131I Induced In Vivo Proteolysis by Photoswitchable azoPROTAC Reinforces Internal Radiotherapy.

Photopharmacology, incorporating photoswitches such as azobenezes into drugs, is an emerging therapeutic method to realize spatiotemporal control of pharmacological activity by light. However, most photoswitchable molecules are triggered by UV light with limited tissue penetration, which greatly restricts the in vivo application. Here, this study proves that 131I can trigger the trans-cis photoisomerization of a reported azobenezen incorporating PROTACs (azoPROTAC). With the presence of 50 µCi mL-1 131I, the azoPROTAC can effectively down-regulate BRD4 and c-Myc levels in 4T1 cells at a similar level as it does under light irradiation (405 nm, 60 mW cm-2). What's more, the degradation of BRD4 can further benefit the 131I-based radiotherapy. The in vivo experiment proves that intratumoral co-adminstration of 131I (300 µCi) and azoPROTC (25 mg kg-1) via hydrogel not only successfully induce protein degradation in 4T1 tumor bearing-mice but also efficiently inhibit tumor growth with enhanced radiotherapeutic effect and anti-tumor immunological effect. This is the first time that a radioisotope is successfully used as a trigger in photopharmacology in a mouse model. It believes that this study will benefit photopharmacology in deep tissue.

Renal Clearable Ultrasmall Single-Crystal Fe Nanoparticles for Highly Selective and Effective Ferroptosis Therapy and Immunotherapy.

Iron-based nanoparticles have attracted much attention because of their ability to induce ferroptosis via a catalyzing Fenton reaction and to further potentiate immunotherapy. However, current iron-based nanoparticles need to be used in cooperation with other treatments or be applied in a high dose for effective therapy because of their low reactive oxygen species production efficacy. Here, we synthesized ultrasmall single-crystal Fe nanoparticles (bcc-USINPs) that stayed stable in a normal physiological environment but were highly active in a tumor microenvironment because of the selective acidic etching of an Fe3O4 shell and the exposure of the Fe(0) core. The bcc-USINPs could efficiently induce tumor cell ferroptosis and immunogenetic cell death at a very low concentration. Intravenous injection of iRGD-bcc-USINPs at three doses of 1 mg/kg could effectively suppress the tumor growth, promote the maturation of dendritic cells, and trigger the adaptive T cell response. Combined with programmed death-ligand 1 (PD-L1) immune checkpoint blockade immunotherapy, the iRGD-bcc-USINP-mediated ferroptosis therapy greatly potentiated the immune response and developed strong immune memory. In addition, these USINPs were quickly renal excreted with no side effects in normal tissues. These iRGD-bcc-USINPs provide a simple, safe, effective, and selectively tumor-responsive Fe(0) delivery system for ferroptosis-based immunotherapy.

Persistent luminescence nanoparticles for cancer theranostics application.

Persistent luminescence nanoparticles (PLNPs) are unique optical materials that emit afterglow luminescence after ceasing excitation. They exhibit unexpected advantages for in vivo optical imaging of tumors, such as autofluorescence-free, high sensitivity, high penetration depth, and multiple excitation sources (UV light, LED, NIR laser, X-ray, and radiopharmaceuticals). Besides, by incorporating other functional molecules, such as photosensitizers, photothermal agents, or therapeutic drugs, PLNPs are also widely used in persistent luminescence (PersL) imaging-guided tumor therapy. In this review, we first summarize the recent developments in the synthesis and surface functionalization of PLNPs, as well as their toxicity studies. We then discuss the in vivo PersL imaging and multimodal imaging from different excitation sources. Furthermore, we highlight PLNPs-based cancer theranostics applications, such as fluorescence-guided surgery, photothermal therapy, photodynamic therapy, drug/gene delivery and combined therapy. Finally, future prospects and challenges of PLNPs in the research of translational medicine are also discussed.

Carrier-free nanoparticles of camptothecin prodrug for chemo-photothermal therapy: the making, in vitro and in vivo testing.

BACKGROUND: Nanoscale drug delivery systems have emerged as broadly applicable approach for chemo-photothermal therapy. However, these nanoscale drug delivery systems suffer from carrier-induced toxicity, uncontrolled drug release and low drug carrying capacity issues. Thus, to develop carrier-free nanoparticles self-assembled from amphiphilic drug molecules, containing photothermal agent and anticancer drug, are very attractive. RESULTS: In this study, we conjugated camptothecin (CPT) with a photothermal agent new indocyanine green (IR820) via a redox-responsive disulfide linker. The resulting amphiphilic drug-drug conjugate (IR820-SS-CPT) can self-assemble into nanoparticles (IR820-SS-CPT NPs) in aqueous solution, thus remarkably improving the membrane permeability of IR820 and the aqueous solubility of CPT. The disulfide bond in the IR820-SS-CPT NPs could be cleaved in GSH rich tumor microenvironment, leading to the on demand release of the conjugated drug. Importantly, the IR820-SS-CPT NPs displayed an extremely high therapeutic agent loading efficiency (approaching 100%). Besides, in vitro experimental results indicated that IR820-SS-CPT NPs displayed remarkable tumor cell killing efficiency. Especially, the IR820-SS-CPT NPs exhibited excellent anti-tumor effects in vivo. Both in vitro and in vivo experiments were conducted, which have indicated that the design of IR820-SS-CPT NPs can provide an efficient nanotherapeutics for chemo-photothermal therapy. CONCLUSION: A novel activatable amphiphilic small molecular prodrug IR820-SS-CPT has been developed in this study, which integrated multiple advantages of GSH-triggered drug release, high therapeutic agent content, and combined chemo-photothermal therapy into one drug delivery system.

Smart 131 I-Labeled Self-Illuminating Photosensitizers for Deep Tumor Therapy.

Stimulating photosensitizers (PS) by Cerenkov radiation (CR) can overcome the light penetration limitation in traditional photodynamic therapy. However, separate injection of radiopharmaceuticals and PS cannot guarantee their efficient interaction in tumor areas, while co-delivery of radionuclides and PS face the problem of nonnegligible phototoxicity in normal tissues. Here, we describe a 131 I-labeled smart photosensitizer, composed of pyropheophorbide-a (photosensitizer), a diisopropylamino group (pH-sensitive group), an 131 I-labeled tyrosine group (CR donor), and polyethylene glycol, which can self-assemble into nanoparticles (131 I-sPS NPs). The 131 I-sPS NPs showed low phototoxicity in normal tissues due to aggregation-caused quenching effect, but could self-produce reactive oxygen species in tumor sites upon disassembly. Upon intravenous injection, 131 I-sPS NPs showed great tumor inhibition capability in subcutaneous 4T1-tumor-bearing Balb/c mice and orthotopic VX2 liver tumor bearing rabbits. We believed 131 I-sPS NPs could expand the application of CR and provide an effective strategy for deep tumor theranostics.

In Vivo Repeatedly Activated Persistent Luminescence Nanoparticles by Radiopharmaceuticals for Long-Lasting Tumor Optical Imaging.

Persistent luminescence nanoparticles (PLNPs) with rechargeable near-infrared afterglow properties attract much attention for tumor diagnosis in living animals since they can avoid tissue autofluorescence and greatly improve the signal-to-background ratio. Using UV, visible light, or X-ray as excitation sources to power up persistent luminescence (PL) faces the challenges such as limited tissue penetration, inefficient charging capability, or tissue damage caused by irradiation. Here, it is proved that radiopharmaceuticals can efficiently excite ZnGa2 O4 :Cr3+ nanoparticles (ZGCs) for both fluorescence and afterglow luminescence via Cerenkov resonance energy transfer as well as ionizing radiation. 18 F-FDG, a clinically approved tumor-imaging radiopharmaceutical with a short decay half-life around 110 min, is successfully used as the internal light source to in vivo excite intravenously injected ZGCs for tumor luminescence imaging over 3 h. The luminescence with similar decay time can be re-obtained for multiple times upon injection of 18 F-FDG at any time needed with no health concern. It is believed this strategy can not only provide tumor luminescence imaging with high sensitivity, high contrast, and long decay time at desired time, but also guarantee the patients much less radiation exposure, greatly benefiting image-guided surgery in the future.

Dynamically Reversible Iron Oxide Nanoparticle Assemblies for Targeted Amplification of T1-Weighted Magnetic Resonance Imaging of Tumors.

Smart magnetic resonance (MR) contrast agents, by which MR contrast can be selectively enhanced under acidic tumor microenvironment, are anticipated to significantly improve the diagnostic accuracy. Here, we report pH-sensitive iron oxide nanoparticle assemblies (IONAs) that are cross-linked by small-molecular aldehyde derivative ligands. The dynamic formation and cleavage of hydrazone linkages in neutral and acidic environments, respectively, allow the reversible response of the nanoassemblies to pH variations. At neutral pH, IONAs are structurally robust due to the cross-linking by the strong hydrazone bonds. In acidic tumor microenvironment, the hydrazone bonds are cleaved so that the IONAs are quickly disassembled into a large number of hydrophilic extremely small-sized iron oxide nanoparticles (ESIONs). As a result, significantly enhanced T1MR contrast is achieved, as confirmed by the measurement of r1 values at different pH conditions. Such acidity-targeting MR signal amplification by the pH-sensitive IONAs was further validated in vivo, demonstrating a novel T1 magnetic resonance imaging (MRI) strategy for highly sensitive imaging of acidic tumors.

Renal-Clearable Hollow Bismuth Subcarbonate Nanotubes for Tumor Targeted Computed Tomography Imaging and Chemoradiotherapy.

Although metallic nanomaterials with high X-ray attenuation coefficients have been widely used as X-ray computed tomography (CT) contrast agents, their intrinsically poor biodegradability requires them to be cleared from the body to avoid any potential toxicity. On the other hand, extremely small-sized nanomaterials with outstanding renal clearance properties are not much effective for tumor targeting because of their too rapid clearance in vivo. To overcome this dilemma, here we report on the hollow bismuth subcarbonate nanotubes (BNTs) assembled from renal-clearable ultrasmall bismuth subcarbonate nanoclusters for tumor-targeted imaging and chemoradiotherapy. The BNTs could be targeted to tumors with high efficiency and exhibit a high CT contrast effect. Moreover, simultaneous radio- and chemotherapy using drug-loaded BNTs could significantly suppress tumor volumes, highlighting their potential application in CT imaging-guided therapy. Importantly, the elongated nanotubes could be disassembled into isolated small nanoclusters in the acidic tumor microenvironment, accelerating the payload release and kidney excretion. Such body clearable CT contrast agent with high imaging performance and multiple therapeutic functions shall have a substantial potential for biomedical applications.

Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment.

Nanovehicles can efficiently carry and deliver anticancer agents to tumour sites. Compared with normal tissue, the tumour microenvironment has some unique properties, such as vascular abnormalities, hypoxia and acidic pH. There are many types of cells, including tumour cells, macrophages, immune and fibroblast cells, fed by defective blood vessels in the solid tumour. Exploiting the tumour microenvironment can benefit the design of nanoparticles for enhanced therapeutic effectiveness. In this review article, we summarized the recent progress in various nanoformulations for cancer therapy, with a special emphasis on tumour microenvironment stimuli-responsive ones. Numerous tumour microenvironment modulation strategies with promising cancer therapeutic efficacy have also been highlighted. Future challenges and opportunities of design consideration are also discussed in detail. We believe that these tumour microenvironment modulation strategies offer a good chance for the practical translation of nanoparticle formulas into clinic.

Positron emission tomography imaging using radiolabeled inorganic nanomaterials.

CONSPECTUS: Positron emission tomography (PET) is a radionuclide imaging technology that plays an important role in preclinical and clinical research. With administration of a small amount of radiotracer, PET imaging can provide a noninvasive, highly sensitive, and quantitative readout of its organ/tissue targeting efficiency and pharmacokinetics. Various radiotracers have been designed to target specific molecular events. Compared with antibodies, proteins, peptides, and other biologically relevant molecules, nanoparticles represent a new frontier in molecular imaging probe design, enabling the attachment of different imaging modalities, targeting ligands, and therapeutic payloads in a single vector. We introduce the radiolabeled nanoparticle platforms that we and others have developed. Due to the fundamental differences in the various nanoparticles and radioisotopes, most radiolabeling methods are designed case-by-case. We focus on some general rules about selecting appropriate isotopes for given types of nanoparticles, as well as adjusting the labeling strategies according to specific applications. We classified these radiolabeling methods into four categories: (1) complexation reaction of radiometal ions with chelators via coordination chemistry; (2) direct bombardment of nanoparticles via hadronic projectiles; (3) synthesis of nanoparticles using a mixture of radioactive and nonradioactive precursors; (4) chelator-free postsynthetic radiolabeling. Method 1 is generally applicable to different nanomaterials as long as the surface chemistry is well-designed. However, the addition of chelators brings concerns of possible changes to the physicochemical properties of nanomaterials and detachment of the radiometal. Methods 2 and 3 have improved radiochemical stability. The applications are, however, limited by the possible damage to the nanocomponent caused by the proton beams (method 2) and harsh synthetic conditions (method 3). Method 4 is still in its infancy. Although being fast and specific, only a few combinations of isotopes and nanoparticles have been explored. Since the applications of radiolabeled nanoparticles are based on the premise that the radioisotopes are stably attached to the nanomaterials, stability (colloidal and radiochemical) assessment of radiolabeled nanoparticles is also highlighted. Despite the fact that thousands of nanomaterials have been developed for clinical research, only very few have moved to humans. One major reason is the lack of understanding of the biological behavior of nanomaterials. We discuss specific examples of using PET imaging to monitor the in vivo fate of radiolabeled nanoparticles, emphasizing the importance of labeling strategies and caution in interpreting PET data. Design considerations for radiolabeled nanoplatforms for multimodal molecular imaging are also illustrated, with a focus on strategies to combine the strengths of different imaging modalities and to prolong the circulation time.

Monodisperse MPt (M = Fe, Co, Ni, Cu, Zn) nanoparticles prepared from a facile oleylamine reduction of metal salts.

We report a simple, yet general, approach to monodisperse MPt (M = Fe, Co, Ni, Cu, Zn) nanoparticles (NPs) by coreduction of M(acac)2 and Pt(acac)2 (acac = acetylacetonate) with oleylamine at 300 °C. In the current reaction condition, oleylamine serves as the reducing agent, surfactant, and solvent. As an example, we describe in details the synthesis of 9.5 nm CoPt NPs with their compositions controlled from Co37Pt63 to Co69Pt31. These NPs show composition-dependent structural and magnetic properties. The unique oleylamine reduction process makes it possible to prepare MPt NPs with their physical properties and surface chemistry better rationalized for magnetic or catalytic applications.

Core/shell Au/CuPt nanoparticles and their dual electrocatalysis for both reduction and oxidation reactions.

We report a facile synthesis of monodisperse core/shell 5/1.5 nm Au/CuPt nanoparticles by coreduction of platinum acetylacetonate and copper acetylacetonate in the presence of 5 nm Au nanoparticles. The CuPt alloy effect and core/shell interactions make these Au/CuPt nanoparticles a promising catalyst for both oxygen reduction reaction and methanol oxidation reaction in 0.1 M HClO4 solution. Their specific (mass) reduction and oxidation activities reach 2.72 mA/cm(2) (1500 mA/mg Pt) at 0.9 V and 0.755 mA/cm(2) (441 mA/mg Pt) at 0.8 V (vs reversible hydrogen electrode), respectively. Our studies show that the existence of the Au nanoparticle core not only minimizes the Pt usage but also improves the stability of the Au/CuPt catalyst for fuel cell reactions. The results suggest that the core/shell design is indeed effective for optimizing nanoparticle catalysis. The same concept may be extended to other multimetallic nanoparticle systems, making it possible to tune nanoparticle catalysis for many different chemical reactions.

Self-illuminating 64Cu-doped CdSe/ZnS nanocrystals for in vivo tumor imaging.

Construction of self-illuminating semiconducting nanocrystals, also called quantum dots (QDs), has attracted much attention recently due to their potential as highly sensitive optical probes for biological imaging applications. Here we prepared a self-illuminating QD system by doping positron-emitting radionuclide (64)Cu into CdSe/ZnS core/shell QDs via a cation-exchange reaction. The (64)Cu-doped CdSe/ZnS QDs exhibit efficient Cerenkov resonance energy transfer (CRET). The signal of (64)Cu can accurately reflect the biodistribution of the QDs during circulation with no dissociation of (64)Cu from the nanoparticles. We also explored this system for in vivo tumor imaging. This nanoprobe showed high tumor-targeting ability in a U87MG glioblastoma xenograft model (12.7% ID/g at 17 h time point) and feasibility for in vivo luminescence imaging of tumor in the absence of excitation light. The availability of these self-illuminating integrated QDs provides an accurate and convenient tool for in vivo tumor imaging and detection.

Radiation responsive PROTAC nanoparticles for tumor-specific proteolysis enhanced radiotherapy.

Proteolysis targeting chimeras (PROTACs) is a promising strategy for cancer therapy. However, the always-on bioactivity of PROTACs may lead to non-target toxicity, which restricts their antitumor performance. Here, we developed an X-ray radiation responsive PROTAC nanomicelle (RCNprotac) by covalently conjugating a reported small molecule PROTAC (MZ1) to hydrophilic PEG via a diselenide bond-containing carbon chain, which then self-assembled into a 141.80 ± 5.66 nm nanomicelle. The RCNprotac displayed no bioactivity during circulation due to the occupation of the hydroxyl group on the E3 ubiquitin ligand component and could effectively accumulate at the tumor site owing to the enhanced permeability and retention effect. Upon exposure to X-ray radiation, the radiation-sensitive diselenide bonds were broken to specifically release MZ1 for tumor BRD4 protein degradation. Furthermore, the reduction in the BRD4 protein level could increase the tumor's sensitivity to radiation. RCNprotac showed a synergistic enhancement of antitumor effects both in vitro and in vivo. We believe that this X-ray-responsive PROTAC nanomicelle could provide a new strategy for the X-ray-activated spatiotemporally controlled protein degradation and for the BRD4 proteolysis enhanced tumor radiosensitivity.

Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy.

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H2O2-mediated/starvation multimodal cancer therapy. In this approach, a hypoxia-degradable covalent-organic framework (COF) is synthesized to coat a-ZIF-8 in which glucose oxidase (GOx) and CRISPR system are packaged. To intensify intracellular redox dyshomeostasis, DNAzymes which can cleave catalase mRNA are loaded as well. When the nanosystem gets into the tumor, the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx, which amplifies intracellular H+ and hypoxia, accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells. These tandem reactions deplete glucose and oxygen, leading to logic-gated-triggered gene editing as well as synergistic gene/H2O2-mediated/starvation therapy. Overall, this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

Monodisperse Au nanoparticles for selective electrocatalytic reduction of CO2 to CO.

We report selective electrocatalytic reduction of carbon dioxide to carbon monoxide on gold nanoparticles (NPs) in 0.5 M KHCO3 at 25 °C. Among monodisperse 4, 6, 8, and 10 nm NPs tested, the 8 nm Au NPs show the maximum Faradaic efficiency (FE) (up to 90% at -0.67 V vs reversible hydrogen electrode, RHE). Density functional theory calculations suggest that more edge sites (active for CO evolution) than corner sites (active for the competitive H2 evolution reaction) on the Au NP surface facilitates the stabilization of the reduction intermediates, such as COOH*, and the formation of CO. This mechanism is further supported by the fact that Au NPs embedded in a matrix of butyl-3-methylimidazolium hexafluorophosphate for more efficient COOH* stabilization exhibit even higher reaction activity (3 A/g mass activity) and selectivity (97% FE) at -0.52 V (vs RHE). The work demonstrates the great potentials of using monodisperse Au NPs to optimize the available reaction intermediate binding sites for efficient and selective electrocatalytic reduction of CO2 to CO.

Dumbbell-like PtPd-Fe3O4 nanoparticles for enhanced electrochemical detection of H2O2.

Dumbbell-like Pt(x)Pd(100-x)-Fe(3)O(4) nanoparticles (NPs) were synthesized and studied for electrocatalytic reduction and sensing of H(2)O(2). In 0.1 M phosphate buffered saline (PBS) solution, the 4-10 nm Pt(x)Pd(100-x)-Fe(3)O(4) NPs showed the Pt/Pd composition-dependent catalysis with Pt(48)Pd(52)-Fe(3)O(4) NPs having the best activity. The Pt(48)Pd(52)-Fe(3)O(4) NPs were tested for H(2)O(2) detection, and their H(2)O(2) detection limit reached 5 nM, which was suitable for monitoring H(2)O(2) generated from Raw 264.7 cells. These dumbbell-like PtPd-Fe(3)O(4) NPs are the most sensitive probe ever reported and can be used to achieve real-time quantitative detection of H(2)O(2) in biological environment for biological and biomedical applications.

Tuning exchange bias in core/shell FeO/Fe3O4 nanoparticles.

Monodisperse 35 nm FeO nanoparticles (NPs) were synthesized and oxidized in a dry air atmosphere into core/shell FeO/Fe(3)O(4) NPs with both FeO core and Fe(3)O(4) shell dimensions controlled by reaction temperature and time. Temperature-dependent magnetic properties were studied on FeO/Fe(3)O(4) NPs obtained from the FeO NPs oxidized at 60 and 100 °C for 30 min. A large exchange bias (shift in the hysteresis loop) was observed in these core/shell NPs. The relative dimensions of the core and shell determine not only the coercivity and exchange field but also the dominant reversal mechanism of the ferrimagnetic Fe(3)O(4) component. This is the first time demonstration of tuning exchange bias and of controlling asymmetric magnetization reversal in FeO/Fe(3)O(4) NPs with antiferromagnetic core and ferrimagnetic shell.

Biodegradable gold nanovesicles with an ultrastrong plasmonic coupling effect for photoacoustic imaging and photothermal therapy.

The hierarchical assembly of gold nanoparticles (GNPs) allows the localized surface plasmon resonance peaks to be engineered to the near-infrared (NIR) region for enhanced photothermal therapy (PTT). Herein we report a novel theranostic platform based on biodegradable plasmonic gold nanovesicles for photoacoustic (PA) imaging and PTT. The disulfide bond at the terminus of a PEG-b-PCL block-copolymer graft enables dense packing of GNPs during the assembly process and induces ultrastrong plasmonic coupling between adjacent GNPs. The strong NIR absorption induced by plasmon coupling and very high photothermal conversion efficiency (η=37%) enable simultaneous thermal/PA imaging and enhanced PTT efficacy with improved clearance of the dissociated particles after the completion of PTT. The assembly of various nanocrystals with tailored optical, magnetic, and electronic properties into vesicle architectures opens new possibilities for the construction of multifunctional biodegradable platforms for biomedical applications.

Photothermal-Ionic-Pharmacotherapy of Myocardial Infarction with Enhanced Angiogenesis and Antiapoptosis.

Promoting angiogenesis is an effective therapeutic strategy to repair damaged hearts after myocardial infarction (MI). Copper ions and mild heat (41-42 °C) have been shown to promote angiogenesis, but their efficacy in MI is unknown. Here, a multicomponent hydrogel (EDR@PHCuS HG) is developed by encapsulating edaravone (EDR, a free radical scavenger) loaded porous hollow copper sulfide nanoparticles (PHCuS NPs) in a hyaluronic acid hydrogel (HG). Exposed to 808 nm near-infrared (NIR) light irradiation, the EDR@PHCuS HG exhibits controlled copper-ion release and mild photothermal effect to synergistically promote angiogenesis. In addition, released EDR inhibits cardiomyocyte apoptosis to further repair hearts. In the mouse model of MI, treatment with the EDR@PHCuS HG under an 808 nm laser significantly recovers the cardiac function and inhibits ventricular remodeling. This platform elucidates the cardioprotective effects of copper ions and mild heat and will provide a highly efficient treatment for MI.