癌细胞中实现了高效的声动力治疗。声功率为4.5 W 的超声序列仅辐照10 s，便可生成大量的活性氧自由基（ROS），显著提高了肿瘤细胞的凋亡率，癌细胞经处理后的存活率仅为10%。研究还证实除了ROS 的细胞毒性外，惯性空化所造成的机械损伤也能够起到诱导肿瘤细胞凋亡或裂解的作用，且机械损伤在声功率增加或辐照时间变长后成为诱导肿瘤细胞死亡的主要因素。

Keyword ：

：短脉冲聚焦超声 惯性空化 纳米相变液滴 热消融 声动力治疗

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Inertial cavitation is crucial for the therapeutic effects of sonodynamic. Therefore, approaches that can induce highly efficient inertial cavitation should be of benefit for sonodynamic effect. Our previous study demonstrated that highly efficient inertial cavitation activity can be achieved through the combinatorial use of a short-pulsed focused ultrasound (SPFU) sequence and perfluorohexane (PFH) nanodroplets. Herein, we applied the SPFU sequence and PFH nanodroplets in sonodynamic. A hydrophobic sonosensitizer, IR780 iodine, was loaded inside denatured bovine serum albumin-shelled PFH (PFH@BSA-IR780) nanodroplets. The sonodynamic efficacy was validated by treating HeLa cervical cancer cells. Under SPFU exposure, PFH@BSA-IR780 nanodroplets were highly effective in promoting reactive oxygen species generation and inducing cancer cell death. A significant decrease in cell viability was achieved within just 10 s. Besides the cytotoxicity of ROS, the mechanical bioeffects of inertial cavitation also led to severe cell death resulting from higher acoustic power or the longer treatment time. The application of the SPFU sequence coupled with PFH@BSA-IR780 nanodroplets is a promising strategy for efficient sonodynamic. © 2018 Elsevier B.V.

Keyword ：

Cervical cancer cells Denatured bovine serum albumins Focused ultrasound Inertial cavitation Inertial cavitation activity Nanodroplet Reactive oxygen species Sonodynamic effect

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Abstract ：

Sonodynamic therapy (SDT) not only has greater tissue-penetrating depth compared to photo-stimulated therapies, but also can also trigger rapid drug release to achieve synergistic sonochemotherapy. Here, reactive oxygen species (ROS)-responsive IR780/PTL- nanoparticles (NPs) are designed by self-assembly, which contain ROS-cleavable thioketal linkers (TL) to promote paclitaxel (PTX) release during SDT. Under ultrasound (US) stimulation, IR780/PTL-NPs produce high amounts of ROS, which not only induces apoptosis in human glioma (U87) cells but also boosts PTX released by decomposing the ROS-sensitive TL. In the U87 tumor-bearing mouse model, the IR780/PTL-NPs releases the drug at the target sites in a controlled manner upon US irradiation, which significantly inhibits tumor growth and induces apoptosis in the tumor tissues with no obvious toxicity. Taken together, the IR780/PTL-NPs are a novel platform for sonochemotherapy, and can control the spatio-temporal release of chemotherapeutic drugs during SDT.

Keyword ：

cascade-amplifying synergistic effects on-demand drug release ROS-responsive nanoparticles sonochemotherapy

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目前，在乳腺癌的众多治疗研究中，利用纳米粒子进行“化疗-光热协同治疗”已经获得越来越广泛的关注，且具有极好的应用前景。但是，要实现其最大的协同治疗效果，仍存在一些挑战，如：药物缓控释能力不足、纳米材料生物相容性差等问题。针对上述问题，开发一种具有良好药物控释能力的“化疗-光热协同治疗”纳米粒子将会进一步提高乳腺癌的治疗效果。 本研究将利用肿瘤组织的弱酸性环境及光热治疗使肿瘤局部温度升高的特点，以丙烯腈，丙烯酰胺及乙烯基咪唑为单体，通过可逆加成-断裂链转移（RAFT）自由基聚合反应，合成同时具有高临界相转变温度（UCST）及pH双响应型的聚合物：聚乙二醇-聚（丙烯酰胺-丙烯腈-乙烯基咪唑）（mPEG-P(AAm-co-AN-co-VIm)，mPEG-PAAV），并利用该聚合物同时负载化疗药物阿霉素（DOX）及具有光热转化、光声成像功能的IR780，制备出具有“化疗-光热协同治疗”功能的纳米粒子。同时，我们还对该纳米粒子的近红外光光热转换效率、药物控释特性、靶向性、生物安全性及其体内外“化疗-光热协同治疗”效果进行了评价。 结果表明：mPEG-PAAV micelles为粒径均一分布的规则球体。同时，由于聚合物分子内存在pH响应性的咪唑基团，该纳米粒子的UCST会随pH值的降低而降低。此外，该载药纳米粒子mPEG-PAAV micelles/IR780+DOX在近红外激光辐照下能够具有良好的光热转换效率，产生的局部高温不仅可以造成肿瘤组织坏死，而且能够使纳米胶束在高温条件下分解，并加快药物DOX释放，从而在高效抑制4T1小鼠乳腺癌细胞的生长及抑制乳腺癌的肺转移的同时，减小药物的毒副作用。除此之外，该纳米粒子通过光声成像可以监测乳腺癌形状、大小和微血管分布，由此，提高治疗的针对性，达到彻底治愈体内4T1小鼠乳腺癌肿瘤的目的。因此，该纳米粒子展现出极好的化疗-光热协同治疗效果。

Keyword ：

高临界相转变温度 光声成像 化疗-光热协同治疗 纳米胶束 药物控释

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