pH响应型纳米药物用于化疗-光热协同治疗肿瘤

化疗协同光热治疗(PTT)是提高肿瘤疗效的一种新型治疗方式.本研究拟合成一种亚细胞器靶向的近红外响应纳米药物Fe3 O4@PDA-TPP/S2-PEG-hyd-DOX(Fe3 O4-ATSPD)作为新的光热制剂,它可通过磁靶向增强肿瘤细胞的摄取,具有良好的光热稳定性和光热转化效率.在近红外光(NlR)照射下,光热剂多巴胺(PDA)产生光热效应,促使线粒体膜电位显著下降.同时,在内涵体/溶酶体低pH值环境下,Fe3O4-ATSPD释放偶联药物DOX进入细胞核损伤DNA,最终促使肿瘤细胞凋亡.本研究制备的纳米药物能有效整合诊断和治疗,为肿瘤治疗提供新的协同治疗策略.     

光热/pH响应B-CuS-DOX纳米药物用于化疗-光热协同治疗肿瘤

基于纳米材料的化疗-光热协同治疗是一种高效的肿瘤治疗方式, 但如何构建具有高载药量与良好光热转换性能的纳米药物依然面临挑战。本研究通过超声剥离法制备二维硼(boron, B)纳米片, 进一步在其表面原位负载超小粒径硫化铜(CuS)纳米颗粒和化疗药阿霉素(DOX), 形成B-CuS-DOX纳米药物。B-CuS具有高的DOX药物装载能力(864 mg/g)和优异的光热转化性能(在808 nm处的光热转换效率为55.8%), 同时可实现pH及近红外激光双重刺激响应而释放药物。细胞实验表明在808 nm近红外光的照射下, B-CuS-DOX展示了良好的化疗-光热协同治疗效果。本研究构建的纳米药物有望为体内肿瘤治疗提供一种有效的化疗-光热协同治疗策略。     

可控合成空心多孔氧化硅纳米管/CuS体系应用于化疗-光热靶向治疗

多功能药物载体的设计合成并应用于肿瘤的联合治疗得到了研究人员的广泛关注.本文介绍了一种连接靶向基团的化疗-光热联合治疗纳米平台.首先制备了尺寸可控的平均长度为40、55和150 nm的空心多孔氧化硅纳米管,在表面修饰具有光热功能的硫化铜纳米颗粒,然后连接乳糖酸基团实现肝癌细胞靶向功能.平均长度为40 nm、修饰靶向基团的空心多孔材料显示出良好的生物相容性,且具有最大的HepG2细胞吞噬量.负载盐酸阿霉素的纳米复合材料表现出pH和808 nm近红外激光刺激响应的释放效果.将CuS光热治疗和盐酸阿霉素化疗相结合的方法在体外和体内的抑制肿瘤效果都优于单独治疗.研究结果表明,该纳米复合材料在化疗-光热联合治疗方面具有潜在的应用价值.     

荧光碳量子点:合成、特性及在肿瘤治疗中的应用

碳量子点是一种以碳元素为主要成分的新型荧光碳纳米材料。碳量子点是纳米材料的一员,具备纳米材料所共有的表面和界面效应,因而表面非常活跃,易于功能化修饰;纳米材料具有小尺寸效应和量子尺寸效应,使得碳量子点具有优异的荧光性能,荧光量子产率高、稳定性强、光谱可控;另外,碳量子点的水溶性优良,碳元素的构成保证了碳量子点的低细胞毒性和良好的生物相容性,极小的粒径和分子量也有利于其在生物体内的应用。这些突出的性能使得碳量子点在肿瘤体外检测、体内成像、肿瘤靶向载体与治疗等领域中都有重要的应用价值。仅从肿瘤治疗方面而言,碳量子点在许多传统和新兴的肿瘤治疗方法中都有很多深层次的应用。纳米药物载体技术是大部分学者利用碳量子点来改善化学治疗过程最常用的手段。它是将纳米材料作为基本单元,通过物理和化学等手段将药物连接、吸附或者包裹在纳米材料上,利用载体的特殊性能来实现更好的抑癌效果。而碳量子点诸多的优良性能也使其在化学治疗过程中有非常多的应用,包括:(1)改善药物的水溶性,以提升治疗效果;(2)提高药物对病灶处的靶向性,降低对正常细胞的危害;(3)延长药物在人体内的滞留时间;(4)实现药物智能高效释放等。这些复合载药体系具有特异性、靶向性、定量准确、易吸收等特点,可以有效提高治疗效果。此外,碳量子点的光热转化特性、光致发光特性也使得其在光热治疗和光动力治疗等新兴治疗方法中有所应用。光热治疗提高了热疗过程中的安全性和高效性;碳量子点在光动力治疗应用中,可以显著改善光敏剂水溶性差、荧光量子产率低、光源穿透深度不够、癌变组织氧气供应不足等应用难题,为深层肿瘤治疗提供了研究思路。多种方式的协同治疗也可以将治疗效果提升至最大化。本文归纳了碳量子点的合成方法以及新的制备工艺的发展趋势,总结了碳量子点在肿瘤治疗中所具有的优良性能,并着重介绍了碳量子点在光动力治疗、光热治疗和化疗等肿瘤治疗领域中的前沿应用。     

氢氧化铝纳米片:结构依赖性癌症化疗药物的储运（英文）

铝盐佐剂具有极好的安全记录,是各种人类疫苗中唯一获得FDA许可的无机佐剂。据我们所知,目前尚没有关于将其用作化疗药物的递送系统、并系统阐明其结构与载药性能之间关系的研究报道。本研究采用三嵌段共聚物、通过调节反应时间合成了具有可调比表面积和孔径的氢氧化铝(AlOOH)纳米片。AlOOH纳米片的最大比表面积达470 m²/g。其负载化疗药物阿霉素的能力与材料结构密切相关:比表面积和孔径越大,负载化疗药物的量越大。负载有阿霉素的AlOOH纳米片呈现与pH有关的药物释放行为:在pH～5的低p H环境下快速释放,而在pH～7.4的近中性pH下缓慢释放。流式细胞术显示,相比于游离形式的阿霉素,负载在AlOOH纳米片上的阿霉素更易被癌细胞所吞噬。而且负载阿霉素后,与低比表面积的AlOOH纳米片相比,高比表面积的AlOOH纳米片更有利于被癌细胞摄取、诱导癌细胞凋亡和坏死。因此,本研究所合成的AlOOH纳米片有望用作化疗药物递送体系。     

磁性碳纳米管的制备及其在肿瘤细胞光热疗与磁共振成像中的应用

肿瘤是目前最主要的致死原因之一，实现对肿瘤的精准和非侵入性高效诊疗具有重要意义。以具有极高长径比、易于穿透细胞膜并具有优异生物相容性的碳纳米管(CNTs)作为载体，以乙酰丙酮铁为铁源，通过溶剂热法在其表面原位生长具有超顺磁特性的四氧化三铁纳米粒子(Fe₃O₄ NPs)，制备了具有优异水分散稳定性的磁性碳纳米管复合纳米材料。结果表明该磁性碳纳米管具有较高的近红外光热转换性能，在50μg·mL^-1浓度下808 nm激光照射10 min即可升温至48.6℃，且具有良好的光热稳定性。细胞及成像实验结果表明该复合纳米材料具有较好的生物相容性并对人宫颈癌细胞(HeLa)具有优异的光热杀伤效果，在体外模拟肿瘤微环境中磁共振成像(MRI) T₂弛豫率r₂可达215.61 mmol^-1·L·s^-1，表明制备的磁性碳纳米管具有出色的生物安全性、磁性和光热特性，有望用于磁靶向的肿瘤光热疗与磁共振成像的一体化诊疗。     

中科院制成具有强可见—近红外吸收峰和高光热转换效率的超碳纳米点

正日前,中国科学院长春光学精密机械与物理研究所研究员曲松楠课题组首次研制出在可见-近红外区具有强吸收和高光热转换效率的超碳纳米点,该工作突破了碳基纳米材料在可见到近红外波段的吸收系数低的限制,并实现近红外区高达53%的光热转换效率,为该类材料国际上报道的最高值,在开发基于碳纳米点的光热治疗试剂方面具有重要的应用前景。碳纳米点具有发光性能优异、水溶性好、生物相容性高、低成本、易修饰等诸多优点,在生物医疗领域展现了独有的     

碳基光热转换纳米材料的表面功能化和生物应用

光热治疗技术已经引起了广泛的重视,其走向应用的前提是开发出高效稳定的光热转换材料.碳基光热转换纳米材料具有毒性小、稳定性高等优点,已经成为了研究的热点.综述了碳基光热转换纳米材料(包括纳米碳管和石墨烯)的研究进展,重点论述了其表面改性技术(包括非共价键改性和共价键改性方法);随后总结了其表面功能化方法,主要有RGD、抗体、叶酸和DNA等靶向性功能化的修饰方法;最后介绍了其在光热治疗、近红外热成像等生物医药方面的应用.     

稀土上转换发光材料的设计及在光动力治疗中的应用研究进展

作为一种新兴的无创治疗方法,光动力治疗在癌症治疗方面具有副作用小、累积毒性小、有效杀伤肿瘤以及精准的靶向治疗而不损伤邻近组织等优势,是理想的癌症治疗方法之一。本文首先简要概括了光动力治疗的机理、基本要素以及细胞作用机制,讨论了稀土上转化发光材料的设计特点以及光动力治疗对上转化发光材料的要求,进一步详述了上转换发光纳米材料、光敏剂以及靶向体的材料结合方式和应用效果,最后综述了光动力治疗和放疗、化疗及光热治疗相结合的协同治疗的进展。     

介孔有机硅为载体的纳米递送系统制备及其体外化疗-光热联合治疗性能研究

有机/无机杂化的介孔有机硅纳米颗粒因其高的比表面积、丰富的介孔孔道、功能性的骨架以及高的药物装载量等特点而在生物医学领域受到广泛关注。本研究提出以二硫键桥接的有机/无机杂化介孔有机硅纳米颗粒为载体共装载化疗药物和光热剂,设计制备以DNA分子作为控释"开关"修饰介孔有机硅纳米颗粒的纳米递送系统(ICG/DOX-MONs@DNA₂₀)。该纳米递送系统结合了光热剂的光热效应以及DNA分子随温度升高而从颗粒表面脱附的特性,可实现近红外光照射激发药物在肿瘤细胞中的控制释放,同时获得药物化疗–光热联合治疗肿瘤的效果。实验结果表明,纳米递送系统在近红外光照下能迅速升温至43℃以上的热疗温度,而且在37℃条件下6h内仅缓慢释放药物12.3%,而当温度升至43℃时则快速释放药物52.4%;细胞实验显示该纳米递送系统能够被HeLa肿瘤细胞吞噬,在近红外光照下有明显的药物化疗-光热联合治疗效果。因此,ICG/DOX-MONs@DNA₂₀纳米递送系统在药物化疗-光热联合治疗肿瘤方面具有应用前景。     

多功能Pt-Ce6纳米平台作为过氧化氢纳米酶和NIR-Ⅱ光热剂用于增强PDT/PTT肿瘤治疗

实体肿瘤的缺氧严重影响着基于氧气的光动力疗法(PDT)的效果.另外,单一治疗模式通常难以达到满意的治疗效果.为此,我们设计合成了一种多功能纳米复合材料Pt-Ce6用于克服肿瘤乏氧,实现PDT/PTT协同治疗.在该体系中,我们使用多孔Pt纳米粒子作为过氧化氢纳米酶、近红外二区(NIR-Ⅱ)光热转换剂和光敏剂二氢卟吩e6(...     

Mitochondria-targeting single-walled carbon nanotubes for cancer photothermal therapy

Nanomaterials have recently attracted much attention as efficient transducers for cancer photothermal therapy, based on their intrinsic absorption properties in the near-infrared region. This study explores a novel therapy model with mitochondria-targeting single-walled carbon nanotubes (SWNTs), which act efficiently to convert 980-nm laser energy into heat and selectively destroy the target mitochondria, thereby inducing mitochondrial depolarization, cytochrome c release, and caspase 3 activation. The laser+SWNTs process affords remarkable efficacy in suppressing tumor growth in a breast cancer model, and results in complete tumor regression in some cases. Laser+SWNTs could prove to be a promising selective local treatment modality, while minimizing adverse side effects.     

Multistage Targeting Strategy Using Magnetic Composite Nanoparticles for Synergism of Photothermal Therapy and Chemotherapy

Mitochondrial‐targeting therapy is an emerging strategy for enhanced cancer treatment. In the present study, a multistage targeting strategy using doxorubicin‐loaded magnetic composite nanoparticles is developed for enhanced efficacy of photothermal and chemical therapy. The nanoparticles with a core–shell–SS–shell architecture are composed of a core of Fe₃O₄ colloidal nanocrystal clusters, an inner shell of polydopamine (PDA) functionalized with triphenylphosphonium (TPP), and an outer shell of methoxy poly(ethylene glycol) linked to the PDA by disulfide bonds. The magnetic core can increase the accumulation of nanoparticles at the tumor site for the first stage of tumor tissue targeting. After the nanoparticles enter the tumor cells, the second stage of mitochondrial targeting is realized as the mPEG shell is detached from the nanoparticles by redox responsiveness to expose the TPP. Using near‐infrared light irradiation at the tumor site, a photothermal effect is generated from the PDA photosensitizer, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the loaded doxorubicin can rapidly enter the mitochondria and subsequently damage the mitochondrial DNA, resulting in cell apoptosis. Thus, the synergism of photothermal therapy and chemotherapy targeting the mitochondria significantly enhances the cancer treatment.     

Molecular Targeting‐Mediated Mild‐Temperature Photothermal Therapy with a Smart Albumin‐Based Nanodrug

Photothermal therapy (PTT) usually requires hyperthermia >50 °C for effective tumor ablation, which inevitably induces heating damage to the surrounding normal tissues/organs. Moreover, low tumor retention and high liver accumulation are the two main obstacles that significantly limit the efficacy and safety of many nanomedicines. To solve these problems, a smart albumin‐based tumor microenvironment‐responsive nanoagent is designed via the self‐assembly of human serum albumin (HSA), dc‐IR825 (a cyanine dye and a photothermal agent), and gambogic acid (GA, a heat shock protein 90 (HSP90) inhibitor and an anticancer agent) to realize molecular targeting‐mediated mild‐temperature PTT. The formed HSA/dc‐IR825/GA nanoparticles (NPs) can escape from mitochondria to the cytosol through mitochondrial disruption under near‐infrared (NIR) laser irradiation. Moreover, the GA molecules block the hyperthermia‐induced overexpression of HSP90, achieving the reduced thermoresistance of tumor cells and effective PTT at a mild temperature (<45 °C). Furthermore, HSA/dc‐IR825/GA NPs show pH‐responsive charge reversal, effective tumor accumulation, and negligible liver deposition, ultimately facilitating synergistic mild‐temperature PTT and chemotherapy. Taken together, the NIR‐activated NPs allow the release of molecular drugs more precisely, ablate tumors more effectively, and inhibit cancer metastasis more persistently, which will advance the development of novel mild‐temperature PTT‐based combination strategies.     

A New Co‐P Nanocomposite with Ultrahigh Relaxivity for In Vivo Magnetic Resonance Imaging‐Guided Tumor Eradication by Chemo/Photothermal Synergistic Therapy

Design of new nanoagents that intrinsically have both diagnostic imaging and therapeutic capabilities is highly desirable for personalized medicine. In this work, a novel nanotheranostic agent is fabricated based on polydopamine (PDA)‐functionalized Co‐P nanocomposites (Co‐P@PDA) for magnetic resonance imaging (MRI)‐guided combined photothermal therapy and chemotherapy. The ultrahigh relaxivity of 224.61 mm ^?1 s^?1 can enable Co‐P@PDA to be applied as an excellent contrast agent for MRI in vitro and in vivo, providing essential and comprehensive information for tumor clinical diagnosis. Moreover, Co‐P@PDA exhibit excellent photothermal performance owing to the strong near‐infrared (NIR) absorbance of both Co‐P nanocomposite and PDA. Highly effective ablation of tumors is achieved in a murine tumor model because the NIR laser not only induces photothermal effects but also triggers the chemotherapeutic drug on‐demand release, which endows the Co‐P@PDA with high curative effects but little toxicity and few side effects. These findings demonstrate that Co‐P@PDA are promising agents for highly effective and precise antitumor treatment and warrant exploration as novel theranostic nanoagents with good potential for future clinical translation.     

NIR-II Imaging-Guided Mitochondrial-Targeting Organic Nanoparticles for Multimodal Synergistic Tumor Therapy

Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial-targeting phototheranostic system, FE-T nanoparticles (FE-T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE-T NPs are engineered by encapsulating the near-infrared (NIR) absorbed photosensitizer IR-FE-TPP within amphiphilic copolymer DSPE-SS-PEG-COOH for high-performing with simultaneous mitochondrial-targeting, near-infrared II (NIR-II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR-FE-TPP and accumulate in mitochondria. After 808 nm irradiation, the mitochondrial localization of FE-T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial-targeting with FE-T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE-T NPs provide an effective mitochondrial-targeting phototheranostic nanoplatform for imaging-guided tumor therapy.     

NIR‐Responsive Polycationic Gatekeeper‐Cloaked Hetero‐Nanoparticles for Multimodal Imaging‐Guided Triple‐Combination Therapy of Cancer

Responsive multifunctional organic/inorganic nanohybrids are promising for effective and precise imaging‐guided therapy of cancer. In this work, a near‐infrared (NIR)‐triggered multifunctional nanoplatform comprising Au nanorods (Au NRs), mesoporous silica, quantum dots (QDs), and two‐armed ethanolamine‐modified poly(glycidyl methacrylate) with cyclodextrin cores (denoted as CD‐PGEA) has been successfully fabricated for multimodal imaging‐guided triple‐combination treatment of cancer. A hierarchical hetero‐structure is first constructed via integration of Au NRs with QDs through a mesoporous silica intermediate layer. The X‐ray opacity and photoacoustic (PA) property of Au NRs are utilized for tomography (CT) and PA imaging, and the imaging sensitivity is further enhanced by the fluorescent QDs. The mesoporous feature of silica allows the loading of a typical antitumor drug, doxorubicin (DOX), which are sealed by the polycationic gatekeepers, low toxic hydroxyl‐rich CD‐PGEA/pDNA complexes, realizing the co‐delivery of drug and gene. The photothermal effect of Au NRs is utilized for photothermal therapy (PTT). More interestingly, such photothermal effect also induces a cascade of NIR‐triggered release of DOX through the facilitated detachment of CD‐PGEA gatekeepers for controlled chemotherapy. The resultant chemotherapy and gene therapy for glioma tumors are complementary for the efficiency of PTT. This work presents a novel responsive multifunctional imaging‐guided therapy platform, which combines fluorescent/PA/CT imaging and gene/chemo/photothermal therapy into one nanostructure.     

Mitochondria-targeting photoacoustic therapy using single-walled carbon nanotubes

In vitro photoacoustic therapy using modified single-walled carbon nanotubes (SWNTs) as "bomb" agents is a newly reported approach for cancer. Herein, a mitochondria-targeting photoacoustic modality using unmodified SWNTs and its in vitro and in vivo antitumor effect are reported. Unmodified SWNTs can be taken up into cancer cells due to a higher mitochondrial transmembrane potential in cancerous cells than normal cells. Under the irradiation of a 1064 nm pulse laser, 79.4% of cancer cells with intracellular SWNTs die within 20 s, while 82.3% of normal cells without SWNTs remain alive. This modality kills cancer cells mainly by triggering cell apoptosis that initiates from mitochondrial damage, through the depolarization of mitochondria and the subsequent release of cytochrome c after photoacoustic therapy. It is very effective in suppressing tumor growth by selectively destroying tumor tissue without causing epidermis injury. Taken together, these discoveries provide a new method using mitochondria-localized SWNTs as photoacoustic transducers for cancer treatment.     

J‐Aggregates of Organic Dye Molecules Complexed with Iron Oxide Nanoparticles for Imaging‐Guided Photothermal Therapy Under 915‐nm Light

Recently, the development of nano‐theranostic agents aiming at imaging guided therapy has received great attention. In this work, a near‐infrared (NIR) heptamethine indocyanine dye, IR825, in the presence of cationic polymer, polyallylamine hydrochloride (PAH), forms J‐aggregates with red‐shifted and significantly enhanced absorbance. After further complexing with ultra‐small iron oxide nanoparticles (IONPs) and the followed functionalization with polyethylene glycol (PEG), the obtained IR825@PAH‐IONP‐PEG composite nanoparticles are highly stable in different physiological media. With a sharp absorbance peak, IR825@PAH‐IONP‐PEG can serve as an effective photothermal agent under laser irradiation at 915 nm, which appears to be optimal in photothermal therapy application considering its improved tissue penetration compared with 808‐nm light and much lower water heating in comparison to 980‐nm light. As revealed by magnetic resonance (MR) imaging, those nanoparticles after intravenous injection exhibit high tumor accumulation, which is then harnessed for in vivo photothermal ablation of tumors, achieving excellent therapeutic efficacy in a mouse tumor model. This study demonstrates for the first time that J‐aggregates of organic dye molecules are an interesting class of photothermal material, which when combined with other imageable nanoprobes could serve as a theranostic agent for imaging‐guided photothermal therapy of cancer.     

Carbon Nanotubes Enabling Highly Efficient Cell Apoptosis by Low‐Intensity Nanosecond Electric Pulses via Perturbing Calcium Handling

Effective induction of targeted cancer cells apoptosis with minimum side effects has always been the primary objective for anti‐tumor therapy. In this study, carbon nanotubes (CNTs) are employed for their unique ability to target tumors and amplify the localized electric field due to the high aspect ratio. Highly efficient and cancer cell specific apoptosis is finally achieved by combining carbon nanotubes with low intensity nanosecond electric pulses (nsEPs). The underlying mechanism may be as follows: the electric field produced by nsEPs is amplified by CNTs, causing an enhanced plasma membrane permeabilization and Ca²⁺ influx, simultaneously triggering Ca²⁺ release from intracellular storages to cytoplasm in a direct/indirect manner. All the changes above lead to excessive mitochondrial Ca²⁺ uptake. Substructural damage and obvious mitochondria membrane potential depolarization are caused subsequently with the combined action of numerously reactive oxygen species production, ultimately initiating the apoptotic process through the translocation of cytochrome c to the cytoplasm and activating apoptotic markers including caspase‐9 and ‐3. Thus, the combination of nanosecond electric field with carbon nanotubes can actually promote HCT116 cell death via mitochondrial signaling pathway‐mediated cell apoptosis. These results may provide a new and highly efficient strategy for cancer therapy.