光触发增强葡萄糖氧化酶催化活性的等离子体囊泡用于程序化光热-饥饿疗法

在肿瘤的饥饿治疗及协同治疗中,基于葡萄糖氧化酶(GOx)的纳米诊疗剂展现出具大的应用前景.自组装等离子体金囊泡(GV),由于具有独特的光学性能、巨大空腔和强局域表面等离子体共振等特性,可作为协同治疗的多功能纳米载体.本文中,我们开发了一种装载GOx的GV(GV-GOx)用于光触发释放GOx,同时增强GOx的催化活性,从而实现程序化光热-饥饿治疗.在近红外激光照射下,由于GV具有等离子体耦合效应, GV-GOx可以产生很强的局部高热,引起封装的GOx释放,同时高热可提高GOx催化活性,从而增强肿瘤的饥饿效应.此外,高光热效应可促进细胞对GV-GOx的摄取,并可通过活体光声/光热双模态成像对协同治疗进行有效监测.令人印象深刻的是,协同光热/饥饿疗法能完全消融4T1荷瘤小鼠的肿瘤,抗肿瘤效果明显优于单一疗法,且没有明显的系统毒性.本工作展示了一种光触发的纳米平台,可用于癌症协同治疗.     

类过氧化氢酶纳米系统缓解缺氧用于联锁三重态癌症治疗

缺氧作为实体瘤的标志,严重地影响了整体抗肿瘤治疗效果,尤其是光动力疗法.在本文中,我们开发了具有近红外光响应性的类过氧化氢酶纳米囊泡:铂/金纳米壳包覆的二氢卟酚e6(Ce6)/白藜芦醇(Res)脂质体(Pt@Au-Ce6/Res-Lips),以解决这一棘手的问题.Pt@Au-Ce6/Res-Lips可以分解肿瘤微环境中过表达的过氧化氢,从而产生大量氧气,以增强光动力疗法的效果.在808 nm激光照射下,金纳米壳在病变部位产生高热,以消融肿瘤细胞,同时可控地诱导光敏剂Ce6和化疗药物Res的释放.此外,在660 nm激光的刺激下,形成了大量的活性氧(ROS)以诱导肿瘤细胞的凋亡和坏死.随着三重态治疗模式(化疗、光热治疗和光动力治疗)的级联,Pt@Au-Ce6/Res-Lips在体外和体内研究中均显示出超高的肿瘤抑制率,这标志着Pt@Au-Ce6/Res-Lips纳米囊泡将有望成为高效的肿瘤治疗药物.     

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。     

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.     

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。     

异质结材料用于肿瘤诊断与治疗的研究进展

癌症是目前全球范围内引起死亡的主要疾病之一,受到人们的高度重视。然而传统的癌症治疗方法仍存在许多缺陷,严重影响了癌症治疗效果并给患者带来了许多不利影响。随着纳米材料的发展,光动力疗法(PDT)和光热疗法(PTT)等新型治疗方法有效弥补了传统治疗方法的不足。其中,将不同成分的纳米半导体材料组合成一个纳米结构的异质结在光动力疗法和光热疗法上有着优异的表现。异质结材料因其特有光学特性和结构设计性,在催化、检测、多模态成像和肿瘤的协同治疗领域中有很大的应用潜力。本文根据结构分类对不同种类异质结的原理进行了大致介绍,并对近年来异质结材料在肿瘤的单重治疗、协同治疗与诊疗一体化中的研究进展进行了系统性的综述,最后对异质结材料在癌症诊断治疗领域的未来发展方向进行了展望。      

纳米材料在光动力治疗肿瘤领域的应用

光动力治疗(PDT),是由光敏剂(或者其纳米粒子)介导,在光的作用下,使生物分子和细胞发生形态或功能上的变化,从而诱导组织细胞损伤及坏死,被称为光敏化-氧化作用的一种非侵入治疗手段。光敏剂纳米粒子、光、单线态氧是光动力疗法的三个重要元素。目前,PDT在临床上主要应用于恶性肿瘤的治疗,具有高选择性、低毒性、微创性、靶向性好、重复治疗、治疗时间短、可与放疗和化疗协同作用等优势,在肿瘤治疗领域具有非常广泛的应用前景。根据已有文献对肿瘤的光动力治疗方法进行了综述,介绍了光敏剂(主要是纳米粒子)和光动力治疗的研究现状,展望了其未来发展方向。研究结果发现以光敏剂纳米粒子为基础的光动力治疗对肿瘤组织具有特异性吸收和滞留作用,特别对体积较小、浅表肿瘤疗效显著,对恶性肿瘤治疗也有很好的辅助作用,在肿瘤治疗领域具有广阔的应用前景。     

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6 h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。     

石墨烯类材料在疾病诊断治疗方面的研究进展

石墨烯是处于蜂窝状晶体点阵上的碳原子以sp2杂化链接形成的单原子层二维晶体,因独特的结构及优异的性能而备受关注,并在复合材料、纳米电子器件、能量储存和转换、液晶显示等众多领域具有重要的应用前景.主要介绍石墨烯类材料在疾病诊断和治疗方面的应用研究,包括生物分子检测、生物成像等诊断检测和药物载体、光动力治疗等肿瘤治疗方面的应用,并展望了其在生物医学领域的发展前景.     

可生物降解纳米药物通过重塑肿瘤微环境和调节能量代谢高效治疗结直肠癌（英文）

顺铂(CDDP)是治疗结直肠癌的常用化疗药物,但其存在清除快、耐药和靶向性差等问题.同时,缺氧、高水平谷胱甘肽和快速能量代谢等复杂的肿瘤微环境,也是导致化疗疗效不理想的原因之一.本文首先在沸石咪唑框架上负载CDDP,而后在表面包裹二氧化锰外壳,最后以透明质酸(HA)作为靶向分子进行修饰,成功构建了一种肿瘤微环境响应型纳米平台(ZIF-90@CDDP@MnO₂@HA),实现了化疗、化学动力学疗法和饥饿疗法的联合治疗.肿瘤微环境响应性药物释放大大提高了化疗的疗效. MnO₂外壳一方面会消耗谷胱甘肽(GSH)以抑制CDDP解毒和活性氧(ROS)清除,同时,释放的Mn²⁺可实现化学动力治疗.另一方面, MnO₂通过原位氧气生成下调低氧诱导转录因子1α的表达,不仅能提高化疗耐受性,还能通过下调己糖激酶2和葡萄糖转运蛋白1的表达,抑制有氧糖酵解,进一步促进饥饿疗法.此外, ZIF-90释放的Zn²⁺会造成线粒体损伤,进一步抑制三磷酸腺苷(ATP)的产生,从而加强饥饿疗法.这种协同治疗策略在...     

Glucose Oxidase‐Instructed Multimodal Synergistic Cancer Therapy

Over the past 3 years, glucose oxidase (GOx) has aroused great research interest in the context of cancer treatment due to its inherent biocompatibility and biodegradability, and its unique catalytic properties against β‐d ‐glucose. GOx can effectively catalyze the oxidation of glucose into gluconic acid and hydrogen peroxide. This process depletes oxygen levels, resulting in elevated acidity, hypoxia, and oxidative stress in the tumor microenvironment. All of these changes can be readily harnessed to develop a multimodal synergistic cancer therapy by combining GOx with other therapeutic approaches. Herein, the representative studies of GOx‐instructed multimodal synergistic cancer therapy are introduced, and their synergistic mechanisms are discussed systematically. The current challenges and future prospects to advance the development of GOx‐based nanomedicines in this cutting‐edge research area are highlighted.     

Cuproptosis-Inducible Chemotherapeutic/Cascade Catalytic Reactor System for Combating with Breast Cancer

Cascade hydroxyl radical generating hydrogel reactor structures including a chemotherapeutic agent are invented for multiple treatment of breast cancer. Glucose oxidase (GOx) and cupric sulfate (Cu) are introduced for transforming accumulated glucose (in cancer cells) to hydroxyl radicals for starvation/chemodynamic therapy. Cu may also suppress cancer cell growth via cuproptosis-mediated cell death. Berberine hydrochloride (BER) is engaged as a chemotherapeutic agent in the hydrogel reactor for combining with starvation/chemodynamic/cuproptosis therapeutic modalities. Moreover, Cu is participated as a gel crosslinker by coordinating with catechol groups in hyaluronic acid-dopamine (HD) polymer. Controlling viscoelasticity of hydrogel reactor can extend the retention time following local injection and provide sustained drug release patterns. Low biodegradation rate of designed HD/BER/GOx/Cu hydrogel can reduce dosing frequency in local cancer therapy and avoid invasiveness-related inconveniences. Especially, it is anticipated that HD/BER/GOx/Cu hydrogel system can be applied for reducing size of breast cancer prior to surgery as well as tumor growth suppression in clinical application.     

Recent Advances in Glucose‐Oxidase‐Based Nanocomposites for Tumor Therapy

Glucose oxidase (GOx) can react with intracellular glucose and oxygen (O₂) to produce hydrogen peroxide (H₂O₂) and gluconic acid, which can cut off the nutrition source of cancer cells and consequently inhibit their proliferation. Therefore, GOx is recognised as an ideal endogenous oxido‐reductase for cancer starvation therapy. This process can further regulate the tumor microenvironment by increasing the hypoxia and the acidity. Thus, GOx offers new possibilities for the elaborate design of multifunctional nanocomposites for tumor therapy. However, natural GOx is expensive to prepare and purify and exhibits immunogenicity, short in vivo half‐life, and systemic toxicity. Furthermore, GOx is highly prone to degrade after exposure to biological conditions. These intrinsic shortcomings will undoubtedly limit its biomedical applications. Accordingly, some nanocarriers can be used to protect GOx from the surrounding environment, thus controlling or preserving the activity. A variety of nanocarriers including hollow mesoporous silica nanoparticles, metal–organic frameworks, organic polymers, and magnetic nanoparticles are summarized for the construction of GOx‐based nanocomposites for multimodal synergistic cancer therapy. In addition, current challenges and promising developments in this area are highlighted.     

Recent Advances in Upconversion Nanoparticles‐Based Multifunctional Nanocomposites for Combined Cancer Therapy

Lanthanide‐doped upconversion nanoparticles (UCNPs) have the ability to generate ultraviolet or visible emissions under continuous‐wave near‐infrared (NIR) excitation. Utilizing this special luminescence property, UCNPs are approved as a new generation of contrast agents in optical imaging with deep tissue‐penetration ability and high signal‐to‐noise ratio. The integration of UCNPs with other functional moieties can endow them with highly enriched functionalities for imaging‐guided cancer therapy, which makes composites based on UCNPs emerge as a new class of theranostic agents in biomedicine. Here, recent progress in combined cancer therapy using functional nanocomposites based on UCNPs is reviewed. Combined therapy referring to the co‐delivery of two or more therapeutic agents or a combination of different treatments is becoming more popular in clinical treatment of cancer because it generates synergistic anti‐cancer effects, reduces individual drug‐related toxicity and suppresses multi‐drug resistance through different mechanisms of action. Here, the recent advances of combined therapy contributed by UCNPs‐based nanocomposites on two main branches are reviewed: i) photodynamic therapy and ii) chemotherapy, which are the two most widely adopted therapies of UCNPs‐based composites. The future prospects and challenges in this emerging field will be also discussed.     

Programmable NIR‐II Photothermal‐Enhanced Starvation‐Primed Chemodynamic Therapy using Glucose Oxidase‐Functionalized Ancient Pigment Nanosheets

Chemodynamic therapy (CDT) has attracted considerable attention recently, but the poor reaction kinetics restrict its practical utility in clinic. Herein, glucose oxidase (GOx) functionalized ancient pigment nanosheets (SrCuSi₄O₁₀, SC) for programmable near‐infrared II (NIR‐II) photothermal‐enhanced starvation primed CDT is developed. The SC nanosheets (SC NSs) are readily exfoliated from SC bulk suspension in water and subsequently functionalized with GOx to form the nanocatalyst (denoted as SC@G NSs). Upon laser irradiation, the photothermal effect of SC NSs can enhance the catalytic activity of GOx for NIR‐II photothermal‐enhanced starvation therapy, which effectively eliminates intratumoral glucose and produces abundant hydrogen peroxide (H₂O₂). Importantly, the high photothermal‐conversion efficiency (46.3%) of SC@G NSs in second biological window permits photothermal therapy of deep‐seated tumors under the guidance of NIR‐II photoacoustic imaging. Moreover, the acidity amplification due to gluconic acid generation will in turn accelerate the degradation of SC NSs, facilitating the release of strontium (Sr) and copper (Cu) ions. Both the elevated H₂O₂ and the released ions will prime the Cu²⁺/Sr²⁺‐H₂O₂ reaction for enhanced CDT. Thus, a programmable NIR‐II photothermal‐enhanced starvation primed CDT is established to combat cancer with minimal side effects.     

A strategy for accurate detection of glucose in human serum and whole blood based on an upconversion nanoparticles-polydopamine nanosystem

The accurate detection of blood glucose is of critical importance in the diagnosis and management of diabetes and its complications. Herein, we report a novel strategy based on an upconversion nanoparticles-polydopamine (UCNPs-PDA) nanosystem for the accurate detection of glucose in human serum and whole blood through a simple blending of test samples with ligand-free UCNPs, dopamine, and glucose oxidase (GOx). Owing to the high affinity of lanthanide ions exposed on the surface of ligand-free UCNPs, dopamine monomers could spontaneously attach to the UCNPs and further polymerize to form a PDA shell, resulting in a remarkable upconversion luminescence (UCL) quenching (97.4%) of UCNPs under 980-nm excitation. Such UCL quenching can be effectively inhibited by H₂O₂ produced from the GOx/glucose enzymatic reaction, thus enabling the detection of H₂O₂ or glucose based on the UCL quenching/inhibition bioassay. Owing to the highly sensitive UCL response and background-free interference of the UCNPs-PDA nanosystem, we achieved a sensitive, selective, and high-throughput bioassay for glucose in human serum and whole blood, thereby revealing the great potential of the UCNPs-PDA nanosystem for the accurate detection of blood glucose or other H₂O₂-generated biomolecules in clinical bioassays.

Open image in new window

     

Light‐Induced ROS Generation and 2‐DG‐Activated Endoplasmic Reticulum Stress by Antitumor Nanosystems: An Effective Combination Therapy by Regulating the Tumor Microenvironment

A multimodal cancer therapeutic nanoplatform is reported. It demonstrates a promising approach to synergistically regulating the tumor microenvironment. The combination of intracellular reactive oxygen species (ROS) generated by irradiation of photosensitizer and endoplasmic reticulum (ER) stress induced by 2‐deoxy‐glucose (2‐DG) has a profound effect on necrotic or apoptotic cell death. Especially, targeting metabolic pathway by 2‐DG is a promising strategy to promote the effect of photodynamic therapy and chemotherapy. The nanoplatform can readily release its cargoes inside cancer cells and combines the advantages of ROS‐sensitive releasing chemotherapeutic drugs, upregulating apoptosis pathways under ER stress, light‐induced generation of cytotoxic ROS, achieving tumor accumulation, and in vivo fluorescence imaging capability. This work highlights the importance of considering multiple intracellular stresses as design parameters for nanoscale functional materials in cell biology, immune response, as well as medical treatments of cancer, Alzheimer's disease, etc.     

Red‐Emitting Upconverting Nanoparticles for Photodynamic Therapy in Cancer Cells Under Near‐Infrared Excitation

Upconverting nanoparticles (UCNPs) have attracted considerable attention as potential photosensitizer carriers for photodynamic therapy (PDT) in deep tissues. In this work, a new and efficient NIR photosensitizing nanoplatform for PDT based on red‐emitting UCNPs is designed. The red emission band matches well with the efficient absorption bands of the widely used commercially available photosensitizers (Ps), benefiting the fluorescence resonance energy transfer (FRET) from UCNPs to the attached photosensitizers and thus efficiently activating them to generate cytotoxic singlet oxygen. Three commonly used photosensitizers, including chlorine e6 (Ce6), zinc phthalocyanine (ZnPc) and methylene blue (MB), are loaded onto the alpha‐cyclodextrin‐modified UCNPs to form Ps@UCNPs complexes that efficiently produce singlet oxygen to kill cancer cells under 980 nm near‐infrared excitation. Moreover, two different kinds of drugs are co‐loaded onto these nanoparticles: chemotherapy drug doxorubicin and PDT agent Ce6. The combinational therapy based on doxorubicin (DOX)‐induced chemotherapy and Ce6‐triggered PDT exhibits higher therapeutic efficacy relative to the individual means for cancer therapy in vitro.     

A Cascade Nanoreactor of Metal-Protein-Polyphenol Capsule for Oxygen-Mediated Synergistic Tumor Starvation and Chemodynamic Therapy

Starvation therapy kills tumor cells via consuming glucose to cut off their energy supply. However, since glucose oxidase (GOx)-mediated glycolysis is oxygen-dependent, the cascade reaction based on GOx faces the challenge of a hypoxic tumor microenvironment. By decomposition of glycolysis production of H₂O₂ into O₂, starvation therapy can be enhanced, but chemodynamic therapy is limited. Here, a close-loop strategy for on demand H₂O₂ and O₂ delivery, release, and recycling is proposed. The nanoreactor (metal-protein-polyphenol capsule) is designed by incorporating two native proteins, GOx and hemoglobin (Hb), in polyphenol networks with zeolitic imidazolate framework as sacrificial templates. Glycolysis occurs in the presence of GOx with O₂ consumption and the produced H₂O₂ reacts with Hb to produce highly cytotoxic hydroxyl radicals (•OH) and methemoglobin (MHb) (Fenton reaction). Benefiting from the different oxygen carrying capacities of Hb and MHb, oxygen on Hb is rapidly released to supplement its consumption during glycolysis. Glycolysis and Fenton reactions are mutually reinforced by oxygen supply, consuming more glucose and producing more hydroxyl radicals and ultimately enhancing both starvation therapy and chemodynamic therapy. This cascade nanoreactor exhibits high efficiency for tumor suppression and provides an effective strategy for oxygen-mediated synergistic starvation therapy and chemodynamic therapy.