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.     

H2O2-responsive theranostic nanomedicine

This review summarizes and discusses the very-recent developments of H₂O₂-responsive theranostic nanoplatforms for versatile biomedical applications, including diagnostic imaging, attenuating tumor hypoxia, enhancing the therapeutic effi ciency of photodynamic therapy/radiation therapy/chemotherapy and theranostic of inflammation/diabetic. It is highly believed that H₂O₂-responsive theranostic nanomedicine will be extensively developed a new specifi c and effi cient theranostic modality to benefi t the personalized biomedicine in the near future.     

Recent progress in theranostic microbubbles

Ultrasonography is an important complement to clinical diagnosis, and the application of microbubbles effectively improved diagnostic accuracy in echography. In scientific research, the sizes of microbubbles range from nanometers to microns. By optimizing the fabrication process, bubble sizes and ultrasound parameters, microbubbles can also be used for drug delivery and therapeutic monitoring. In this review,we summarize the recent advances in the diagnosis and treatment of microbubbles accordin...     

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.     

Inorganic hybrid nanoparticles in cancer theranostics: understanding their combinations for better clinical translation

Drug resistance, tumor heterogeneity, and poor selectivity make cancer treatment with current modalities a challenging and complicated task. Careful planning of diagnosis and therapy is required to build new strategies for treatment and management of cancer. The amalgamation of therapeutics and diagnostics in a single nano agent, known as theranostics is now possible due to the emergence of nanotechnology. Theranostics offers opportunities for personalized medicine by real-time monitoring of drug accumulation and dynamic modification of treatment depending on individual patient needs. Thus potential to reform disease management is held by theranostic nanoparticles. Amongst other nanosystems, inorganic nanoparticles have been widely used for developing theranostic drug delivery systems due to their favorable intrinsic properties. The last decade has seen a surge in development of such theranostic nanoparticles in which various inorganic materials in different combinations have been engineered to maximize the output with respect to specific applications. For example, Fe₃O₄@Au nanoparticles were developed for MRI, hyperthermia and magnetically controlled drug delivery. Several such combinations leading to innovative theranostic applications and their underlying mechanisms have been highlighted in this review. A review of patents and clinical trials of inorganic theranostic nanoparticles is also presented through which we understood that clinical translation still remains in the nascent stage. Thus, it is necessary to find and understand reasons for lack of clinical translations. Therefore, we have discussed the challenges associated with bench-to-bed translation of such inorganic nanoparticles which show immense potential in vitro but fail to deliver in long run.     

Glutathione-triggered non-template synthesized porous carbon nanospheres serve as low toxicity targeted delivery system for cancer multi-therapy

Nanomaterial based drug delivery system have received great attention in clinical application due to their high therapeutic efficacy and lower side effects than classical method, multi-functional nanomaterial also have shown the excellent performance at cancer theranostic and durg tracking in vivo and in vitro. However, most of these works are influenced by the bio-toxicity of applied nanomaterials, which could influence the diagnostic results and treatment effect. Therefore, we have prepared a high biocompatibility porous carbon nanospheres (PCNs) based nano-system (PCN-siRNA-DOX-FA) for targeted drug delivery and theranostic. The surface modifications have increased dispersion and stability of the PCNs, and folic acid (FA) had enhanced the active target ability for FA receptor positive cell lines. Moreover, through the siRNA structure and doxorubicin (DOX) loading, biological and chemical combined multi-therapy was achieved in cancerous cells. This constructed nano-system could positively improve the biotoxicity problem of nanomaterial and provide a potential platform for clinical cancer theranostic applications.     

Carbon nanomaterials in microbial sensing and bactericidal applications

The spread of antimicrobial resistance and lesser development of new antibiotics have intensified the search for new antimicrobial and diagnostic vehicles. Carbon nanomaterials (CNMs), which broadly include carbon dots, carbon nanotubes, and graphene/graphene oxide nanostructures, have emerged as promising theranostic materials exhibiting, in many instances, potent antibacterial activities and diagnostic capabilities. Ease of synthesis, tunable physicochemical properties, biocompatibility, and diverse modes of action make CNMs a powerful class of theranostic nanomaterials. This review discusses recent studies illuminating innovative new CNMs and their applications in bacterial theranostics. We particularly emphasize the relationship between the structural parameters and overall chemical properties of CNMs and their biological impact and utilization. Overall, the expanding work on the development and use of CNMs in therapeutic, sensing, and diagnostic applications in the microbial world underscores the considerable potential of these nanomaterials.     

PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response

Theranostics are emerging as a pillar of cancer therapy that enable the use of single molecule constructs for diagnostic and therapeutic application. As poly adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) is overexpressed in various cancer types, and is localized to the nucleus, PARP-1 can be safely targeted with Auger emitters to induce DNA damage in tumors. Here, we investigated a radioiodinated PARP inhibitor, [¹²⁵I]KX1, and show drug target specific DNA damage and subsequent killing of BRCA1 and non-BRCA mutant ovarian cancer cells at sub-pharmacological concentrations several orders of magnitude lower than traditional PARP inhibitors. Furthermore, we demonstrated that viable tumor tissue from ovarian cancer patients can be used to screen tumor radiosensitivity ex-vivo, enabling the direct assessment of therapeutic efficacy. Finally, we showed tumors can be imaged by single-photon computed tomography (SPECT) with PARP theranostic, [¹²³I]KX1, in a human ovarian cancer xenograft mouse model. These data support the utility of PARP-1 targeted radiopharmaceutical therapy as a theranostic option for PARP-1 overexpressing ovarian cancers.     

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.     

Marine Exopolysaccharide Complexed With Scandium Aimed as Theranostic Agents

(1) Background: Exopolysaccharide (EPS) derivatives, produced by Alteromonas infernus bacterium, showed anti-metastatic properties. They may represent a new class of ligands to be combined with theranostic radionuclides, such as ⁴⁷Sc/⁴⁴Sc. The goal of this work was to investigate the feasibility of such coupling. (2) Methods: EPSs, as well as heparin used as a drug reference, were characterized in terms of molar mass and dispersity using Asymmetrical Flow Field-Flow Fractionation coupled to Multi-Angle Light Scattering (AF4-MALS). The intrinsic viscosity of EPSs at different ionic strengths were measured in order to establish the conformation. To determine the stability constants of Sc with EPS and heparin, a Free-ion selective radiotracer extraction (FISRE) method has been used. (3) Results: AF4-MALS showed that radical depolymerization produces monodisperse EPSs, suitable for therapeutic use. EPS conformation exhibited a lower hydrodynamic volume for the highest ionic strengths. The resulting random-coiled conformation could affect the complexation with metal for high concentration. The LogK of Sc-EPS complexes have been determined and showing that they are comparable to the Sc-Hep. (4) Conclusions: EPSs are very promising to be coupled with the theranostic pair of scandium for Nuclear Medicine.     

Theranostic nanomedicine by surface nanopore engineering

Theranostic nanomedicine that integrates diagnostic and therapeutic agents into one nanosystem has gained considerable momentum in the field of cancer treatment. Among diverse strategies for achieving theranostic capabilities, surface-nanopore engineering based on mesoporous silica coating has attracted great interest because of their negligible cytotoxicity and chemically active surface that can be easily modified to introduce various functional groups(e.g.,-COOH,-NH_2,-SH, etc.) via silanization, which can satisfy various requirements of conjugating biological molecules or functional nanoparticles. In addition,the nanopore-engineered biomaterials possess large surface area and high pore volume, ensuring desirable loading of therapeutic guest molecules. In this review, we comprehensively summarize the synthetic procedure/paradigm of nanopore engineering and further broad theranostic applications. Such nanopore-engineering strategy endows the biocompatible nanocomposites(e.g., Au,Ag, graphene, upconversion nanoparticles, Fe_3O_4, MXene, etc.) with versatile functional moieties, which enables the development of multifunctional nanoplatforms for multimodal diagnostic bio-imaging, photothermal therapy, photodynamic therapy,targeted drug delivery, synergetic therapy and imaging-guided therapies. Therefore, mesoporous silica-based surface-nanopore engineering integrates intriguing unique features for broadening the biomedical applications of the single mono-functional nanosystem, facilitating the development and further clinical translation of theranostic nanomedicine.     

Photophysical Properties of Emissive Pyrido[3,2‐c]carbazole Derivatives and Apoptosis Induction: Development towards Theranostic Agents in Response to Light Stimulus

Pyridocarbazole moieties are present in many natural products, such as olivacine and ellipticine, and their derivatives are well‐known anticancer agents. To develop functional therapeutic and diagnostic compounds, three emissive pyrido[3,2‐c]carbazole derivatives, PC‐X , containing secondary or tertiary amine groups, were synthesized from an aminoquinoline derivative using a palladium complex as the catalyst. X‐ray diffraction analyses revealed that PC‐X showed highly planar structures between the pyridine ring and the carbazole framework, exhibiting high fluorescence intensities along with solvatochromic behavior. Imaging of HeLa cells treated with PC‐X showed no specific accumulation into the organelles; however, a comparative examination showed that the accumulation in mitochondria was the highest as compared to nuclei and lysosomes. Cytotoxicity analysis using HeLa cells showed that PC‐H, containing a secondary amine group showed the highest cytotoxicity (IC₅₀≈20 μm ) as compared to another PC‐X having a tertiary amine group. Colocalization with MitoTracker, a typical mitochondrial staining dye, showed apoptosis‐like behavior with remarkable appearance of blebbing during irradiation with near UV light (403 nm), suggesting that the PC‐H may not only behave as a fluorescence probe for the imaging organelles, but also as a therapeutic agent for inducing apoptosis in HeLa cells, thereby functioning as a theranostic agent.     

Dual-Emissive Platinum(II) Metallacage with a Sensitive Oxygen Response for Imaging of Hypoxia and Imaging-Guided Chemotherapy

Imaging of hypoxia in vivo helps with accurate cancer diagnosis and evaluation of therapeutic outcomes. A Pt^II metallacage with oxygen-responsive red phosphorescence and steady fluorescence for in vivo hypoxia imaging and chemotherapy is reported. The therapeutic agent and diagnostic probe were integrated into the metallacage through heteroligation-directed self-assembly. Nanoformulation by encapsulating the metallacage into nanoparticles greatly enhanced its stability the in physiological environment, rendering biomedical applications feasible. Apart from enhanced red phosphorescence upon hypoxia, the ratio between red and blue emissions, which only varies with intracellular oxygen level, provides a more precise standard for hypoxia imaging and detection. Moreover, in vivo explorations demonstrate the promising potential applications of the metallacage-loaded nanoparticles as theranostic agents for tumor hypoxia imaging and chemotherapy.     

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。     

Plant-Based Synthesis of Gold Nanoparticles and Theranostic Applications: A Review

Bionanotechnology is a branch of science that has revolutionized modern science and technology. Nanomaterials, especially noble metals, have attracted researchers due to their size and application in different branches of sciences that benefit humanity. Metal nanoparticles can be synthesized using green methods, which are good for the environment, economically viable, and facilitate synthesis. Due to their size and form, gold nanoparticles have become significant. Plant materials are of particular interest in the synthesis and manufacture of theranostic gold nanoparticles (NPs), which have been generated using various materials. On the other hand, chemically produced nanoparticles have several drawbacks in terms of cost, toxicity, and effectiveness. A plant-mediated integration of metallic nanoparticles has been developed in the field of nanotechnology to overcome the drawbacks of traditional synthesis, such as physical and synthetic strategies. Nanomaterials′ tunable features make them sophisticated tools in the biomedical platform, especially for developing new diagnostics and therapeutics for malignancy, neurodegenerative, and other chronic disorders. Therefore, this review outlines the theranostic approach, the different plant materials utilized in theranostic applications, and future directions based on current breakthroughs in these fields.     

Engineered Targeted Hyaluronic Acid–Glutathione‐Stabilized Gold Nanoclusters/Graphene Oxide–5‐Fluorouracil as a Smart Theranostic Platform for Stimulus‐Controlled Fluorescence Imaging‐Assisted Synergetic Chemo/Phototherapy

A theranostic platform with integrated diagnostic and therapeutic functions as well as specific targeted and controlled combination therapy to enhance treatment efficacy is of great importance for a wide range of biomedical applications. Here, we first attempted to develop biocompatible hyaluronic acid (HA)–glutathione (GSH) conjugate stabilized gold nanoclusters (GNCs) combined with graphene oxide (GO), accompanied by loading 5‐fluorouracil (5FU), as a novel theranostic platform (HG‐GNCs/GO‐5FU, HG refers to HA‐GSH). Multifunctional HG‐GNCs possessed excellent fluorescence, photosensitivity and specific targeting ability to the cancer cells while their fluorescence and singlet oxygen generation could be strongly inhibited by GO and then effectively restored by lysosomal hyaluronidase in tumor cells. The sustained and complete release of 5FU from HG‐GNCs/GO could also be stimulated successively by enzymatic degradation of HA and light‐induced heat effect of GO under laser irradiation so that turn‐on cell imaging‐assisted synergistic therapeutic strategies associated with triple enzyme/light‐controlled chemo/photothermal/photodynamic therapy could be achieved at the same time, reducing greatly the side effects of materials to normal cells. Our study presents a novel strategy to combine targeting and bioimaging with triple therapies to enhance the antitumor effect.     

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.     

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.     

Targeted and modular architectural polymers employing bioorthogonal chemistry for quantitative therapeutic delivery

There remain several key challenges to existing therapeutic systems for cancer therapy, such as quantitatively determining the true, tissue-specific drug release profile in vivo, as well as reducing side-effects for an increased standard of care. Hence, it is crucial to engineer new materials that allow for a better understanding of the in vivo pharmacokinetic/pharmacodynamic behaviours of therapeutics. We have expanded on recent “click-to-release” bioorthogonal pro-drug activation of antibody-drug conjugates (ADCs) to develop a modular and controlled theranostic system for quantitatively assessing site-specific drug activation and deposition from a nanocarrier molecule, by employing defined chemistries. The exploitation of quantitative imaging using positron emission tomography (PET) together with pre-targeted bioorthogonal chemistries in our system provided an effective means to assess in real-time the exact amount of active drug administered at precise sites in the animal; our methodology introduces flexibility in both the targeting and therapeutic components that is specific to nanomedicines and offers unique advantages over other technologies. In this approach, the in vivo click reaction facilitates pro-drug activation as well as provides a quantitative means to investigate the dynamic behaviour of the therapeutic agent.

There remain several key challenges to existing therapeutic systems for cancer therapy, such as quantitatively determining the true, tissue-specific drug release profile in vivo, as well as reducing side-effects for an increased standard of care.