金属-有机框架材料在癌症诊疗中的应用

成像技术的迅速发展使科学家和临床医生能够准确地了解癌症的发病机制和病理过程, 并根据患者的情况制定个性化的治疗策略. 将各种成像与治疗试剂整合为一体的癌症诊疗平台, 可以同时用于癌症的诊断和治疗, 受到了广泛的关注. 金属-有机框架材料(MOFs)是由有机配体和金属离子/离子簇自组装而成的一种有趣而独特的多孔有机-无机杂化材料. 由于其易于后修饰、 孔隙和结构可设计、 功能可调等特点, 已被证明具有成为癌症诊疗药物负载平台的巨大潜力. 本文介绍了将诊疗药物负载到MOFs中的策略, 并综合评述了在磁共振成像、 计算机断层扫描成像、 正电子发射断层扫描成像、 光学成像和光声成像等多种成像技术指导下, MOFs作为癌症诊断和治疗平台的发展概况. 此外, 还讨论了MOFs在癌症诊疗和临床转化方面当前面临的挑战和发展前景.     

FeOOH-loaded mesoporous silica nanoparticles as a theranostic platform with pH-responsive MRI contrast enhancement and drug release

The development of stimuli-responsive theranostic platforms is of great demand for efficient cancer treatment because they can enhance diagnostic specificity and sensitivity.In this work,we report a p H-responsive theranostic nanoplatform based on Fe OOH clusters loaded mesoporous silica nanoparticles(Fe@MSNs).The as-synthesized Fe@MSNs possess activatable T_1magnetic resonance imaging(MRI)performance that can respond to the acidic microenvironment of solid tumor to turn on T_1singals by releasing paramagnetic Fe~(3+)ions.The Fe@MSNs are biocompatible without appreciable cytotoxicity.Moreover,the unique mesoporous structure endows the Fe@MSNs with significant advantages to effectively deliver chemotherapeutic drug for inhibiting the growth of solid tumor.We believe that this novel p H-responsive theranostic nanoplatform holds great promise in cancer treatment.     

Mn~(2+)-doped ZrO_2@PDA nanocomposite for multimodal imaging-guided chemo-photothermal combination therapy

Developing low toxicity and multifunctional theranostic nanoplatform is the key for precise cancer diagnosis and treatment.Herein,an inorganic-organic hybrid nanocomposite is designed by modifying zirconium dioxide(ZrO_2) with polydopamine(PDA) followed by doping Mn~(2+) ions and functionalizing with Tween 20(Tween-ZrO_2@PDA-Mn~(2+)) for multimodal imaging and chemo-photothermal combination therapy.The as-prepared nanocomposite exhibits good biocompatibility in vitro and in vivo.Specifically,it can be employed as a multifunctional platform not only for computed tomography(CT)imaging and T_1-weighted magnetic resonance(MR) imaging,but also for efficient chemotherapeutic drug doxorubicin hydrochloride(DOX) loading.Importantly,because of the pronounced photothermal conversion performance and controllable DOX release ability triggered by the near-infrared(NIR)irradiation and acidic pH,the synergistic effect between photothermal the rapy and chemotherapy results in an enhanced cancer treatment efficacy in vivo.Our work provides a high-performance inorganicorganic hybrid nanotheranostic platform for chemo-photothermal cancer therapy guided by CT and MR imaging.     

Novel photo-theranostic GdB6 nanoparticles for fluorescence imaging and NIR-photothermal therapy

The development of multifunctional theranostic nano-agents is an important resolution for personalized treatment of cancer. In this work, we synthesized a new kind of gadolinium boride nanoparticles (GBN) by a microwave-assisted chemical etching method, and discovered their optical characteristics including fluorescence imaging and near-infrared (NIR) photothermal conversion capability. Bright greenishyellow fluorescence enabled for intracellular localization, while effective NIR-photothermal conversion supported photothermal therapy (PTT). In vitro and in vivo results indicated that GBN exhibited a superior antitumor performance and high biocompatibility. This study demonstrated a promising multifunctional theranostic nanoplatform for cancer treatment.     

Functionalization of Metal and Carbon Nanoparticles with Potential in Cancer Theranostics

Cancer theranostics is a new concept of medical approach that attempts to combine in a unique nanoplatform diagnosis, monitoring and therapy so as to provide eradication of a solid tumor in a non-invasive fashion. There are many available solutions to tackle cancer using theranostic agents such as photothermal therapy (PTT) and photodynamic therapy (PDT) under the guidance of imaging techniques (e.g., magnetic resonance—MRI, photoacoustic—PA or computed tomography—CT imaging). Additionally, there are several potential theranostic nanoplatforms able to combine diagnosis and therapy at once, such as gold nanoparticles (GNPs), graphene oxide (GO), superparamagnetic iron oxide nanoparticles (SPIONs) and carbon nanodots (CDs). Currently, surface functionalization of these nanoplatforms is an extremely useful protocol for effectively tuning their structures, interface features and physicochemical properties. This approach is much more reliable and amenable to fine adjustment, reaching both physicochemical and regulatory requirements as a function of the specific field of application. Here, we summarize and compare the most promising metal- and carbon-based theranostic tools reported as potential candidates in precision cancer theranostics. We focused our review on the latest developments in surface functionalization strategies for these nanosystems, or hybrid nanocomposites consisting of their combination, and discuss their main characteristics and potential applications in precision cancer medicine.     

A H_2S-triggered two-photon ratiometric fluorescent theranostic prodrug for bio-imaging

Hydrogen sulfide(H_2 S) is a signaling molecule that plays important roles in biological systems.The exploration of H_2 S as a new drug release trigger and its related fluorescent theranostic system is crucial for cancer bio-imaging and therapy.Herein,we designed a new two-photon ratiometric fluorescent theranostic prodrug(compound 1) and studied its spectroscopic properties and application in in vivo imaging.Compound 1 specifically reacted with H_2 S and released the free active therapeutic component of 7-ethyl-10-hydroxycamptothecin,which was accompanied with a red-shift fluorescence emission signal from 460 nm to 545 nm.The exogenous and endogenous H_2 S in living cells were imaged by compound 1 under one-photon and two-photon excitation.Furthermore,compound 1 monitored the H_2 S concentration changes in Caenorhabditis elegans by fluorescence imaging.Additionally,it showed effective drug release activation in situ tumor with exogenous and endogenous H_2 S as the trigger.The H_2 S-sensitive activation and drug-release properties highlight the potential of theranostic compound 1 in future cancer treatment and therapy.     

Cyanostilbene-based near-infrared emissive platinum(II) metallacycles for cancer theranostics

In this work,a near-infrared emissive dipyridyl ligand was synthesized and used to prepare three platinum (II) metallacycles with different shapes via metal-coordination-driven self-assembly with different platinum (II) precursors.These metallacycles were further used for both cell imaging and cancer therapy, offering a new type of theranostic agents towards cancer treatment.     

Cyanostilbene-based near-infrared emissive platinum(Ⅱ) metallacycles for cancer theranostics

In this work,a near-infrared emissive dipyridyl ligand was synthesized and used to prepare three platinum(Ⅱ) metallacycles with different shapes via metal-coordination-driven self-assembly with different platinum(Ⅱ) precursors.These metallacycles were further used for both cell imaging and cancer therapy,offering a new type of theranostic agents towards cancer treatment.     

整合荧光成像和化疗的有机小分子诊疗探针的研究进展

将诊断与治疗功能结合为一体是当前应对癌症的一种新兴策略. 诊疗一体化作为一种潜在的新型医学诊治方式, 在快速获得体内信息、 改善生物分布、 减少剂量和降低毒副作用等方面具有潜在的应用前景. 荧光成像被广泛应用于医学诊断, 近年来近红外荧光成像技术得到飞速发展, 在活体成像方面具有较好的穿透深度和成像分辨率. 本文综合评述了部分整合荧光成像和化疗的有机单分子诊疗试剂的相关研究, 并对诊疗一体化探针的未来研究进行了展望.     

A two-dimensional molecular beacon for mRNA-activated intelligent cancer theranostics

Ideal theranostics should possess directly correlated imaging and therapy modalities that could be simultaneously activated in the disease site to generate high imaging contrast and therapeutic efficacy with minimal side effects. However, so far it still remains challenging to engineer all these characteristics into a single theranostic probe. Herein, we report a new type of photosensitizer (PS)-derived “two-dimensional” molecular beacon (TMB) that could be specifically activated within tumor cells to exhibit both high imaging contrast and therapeutic efficacy that outperforms conventional photosensitizers for cancer theranostics. The TMB is constructed by integrating a photosensitizer (chlorin e6 (Ce6)), a quantum dot (QD), and a dark quencher (BHQ3) into a hairpin DNA molecule to generate multiple synergistic FRET modes. The imaging modality and therapy modality, which are mediated by FRET between the QD and BHQ3 and FRET between the QD and Ce6 respectively, are interconnected within the TMB and could be simultaneously activated by tumor mRNA molecules. We show that highly effective cancer imaging and therapy could be achieved for cancer cell lines and xenografted tumor models. The reported TMB represents an unprecedented theranostic platform for intelligent cancer theranostics.     

ZnO‐Functionalized Upconverting Nanotheranostic Agent: Multi‐Modality Imaging‐Guided Chemotherapy with On‐Demand Drug Release Triggered by pH

Limited therapeutic efficiency and severe side effects in patients are two major issues existing in current chemotherapy of cancers in clinic. To design a proper theranostic platform seems thus quite needed to target cancer cells accurately by bioimaging and simultaneously release drugs on demand without premature leakage. A novel ZnO‐functionalized upconverting nanotheranostic platform has been fabricated for clear multi‐modality bioimaging (upconversion luminescence (UCL), computed tomography (CT), and magnetic resonance imaging (MRI)) and specific pH‐triggered on‐demand drug release. In our theranostic platform multi‐modality imaging provides much more detailed and exact information for cancer diagnosis than single‐modality imaging. In addition, ZnO can play the role of a “gatekeeper” to efficiently block the drug in the mesopores of the as‐prepared agents until it is dissolved in the acidic environment around tumors to realize sustained release of the drug. More importantly, the biodegradable ZnO, which is non‐toxic against normal tissues, endows the as‐prepared agents with high therapeutic effectiveness but very low side effects. These findings are of great interests and will inspire us much to develop novel effective imaging‐guided on‐demand chemotherapies in cancer treatment.     

Polyethylene glycol phospholipids encapsulated silicon 2,3-naphthalocyanine dihydroxide nanoparticles (SiNcOH-DSPEPEG(NH2) NPs) for single NIR laser induced cancer combination therapy

Currently, the combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has emerged as a powerful technique for cancer treatment. However, most examples of combined PTT and PDT reported use multi-component nanocomposites under excitation of separate wavelength, resulting in complex treatment process. In this work, a novel theranostic nanoplatform (SiNcOH-DSPE-PEG(NH₂) NPs) has been successfully developed by coating silicon 2,3-naphthalocyanine dihydroxide (SiNcOH) with DSPE-PEG and DSPE-PEG-NH₂ for photoacoustic (PA) imaging-guided PTT and PDT tumor ablation for the first time. The as-prepared single-agent SiNcOH-DSPE-PEG(NH₂) NPs not only have good water solubility and biocompatibility, but also exhibit high photothermal conversion efficiency and singlet oxygen generation capability upon 808 nm NIR laser irradiation. In addition, owing to their high absorption at NIR region, the SiNcOH-DSPE-PEG(NH₂) NPs can also be employed as an effective diagnostic nanoagent for photoacoustic (PA) imaging. In vitro and in vivo experimental results clearly indicated that the simultaneously combined PTT and PDT under the guidance of PA imaging with single NIR laser excitation can effectively kill cancer cells or eradicate tumor tissues. Taking facile synthesis and high efficiency in cancer treatment by SiNcOH-DSPE-PEG(NH₂) NPs into consideration, our study provides a promising strategy to realize molecular imaging-guided combination therapy.     

纳米技术在物理刺激诱导肿瘤治疗中的应用探索

物理刺激诱导的治疗通常是利用多功能诊疗试剂对外界物理刺激,如光、磁场、超声、射频以及X射线等的响应性进行治疗的策略。近年来,这种新颖的癌症治疗方法在临床前期的动物实验组取得了良好的实验结果,因而该策略也备受关注。与传统的化疗疗法不同,物理刺激响应性的试剂本身通常是无毒性的,只有在特定的物理刺激之下才会在病灶部位产生治疗效果。此外,物理刺激诱导的治疗方法还可以与传统治疗策略结合,通过不同的机制达到协同治疗的目的。在这篇综述中,我们将阐述物理刺激诱导治疗的最新发展动态,并深入讨论纳米诊疗试剂在该治疗策略中的重要作用。     

Silica-based nanoprobes for biomedical imaging and theranostic applications

Nanoparticle-based contrast agents are attracting a great deal of attention for various biomedical imaging and theranostic applications. Compared to conventional contrast agents, nanoparticles possess several potential advantages to improve in vivo detection and to enhance targeting efficiency. Silica-based nanoprobes can be engineered to achieve longer blood circulation times, specific clearance pathways, and multivalent binding. In this tutorial review, we summarize the latest progress on designing silica-based nanoprobes for imaging and theranostic applications. The synthesis of both solid silica and mesoporous silica nanoparticles is described, along with different approaches used for surface functionalization. Special emphasis is placed on the application of silica-based nanoprobes in optical, magnetic resonance, and multimodal imaging. The latest breakthroughs in the applications of silica nanoparticles as theranostic agents are also highlighted.     

Platinum(II)–Gadolinium(III) Complexes as Potential Single‐Molecular Theranostic Agents for Cancer Treatment

Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)–gadolinium(III) complexes with the formula [{Pt(NH₃)₂Cl}₂GdL](NO₃)₂ possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt–Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mM ), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd–DTPA. T₁‐weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt–Gd complexes promising theranostic agents for cancer treatment.     

Design of an intelligent sub-50 nm nuclear-targeting nanotheranostic system for imaging guided intranuclear radiosensitization

Clinically applied chemotherapy and radiotherapy is sometimes not effective due to the limited dose acting on DNA chains resident in the nuclei of cancerous cells. Herein, we develop a new theranostic technique of “intranuclear radiosensitization” aimed at directly damaging the DNA within the nucleus by a remarkable synergetic chemo-/radiotherapeutic effect based on intranuclear chemodrug-sensitized radiation enhancement. To achieve this goal, a sub-50 nm nuclear-targeting rattle-structured upconversion core/mesoporous silica nanotheranostic system was firstly constructed to directly transport the radiosensitizing drug Mitomycin C (MMC) into the nucleus for substantially enhanced synergetic chemo-/radiotherapy and simultaneous magnetic/upconversion luminescent (MR/UCL) bimodal imaging, which can lead to efficient cancer treatment as well as multi-drug resistance circumvention in vitro and in vivo. We hope the technique of intranuclear radiosensitization along with the design of nuclear-targeting nanotheranostics will contribute greatly to the development of cancer theranostics as well as to the improvement of the overall therapeutic effectiveness.     

PAMAM Dendrimer‐Based Nanodevices for Nuclear Medicine Applications

Nuclear medicine, involving nuclear medicine imaging and radiotherapy (RT), has become a mainstay of theranostics in the field of nanomedicine and several examples have been successfully translated into clinical practice. The combination of radionuclides with dendrimers has long been investigated in nuclear imaging, such as positron emission tomography (PET) and single‐photon emission computed tomography (SPECT), providing functional information for whole body quantitative analysis with high sensitivity due to the unique structural advantages of the dendrimer platform. Besides, radioisotopes with both therapeutic and imaging functionalities can also be combined with dendrimer platforms for theranostic applications. In this review, the recent advances in the development of radionuclide‐labeled poly(amidoamine) dendrimer‐based nanodevices for targeted PET, SPECT, SPECT/computed tomography, SPECT/magnetic resonance imaging of tumors, RT, as well as for SPECT‐imaging‐guided RT of cancer are summarized. Current restrictions hindering the clinical translation of dendrimer‐based nuclear nanodevices and future prospects are also discussed.     

Dual-Targeting Biomimetic Semiconducting Polymer Nanocomposites for Amplified Theranostics of Bone Metastasis

Bone metastasis is a type of metastatic tumors that involves the spreads of malignant tumor cells into skeleton, and its diagnosis and treatment remain a big challenge due to the unique tumor microenvironment. We herein develop osteoclast and tumor cell dual-targeting biomimetic semiconducting polymer nanocomposites (SPFeN_OC) for amplified theranostics of bone metastasis. SPFeN_OC contain semiconducting polymer and iron oxide (Fe₃O₄) nanoparticles inside core and surface camouflaged hybrid membrane of cancer cells and osteoclasts. The hybrid membrane camouflage enables their targeting to both metastatic tumor cells and osteoclasts in bone metastasis through homologous targeting mechanism, thus achieving an enhanced nanoparticle accumulation in tumors. The semiconducting polymer mediates near-infrared (NIR) fluorescence imaging and sonodynamic therapy (SDT), and Fe₃O₄ nanoparticles are used for magnetic resonance (MR) imaging and chemodynamic therapy (CDT). Because both cancer cells and osteoclasts are killed synchronously via the combinational action of SDT and CDT, the vicious cycle in bone metastasis is broken to realize high antitumor efficacy. Therefore, 4T1 breast cancer-based bone metastasis can be effectively detected and cured by using SPFeN_OC as dual-targeting theranostic nanoagents. This study provides an unusual biomimetic nanoplatform that simultaneously targets osteoclasts and cancer cells for amplified theranostics of bone metastasis.     

Development of nitroxide‐based theranostic compounds that act both as anti‐inflammatory drugs and brain redox imaging probes in MRI

Theranostic probes provide both therapeutic and diagnostic imaging capabilities in one molecule and show significant promise for use in magnetic resonance imaging (MRI) examinations. The present study describes for the first time the synthesis and utility of nitroxide‐based contrast agents exhibiting a nonsteroidal anti‐inflammatory drug effect. The target theranostic probes were prepared by connecting the carboxyl group of ibuprofen or ketoprofen to the hydroxyl group of 3‐hydroxymethyl‐2,2,5,5‐tetramethylprrolidine‐1‐oxyl by a condensation reaction in the presence of dicyclohexylcarbodiimide and 4‐dimethylaminopyridine in dichloromethane. MRI of mouse heads after administration of either synthesized theranostic probe indicated that the probes enter the brain by passing through the blood–brain barrier (BBB), resulting in T1 contrast enhancement in mouse brain. This enhancement persisted for the duration of the half‐life of about 40 min, which is longer than that obtained by most of pyrrolidine nitroxide molecules. The therapeutic capacities of these theranostic probes were examined using a lipopolysaccharide (LPS)‐induced brain inflammation model. The production of nitric oxide, an inflammation marker in septic mouse brain induced by LPS, was remarkably inhibited by the addition of either synthesized probe, indicating that they also act as anti‐inflammatory drugs. The present results indicate that nitroxide‐based theranostic probes act as both BBB‐permeable redox‐sensitive contrast agents and as an anti‐inflammatory drug in septic mouse brain. Copyright © 2016 John Wiley & Sons, Ltd.     

Magnetic Hybrid Wax Nanocomposites as Externally Controlled Theranostic Vehicles: High MRI Enhancement and Synergistic Magnetically Assisted Thermo/Chemo Therapy

To fight against cancer, smarter drugs and drug delivery systems are required both to boost the efficiency of current treatments while reducing deleterious side effects, and combine diagnosis/monitoring with therapy (theranosis) in the search for the final goal of personalized medicine. This work presents the design, preparation, and proof-of-principle validation of a novel hybrid organic–inorganic nanocomposite joining together non-invasive imaging capabilities through magnetic resonance imaging and externally actuated therapeutic properties through a combination of chemo- and thermotherapy. The lipidic matrix of the nanocomposite was composed of carnauba wax, which was simultaneously dual loaded with magnetite nanoparticles and the anticancer drug Oncocalyxone A. Obtained formulations were fully characterized and showed outstanding performances as T₂-contrast agents in magnetic resonance imaging (r₂>800 mm ⁻¹ s⁻¹), heat generating sources in magnetic hyperthermia (specific absorption rate, SAR>200 W g⁻¹_Fe), and magnetically responsive drug delivery vehicles. The potential of the designed formulations as theranostic agents was validated in vitro and results indicated a synergistic thermo/chemotherapeutic effect derived from heat generation and controlled drug delivery to cancer growth. Thereby, this external control over the drug delivery profile and the integrated imaging capability open the door to personalized cancer medicine and real-time monitoring of tumor progression.