Theranostic Nanoplatform with Hydrogen Sulfide Activatable NIR Responsiveness for Imaging‐Guided On‐Demand Drug Release

NIR light responsive nanoplatforms hold great promise for on‐demand drug release in precision cancer medicine. However, currently available systems utilize “always‐on” photothermal transducers that lack target specificity, and thus inaccurately differentiate tumors from normal tissues. Developed here is a theranostic nanoplatform featuring H₂S‐mediated in situ production of NIR photothermal agents for imaging‐guided and photocontrolled drug release. The system targets H₂S‐rich cancers. This nanoplatform shows H₂S‐activatable NIR‐II emission and NIR light controllable release of the drug Camptothecin‐11. Upon administering the system to HCT116 tumor‐bearing mice, the tumor is greatly suppressed with minimal side effects, arising from the synergy of the cancer‐specific and NIR light activated therapy. This theranostic nanoplatform thus sheds light on precision medicine with guidance through NIR‐II imaging.     

Conjugated‐Polyelectrolyte‐Based Polyprodrug: Targeted and Image‐Guided Photodynamic and Chemotherapy with On‐Demand Drug Release upon Irradiation with a Single Light Source

Nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform are highly desirable for molecular medicine. Herein we report a novel theranostic platform based on a conjugated‐polyelectrolyte (CPE) polyprodrug that contains functionality for image, chemo‐ and photodynamic therapy (PDT), and on‐demand drug release upon irradiation with a single light source. Specifically, the PEGylated CPE serves as a photosensitizer and a carrier, and is covalently conjugated to doxorubicin through a linker that can be cleaved by reactive oxygen species (ROS). Under appropriate light irradiation, the CPE can generate ROS, not only for PDT, but also for on‐demand drug release and chemotherapy. This nanoplatform will offer on‐demand PDT and chemotherapy with drug release triggered by one light switch, which has great potential in cancer treatment.     

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.     

Semi‐Interpenetrated Hydrogels‐Microfibers Electroactive Assemblies for Release and Real‐Time Monitoring of Drugs

Simultaneous drug release and monitoring using a single polymeric platform represents a significant advance in the utilization of biomaterials for therapeutic use. Tracking drug release by real‐time electrochemical detection using the same platform is a simple way to guide the dosage of the drug, improve the desired therapeutic effect, and reduce the adverse side effects. The platform developed in this work takes advantage of the flexibility and loading capacity of hydrogels, the mechanical strength of microfibers, and the capacity of conducting polymers to detect the redox properties of drugs. The engineered platform is prepared by assembling two spin‐coated layers of poly‐γ‐glutamic acid hydrogel, loaded with poly(3,4‐ethylenedioxythiophene) (PEDOT) microparticles, and separated by a electrospun layer of poly‐ε‐caprolactone microfibers. Loaded PEDOT microparticles are used as reaction nuclei for the polymerization of poly(hydroxymethyl‐3,4‐ethylenedioxythiophene) (PHMeDOT), that semi‐interpenetrate the whole three layered system while forming a dense network of electrical conduction paths. After demonstrating its properties, the platform is loaded with levofloxacin and its release monitored externally by UV–vis spectroscopy and in situ by using the PHMeDOT network. In situ real‐time electrochemical monitoring of the drug release from the engineered platform holds great promise for the development of multi‐functional devices for advanced biomedical applications.     

Polyethylenimine‐Based Nanogels for Biomedical Applications

Nanogels (NGs) are 3‐dimensional (3D) networks composed of hydrophilic or amphiphilic polymer chains, allowing for effective and homogeneous encapsulation of drugs, genes, or imaging agents for biomedical applications. Polyethylenimine (PEI), possessing abundant positively charged amine groups, is an ideal platform for the development of NGs. A variety of effective PEI‐based NGs have been designed and much effort has been devoted to study the relationship between the structure and function of the NGs. In particular, PEI‐based NGs can be prepared either using PEI as the major NG component or using PEI as a crosslinker. This review reports the recent progresses in the design of PEI‐based NGs for gene and drug delivery and for bioimaging applications with a target focus to tackle the diagnosis and therapy of cancer.     

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.     

Multifunctional AuI‐based AIEgens: Manipulating Molecular Structures and Boosting Specific Cancer Cell Imaging and Theranostics

Gold(I) N‐heterocyclic carbene (Au^I‐NHC) complexes have emerged as potential anticancer agents owing to their high cytotoxicity and stability. Integration of their above unique functions with customized aggregation‐induced emission (AIE) luminogens to achieve specific bioimaging and efficient theranostics to cancer is highly desirable but is rarely studied. Now, a series of novel Au^I‐NHC compounds were developed with AIE characteristics. A complex with a PPh₃ ligand was selected out as it could achieve both prominent specific imaging of various cancer cells and efficient inhibition of their growth with negligible toxic effects on normal cells due to the targeting binding and strong inhibition towards thioredoxin reductase. This complex could also act as a powerful radiosensitizer to boost the anticancer efficacy with performance superior to that of popularly used auranofin. It holds great potential as a specific and effective theranostic drug in cancer diagnosis and precise therapy.     

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.     

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored,Activatable Cancer Chemotherapy

The development of biodegradable inorganic nanoparticles with a tumor microenvironment‐activated therapeutic mode of action is urgently needed for precision cancer medicine. Herein, the synthesis of ultrathin lanthanide nanoscrolls (Gd₂O₃ NSs) is reported, which biodegrade upon encountering the tumor microenvironment. The Gd₂O₃ NSs showed highly controlled magnetic properties, which enabled their high‐resolution magnetic resonance imaging (MRI). Importantly, Gd₂O₃ NSs degrade in a pH‐responsive manner and selectively penetrate tumor tissue, enabling the targeted release of anti‐cancer drugs. Gd₂O₃ NSs can be efficiently loaded with an anti‐cancer drug (DOX, 80 %) and significantly inhibit tumor growth with negligible cellular and tissue toxicity both in vitro and in vivo. This study may provide a novel strategy to design tumor microenvironment‐responsive inorganic nanomaterials for biocompatible bioimaging and biodegradation‐enhanced cancer therapy.     

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored,Activatable Cancer Chemotherapy

The development of biodegradable inorganic nanoparticles with a tumor microenvironment‐activated therapeutic mode of action is urgently needed for precision cancer medicine. Herein, the synthesis of ultrathin lanthanide nanoscrolls (Gd₂O₃ NSs) is reported, which biodegrade upon encountering the tumor microenvironment. The Gd₂O₃ NSs showed highly controlled magnetic properties, which enabled their high‐resolution magnetic resonance imaging (MRI). Importantly, Gd₂O₃ NSs degrade in a pH‐responsive manner and selectively penetrate tumor tissue, enabling the targeted release of anti‐cancer drugs. Gd₂O₃ NSs can be efficiently loaded with an anti‐cancer drug (DOX, 80 %) and significantly inhibit tumor growth with negligible cellular and tissue toxicity both in vitro and in vivo. This study may provide a novel strategy to design tumor microenvironment‐responsive inorganic nanomaterials for biocompatible bioimaging and biodegradation‐enhanced cancer therapy.     

Self-Assembled Plasmonic Vesicles of SERS-Encoded Amphiphilic Gold Nanoparticles for Cancer Cell Targeting and Traceable Intracellular Drug Delivery

We report the development of bioconjugated plasmonic vesicles assembled from SERS-encoded amphiphilic gold nanoparticles for cancer-targeted drug delivery. This new type of plasmonic assemblies with a hollow cavity can play multifunctional roles as delivery carriers for anticancer drugs and SERS-active plasmonic imaging probes to specifically label targeted cancer cells and monitor intracellular drug delivery. We have shown that the pH-responsive disassembly of the plasmonic vesicle, stimulated by the hydrophobic-to-hydrophilic transition of the hydrophobic brushes in acidic intracellular compartments, allows for triggered intracellular drug release. Because self-assembled plasmonic vesicles exhibit significantly different plasmonic properties and greatly enhanced SERS intensity in comparison with single gold nanoparticles due to strong interparticle plasmonic coupling, disassembly of the vesicles in endocytic compartments leads to dramatic changes in scattering properties and SERS signals, which can serve as independent feedback mechanisms to signal cargo release from the vesicles. The unique structural and optical properties of the plasmonic vesicle have made it a promising platform for targeted combination therapy and theranostic applications by taking advantage of recent advances in gold nanostructure based in vivo bioimaging and photothermal therapy and their loading capacity for both hydrophilic (nucleic acids and proteins) and hydrophobic (small molecules) therapeutic agents.     

Chemical Design of Nuclear‐Targeting Mesoporous Silica Nanoparticles for Intra‐nuclear Drug Delivery

Targeted drug delivery has been widely explored for efficient tumor therapy with desired efficacy but minimized side effects. It is widely known that large numbers of DNA‐toxins, such as doxorubicin, genes, reactive oxygen species, serving as therapeutic agents, can result in maximized therapeutic effects via the interaction directly with DNA helix. So after cellular uptake, these agents should be further delivered into cell nuclei to play their essential roles in damaging the DNA helix in cancer cells. Here, we demonstrate the first paradigm established in our laboratory in developing nuclear‐targeted drug delivery systems (DDSs) based on MSNs for enhanced therapeutic efficiency in the hope of speeding their translation into the clinics. Firstly, nuclear‐targeting DDSs based on MSNs, capable of intranuclear accumulation and drug release therein, were designed and constructed for the first time, resulting in much enhanced anticancer effects both in vitro and in vivo. Such an MSNs‐based and nuclear‐targeted drug/agent delivery strategy was further applied to overcome multidrug resistance (MDR) of malignant tumors, intra‐nuclearly deliver therapeutic genes, photosensitizers, radio‐enhancement agents and photothermal agents to realize efficient gene therapy, photodynamic therapy, radiation therapy and photothermal therapy, respectively.     

Hydrophobic Cysteine Poly(disulfide)‐based Redox‐Hypersensitive Nanoparticle Platform for Cancer Theranostics

Selective tumor targeting and drug delivery are critical for cancer treatment. Stimulus‐sensitive nanoparticle (NP) systems have been designed to specifically respond to significant abnormalities in the tumor microenvironment, which could dramatically improve therapeutic performance in terms of enhanced efficiency, targetability, and reduced side‐effects. We report the development of a novel L ‐cysteine‐based poly (disulfide amide) (Cys‐PDSA) family for fabricating redox‐triggered NPs, with high hydrophobic drug loading capacity (up to 25 wt % docetaxel) and tunable properties. The polymers are synthesized through one‐step rapid polycondensation of two nontoxic building blocks: L ‐cystine ester and versatile fatty diacids, which make the polymer redox responsive and give it a tunable polymer structure, respectively. Alterations to the diacid structure could rationally tune the physicochemical properties of the polymers and the corresponding NPs, leading to the control of NP size, hydrophobicity, degradation rate, redox response, and secondary self‐assembly after NP reductive dissociation. In vitro and in vivo results demonstrate these NPs’ excellent biocompatibility, high selectivity of redox‐triggered drug release, and significant anticancer performance. This system provides a promising strategy for advanced anticancer theranostic applications.     

Efficient Uptake of 177Lu‐Porphyrin‐PEG Nanocomplexes by Tumor Mitochondria for Multimodal‐Imaging‐Guided Combination Therapy

The benefits to intracellular drug delivery from nanomedicine have been limited by biological barriers and to some extent by targeting capability. We investigated a size‐controlled, dual tumor‐mitochondria‐targeted theranostic nanoplatform (Porphyrin‐PEG Nanocomplexes, PPNs). The maximum tumor accumulation (15.6 %ID g^?1, 72 h p.i.) and ideal tumor‐to‐muscle ratio (16.6, 72 h p.i.) was achieved using an optimized PPN particle size of approximately 10 nm, as measured by using PET imaging tracing. The stable coordination of PPNs with ¹⁷⁷Lu enables the integration of fluorescence imaging (FL) and photodynamic therapy (PDT) with positron emission tomography (PET) imaging and internal radiotherapy (RT). Furthermore, the efficient tumor and mitochondrial uptake of ¹⁷⁷Lu‐PPNs greatly enhanced the efficacies of RT and/or PDT. This work developed a facile approach for the fabrication of tumor‐targeted multi‐modal nanotheranostic agents, which enables precision and radionuclide‐based combination tumor therapy.     

A Catalase‐Like Metal‐Organic Framework Nanohybrid for O2‐Evolving Synergistic Chemoradiotherapy

Tumor hypoxia, the “Achilles’ heel” of current cancer therapies, is indispensable to drug resistance and poor therapeutic outcomes especially for radiotherapy. Here we propose an in situ catalytic oxygenation strategy in tumor using porphyrinic metal‐organic framework (MOF)‐gold nanoparticles (AuNPs) nanohybrid as a therapeutic platform to achieve O₂‐evolving chemoradiotherapy. The AuNPs decorated on the surface of MOF effectively stabilize the nanocomposite and serve as radiosensitizers, whereas the MOF scaffold acts as a container to encapsulate chemotherapeutic drug doxorubicin. In vitro and in vivo studies verify that the catalase‐like nanohybrid significantly enhances the radiotherapy effect, alleviating tumor hypoxia and achieving synergistic anticancer efficacy. This hybrid nanomaterial remarkably suppresses the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theranostic nanomedicines.     

Hydrogen Peroxide and Glutathione Dual Redox‐Responsive Nanoparticles for Controlled DOX Release

Polymer nanoparticulate drug delivery systems that respond to reactive oxygen species (ROS) and glutathione (GSH) simultaneously at biologically relevant levels hold great promise to improve the therapeutic efficacy to cancer cells with reduced side effects of chemo drugs. Herein, a novel redox dual‐responsive amphiphilic block copolymer (ABP) that consists of a hydrophilic poly (ethylene oxide) block and a hydrophobic block bearing disulfide linked phenylboronic ester group as pendant is synthesized, and the DOX loaded nanoparticles (BSN‐DOX) based on ABPs with varied hydrophobic block length are fabricated for DOX delivery. The self‐immolative leaving reaction of phenylboronic ester triggered by extracellular ROS and the cleavage of disulfide linkages induced by intracellular GSH both lead to rapid DOX release from BSN‐DOX, resulting in an on‐demand DOX release. Moreover, BSN‐DOX show better tumor inhibition and lower side effects in vivo compared with free drug.     

Novel multifunctional theranostic nanoagents based on Ho3+ for CT/MRI dual-modality imaging-guided photothermal therapy

Because of the intrinsic defects of traditional treatment of cancer,it is quite needed to construct novel theranostic nanoagents that can not only improve the accuracy of imaging diagnosis but also achieve highly efficient therapy of cancer.Herein,we fabricated polydopamine-functionalized ammonium holmium fluoride nanocomposites(AHF@PDA)for dual-modality bioimaging(magnetic resonance imaging(MRI)and computed tomography(CT))owing to the high X-ray attenuation feature and magnetic property of Ho³⁺.Moreover,PDA shell endows AHF@PDA with excellent photothermal conversion performances and robust biocompatibility,leading to good treatment effect in vitro and in vivo.All above positive results certify that AHF@PDA have good potential as theranostic agents for clinical application in the future.     

Dual‐Functional Nanographene Oxide as Cancer‐Targeted Drug‐Delivery System to Selectively Induce Cancer‐Cell Apoptosis

Construction of bioresponsive drug‐delivery nanosystems could enhance the anticancer efficacy of anticancer agents and reduce their toxic side effects. Herein, by using transferrin (Tf) as a surface decorator, we constructed a cancer‐targeted nanographene oxide (NGO) nanosystem for use in drug delivery. This nanosystem (Tf‐NGO@HPIP) drastically enhanced the cellular uptake, retention, and anticancer efficacy of loaded drugs but showed much lower toxicity to normal cells. The nanosystem was internalized through receptor‐mediated endocytosis and triggered pH‐dependent drug release in acidic environments and in the presence of cellular enzymes. Moreover, Tf‐NGO@HPIP effectively induced cancer‐cell apoptosis through activation of superoxide‐mediated p53 and MAPK pathways along with inactivation of ERK and AKT. Taken together, this study demonstrates a good strategy for the construction of bioresponsive NGO drug‐delivery nanosystems and their use as efficient anticancer drug carriers.     

Hybrid cross‐linked hydrogels as a technology platform for in vitro release of cephradine

Hydrogel‐based drug delivery systems can leverage therapeutically favorable upshots of drug release and found clinical uses. Hydrogels offer temporal and spatial control over the release of different therapeutic agents. Because of their tailor made controllable degradability, physical properties, and ability to prevent the labile drugs from degradation, hydrogels provide platform on which diverse physicochemical interactions with entrapped drugs cause to control drug release. Herein, we report the fabrication of novel vinyltrimethoxy silane (VTMS) cross‐linked chitosan/polyvinyl pyrrolidone hydrogels. Swelling in distilled water in conjunction with different buffer and electrolyte solutions was performed to assess the swellability of hydrogels. Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and X‐ray diffraction (XRD) analysis were further conducted to investigate the possible interactions between components, thermal stability, and crystallinity of as‐prepared hybrid hydrogels, respectively. In vitro time‐dependent biodegradability, antimicrobial study, and cytotoxicity were also carried out to evaluate their extensive biocompatibility and cytotoxic behavior. More interestingly, in vitro drug release study allowed for the controlled release of cephradine. Therefore, this facile strategy developed the novel biocompatible and biodegradable hybrid hydrogels, which could significantly expand the scope of these hydrogels in other biomedical applications like scaffolds, skin regeneration, tissue engineering, etc.     

Near‐Infrared‐Controlled,Targeted Hydrophobic Drug‐Delivery System for Synergistic Cancer Therapy

Hydrophobicity has been an obstacle that hinders the use of many anticancer drugs. A critical challenge for cancer therapy concerns the limited availability of effective biocompatible delivery systems for most hydrophobic therapeutic anticancer drugs. In this study, we have developed a targeted near‐infrared (NIR)‐regulated hydrophobic drug‐delivery platform based on gold nanorods incorporated within a mesoporous silica framework (AuMPs). Upon application of NIR light, the photothermal effect of the gold nanorods leads to a rapid rise in the local temperature, thus resulting in the release of the entrapped drug molecules. By integrating chemotherapy and photothermotherapy into one system, we have studied the therapeutic effects of camptothecin‐loaded AuMP‐polyethylene glycol‐folic acid nanocarrier. Results revealed a synergistic effect in vitro and in vivo, which would make it possible to enhance the therapeutic effect of hydrophobic drugs and decrease drug side effects. Studies have shown the feasibility of using this nanocarrier as a targeted and noninvasive remote‐controlled hydrophobic drug‐delivery system with high spatial/temperal resolution. Owing to these advantages, we envision that this NIR‐controlled, targeted drug‐delivery method would promote the development of high‐performance hydrophobic anticancer drug‐delivery system in future clinical applications.