Passive Accumulation Research Articles

Size-dependent Nanoparticle Accumulation In Venous Malformations

Objective: The current treatment of venous malformations (VMs) consists of medications with systemic toxicity and procedural interventions with high technical difficulty and risk of hemorrhage. Using nanoparticles (NPs) to enhance drug delivery to VMs could enhance efficacy and decrease systemic toxicity. NPs can accumulate in tissues with abnormal vasculature, a concept known as the enhanced permeation and retention (EPR) effect. EPR has been documented in tumors, bioengineered vessels, and VMs. However, in VMs, it is unknown if NP size affects EPR and if so, which particle size improves NP accumulation. Methods: In this study, we used a murine model of subcutaneous VMs using human umbilical vein endothelial cells that express the most frequent VM-causing tyrosine kinase with immunoglobulin and EGF homology domains mutation, tyrosine kinase with immunoglobulin and EGF homology domains-L914F. Hollow silica NPs coated in polyethylene glycol (PEG) and conjugated to a fluorophore were administered systemically via tail vein injection. We studied the accumulation of a range of NP sizes within the VM and organs using confocal microscopy and an in vivo imaging system. Results: The 20, 50, 80, and 180 nm PEGylated, fluorophore-tagged hollow silica NPs were spherical and had hydrodynamic diameters of 31.6 ± 0.9, 58.5 ± 0.1, 87.1 ± 2.4, and 232 ± 1.26 nm, respectively. Following systemic NP administration, 20 nm NPs had 2 times more fluorescence accumulation within VMs compared with 50 nm, and 6 times more fluorescence accumulation compared with larger (greater than 80 nm) NPs (P < .01). Conclusion: This study helps to determine the optimal NP size for passive accumulation within VMs and lays the foundation for engineering NPs for the treatment of VMs.

Passive accumulation of alkaloids in inconspicuously colored frogs refines the evolutionary paradigm of acquired chemical defenses.

Comprender los orígenes de fenotipos novedosos y complejos es un objetivo central en biología evolutiva. Las ranas venenosas de la familia Dendrobatidae han desarrollado una novedosa habilidad para adquirir alcaloides de su dieta como defensas químicas, al menos tres veces. Sin embargo, el muestreo de taxones en busca de alcaloides ha estado sesgado hacia las especies coloridas, sin prestar atención similar a las poco conspicuas que a menudo se presume, no tienen defensas. Como resultado, nuestra comprensión de cómo evolucionan las defensas químicas en este grupo es incompleta. Aquí, proporcionamos nuevos datos que muestran que, en contraste con estudios anteriores, las especies de cada clado de ranas venenosas no defendidas tienen cantidades bajas pero cuantificables de alcaloides. Confirmamos que los dendrobátidos no defendidos consumen regularmente ácaros y hormigas, que son fuentes conocidas de alcaloides. Por lo tanto, nuestros datos sugieren que la dieta es insuficiente para explicar el fenotipo defendido. Nuestros datos respaldan la existencia de un fenotipo intermedio entre consumo y secuestro de toxinas (acumulación pasiva), que difiere del secuestro en que no implica formas derivadas de mecanismos de transporte y almacenamiento, pero da lugar a bajos niveles de acumulación de toxinas. Discutimos el concepto de acumulación pasiva y su potencial rol en el origen de defensas químicas en ranas venenosas y otros organismos que secuestran toxinas. Considerando ideas de farmacocinética, incorporamos datos nuevos y antiguos de ranas venenosas dentro de un modelo evolutivo que podría ayudar a explicar los orígenes de defensas químicas adquiridas en animales, y proporcionar una visión de los procesos moleculares que regulan el destino de las toxinas ingeridas.

Inflammation-Responsive Polyion Complex Vesicles for Autoimmune Disease Therapy via Cell-Free DNA Scavenging and Inflammatory Microenvironment Modulation.

Cell-free DNA (cfDNA) scavenging represents a promising anti-inflammatory modality for autoimmune disease (AID) treatment. However, it remains challenging for existing systems to achieve inflammation-targeted cfDNA scavenging and the management of cfDNA-unrelated inflammatory pathways. Herein, inflammation-responsive polyion complex vesicles (PICsomes) are developed, bridging inflammation-instructed cfDNA scavenging, and methotrexate (MTX) delivery for AID management. A positively charged, PEGylated polypeptide with guanidine side chains (PEG-PG) is developed, which self-assembles with a negatively charged, cis-aconitic anhydride-modified poly-L-lysine (PC) to form the PICsomes and encapsulate MTX disodium salt. The neutrally charged PICsomes feature prolonged blood circulation after systemic administration, allowing for passive accumulation to the inflamed tissues. In the slightly acidic inflammatory microenvironment, PC transforms from negatively charged to positively charged, thereby disintegrating the PICsomes and liberating the PEG-PG and MTX. Consequently, PEG-PG-mediated cfDNA scavenging and MTX-mediated immunosuppression cooperate to inhibit inflammation and ameliorate the inflammatory microenvironment, promoting tissue repair in AID mouse models including collagen-induced arthritis and 2,4,6-trinitrobenzenesulfonic acid-induced colitis.

Quantum jump photodetector for narrowband photon counting with a single atom

Using a single neutral Rb87 atom held in an optical trap, and “quantum jump” detection of single-photon-initiated state changes, we demonstrate a single-photon quantum jump photodetector (QJPD) with intrinsically narrow bandwidth and strong rejection of out-of-band photons, of interest for detecting weak optical signals in the presence of a strong broadband background. By analyzing fluorescence photon count distributions for the bright and dark states with and without excitation, we measure quantum efficiency of 2.9(2)×10−3, a record for single-pass quantum jump production, and signal-photon-unprovoked “dark jump” rate—analogous to the dark count rate of other detectors —of 3(10)×10−3jumps/s during passive accumulation plus 4.0(4)×10−3 jumps per readout, orders of magnitude below those of traditional single-photon detectors. Available methods can substantially improve QJPD quantum efficiency, dark jump rate, bandwidth, and tunability. Published by the American Physical Society 2024

Bone aluminum accumulation in the current era.

In the last few years, evidence from the Brazilian Registry of Bone Biopsy (REBRABO) has pointed out a high incidence of aluminum (Al) accumulation in the bones of patients with CKD under dialysis. This surprising finding does not appear to be merely a passive metal accumulation, as prospective data from REBRABO suggest that the presence of Al in bone may be independently associated with major adverse cardiovascular events. This information contrasts with the perception of epidemiologic control of this condition around the world. In this opinion paper, we discussed why the diagnosis of Al accumulation in bone is not reported in other parts of the world. We also discuss a range of possibilities to understand why bone Al accumulation still occurs, not as a classical syndrome with systemic signs of intoxication, as occurred it has in the past.

STING-Activating Polymer-Drug Conjugates for Cancer Immunotherapy.

The stimulator of interferon genes (STING) pathway links innate and adaptive antitumor immunity and therefore plays an important role in cancer immune surveillance. This has prompted widespread development of STING agonists for cancer immunotherapy, but pharmacological barriers continue to limit the clinical impact of STING agonists and motivate the development of drug delivery systems to improve their efficacy and/or safety. We developed SAPCon, a STING-activating polymer-drug conjugate platform based on strain-promoted azide-alkyne cycloaddition of a novel dimeric amidobenzimidazole (diABZI) STING prodrug to hydrophilic poly(dimethylacrylamide-co-azido-ethylmethacrylate) polymer chains through a cathepsin B-responsive linker to increase circulation time and enable passive tumor accumulation. We found that intravenously administered SAPCon accumulated at tumor sites, where it was endocytosed by tumor-associated myeloid cells, resulting in increased STING activation in the tumor tissue. Consequently, SAPCon promoted an immunogenic tumor microenvironment characterized by increased frequency of activated macrophages and dendritic cells and improved infiltration of CD8+ T cells, resulting in inhibition of tumor growth, prolonged survival, and enhanced response to anti-PD-1 immune checkpoint blockade in orthotopic breast cancer models. Collectively, these studies position SAPCon as a modular and programmable platform for improving the efficacy of systemically administered STING agonists for cancer immunotherapy.

Unravelling the role of tumor microenvironment responsive nanobiomaterials in spatiotemporal controlled drug delivery for lung cancer therapy.

Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals.

Anti-EGFR immunoliposomes for cabazitaxel delivery: From formulation development to in vivo evaluation in prostate cancer xenograft model

Liposomes functionalized with monoclonal antibodies offer targeted therapy for cancer, boasting advantages like sustained drug release, enhanced stability, passive accumulation in tumors, and interaction with overexpressed receptors on cancer cells. This study aimed to develop and characterize anti-EGFR immunoliposomes loaded with cabazitaxel and assess their properties against prostate cancer in vitro and in vivo. Using a Box-Behnken design, a formulation with soy phosphatidylcholine, 10% cholesterol, and a 1:20 drug-lipid ratio yielded nanometric particle size, low polydispersity and high drug encapsulation. Immunoliposomes were conjugated with cetuximab through DSPE-PEG-Maleimide lipid anchor. Characterization confirmed intact antibody structure and interaction with EGFR receptor following conjugation. Cabazitaxel was dispersed within the liposomes in the amorphous state, confirmed by solid-state analyses. In vitro release studies showed slower cabazitaxel release from immunoliposomes. Immunoliposomes had enhanced cabazitaxel cytotoxicity in EGFR-overexpressing DU145 cells without affecting non-tumor L929 cells. Cetuximab played an important role to improve cellular uptake in a time-dependent fashion in EGFR-overexpressing prostate cancer cells. In vivo, immunoliposomes led to significant tumor regression, improved survival, and reduced weight loss in xenograft mice. While cabazitaxel induced leukopenia, consistent with clinical findings, histological analysis revealed no evident toxicity. In conclusion, the immunoliposomes displayed suitable physicochemical properties for cabazitaxel delivery, exhibited cytotoxicity against EGFR-expressing prostate cancer cells, with high cell uptake, and induced significant tumor regression in vivo, with manageable systemic toxicity.

An intelligent and self-assembled nanoscale metal organic framework (99mTC-DOX loaded Fe3O4@FeIII-tannic acid) for tumor targeted chemo/chemodynamic theranostics

BackgroundRecent advances in clinical transformation research have focused on chemodynamic theranostics as an emerging strategy for tackling cancer. Nevertheless, its effectiveness is hampered by the tumor's glutathione antioxidant effect, poor acidic tumor microenvironment (TME) and inadequate endogenous H2O2. Hence, we designed an activatable theranostics (99mTc-DOX loaded AA-Fe3O4@FeIII-TA) that effectively boost the catalytic efficiency of the Fenton-reaction-induced ROS production and augment the chemotherapeutic efficacy combined with diagnostic action.ResultsA cross-linked matrix of tannic acid-ferric salt (FeIII-TA) as a pH-responsive shell onto ascorbic acid-decorated iron-oxide nanoparticles (AA-Fe3O4NPs) was prepared demonstrating a metal–organic- framework (MOF) nanostructure, followed by loading of 99mTc-labelled DOX. The platform (99mTc-DOX loaded AA-Fe3O4@FeIII-TA) displayed suitable physical–chemical properties, including 69.8 nm particle size, 94.8 nm hydrodynamic size, − 21 mV zeta potential, effective FeIII-TA shell crosslinking onto AA-Fe3O4NPs and 94% loading efficiency for 99mTc-DOX. The results of the in-vitro release investigations showed that the platform exhibited a pH-dependent release manner with 98.3% of the 99mTc-DOX being released at pH 5 (simulating the tumor’s pH) and only 10% being released at the physiological pH (pH 7.4). This indicates that there was negligible payload leakage into the systemic circulation during the platform's passive accumulation inside tumor. Due to the acidic TME nature, the MOF shell might be degraded releasing free FeIII, TA and a sustained release of 99mTc-DOX. Besides its chemotherapeutic impact and capacity to raise intracellular H2O2 content, the released 99mTc-DOX might be used as SPECT imaging tracer for concurrent tumor diagnosis. Furthermore, the mild acidity of the tumor may be overcome by the released TA, which might raise the acidification level of cancer cells. The released FeIII, TA and the endogenous GSH could engage in a redox reaction that depletes GSH and reduces FeIII to FeII ions which subsequently catalyze the elevated concentration of H2O2 to reactive •OH via Fenton-like reaction, increasing the effectiveness of chemodynamic therapy. Moreover, the in-vivo evaluation in tumor-bearing mice showed significant radioactivity accumulation in the tumor lesion (16.8%ID/g at 1 h post-injection) with a potential target/non-target ratio of 8.ConclusionsThe 99mTc-DOX loaded AA-Fe3O4@FeIII-TA could be introduced as an effective chemo/chemodynamic theranostics.Graphical

Comparison of passive targeted delivery of inorganic and organic nanocarriers among different types of tumors

In this study, we have considered four types of nanoparticles (NPs): polylactic acid (PLA), gold (Au), calcium carbonate (CaCO3), and silica (SiO2) with similar sizes (TEM: 50–110 nm and DLS: 110–140 nm) to examine their passive accumulation in three different tumors: colon (CT26), melanoma (B16-F10), and breast (4T1) cancers. Our results demonstrate that each tumor model showed a different accumulation of NPs, in the following order: CT26 > B16-F10 > 4T1. The Au and PLA NPs were evidently characterized by a higher delivery efficiency in case of CT26 tumors compared to CaCO3 and SiO2 NPs. The Au NPs demonstrated the highest accumulation in B16-F10 cells compared to other NPs. These results were verified using SPECT, ex vivo fluorescence bioimaging, direct radiometry and histological analysis. Thus, this work contributes to new knowledge in passive tumor targeting of NPs and can be used for the development of new strategies for delivery of bioactive compounds.

Simulation of soil-structure interaction of integral abutment bridges using advanced constitutive relations

Integral bridges have been proposed as an attractive design concept that negate the requirements for expansion joints. However, owing to structural continuity, seasonal and diurnal thermal fluctuations have subjected the abutments to long-term cyclic interaction with approach backfills. This resulted in two notable geotechnical complications: ratcheting of lateral stresses and progressive soil deformation. To understand these phenomena, considerable research has been conducted using numerical methods. Here, either Winkler springs or simple constitutive relations, such as the Mohr-Coulomb model, are predominantly utilized. However, the former is based on monotonic displacement-dependent stiffness theories, and the latter is constrained by the limitations of the traditional yield surface plasticity. Hence, neither possesses the capability to simulate the hysteretic response, which is a characteristic of integral bridge approaches. Therefore, this study aims to present the advantages of using advanced constitutive relations to predict the long-term behavior of integral bridge approach backfills. First, using a lateral cyclic triaxial simulation, the significance of soil densification was highlighted by comparing the performance of the Mohr-Coulomb model with that of the bounding surface Dafalias-Manzari-2004 model. Subsequently, further comparisons were performed with the centrifuge model data of the integral abutment. At both the element and boundary value levels, the Mohr-Coulomb model could not capture the gradual accumulation of the lateral stresses. Conversely, the Dafalias-Manzari-2004 model can estimate the long-term passive pressure accumulation along the height of the abutment.

Simultaneous determination of Cd, Pb, Cu and Zn as total and labile fractions in soil using a small-sized electrothermal vaporization capacitively coupled plasma microtorch optical emission spectrometer after diffusive gradients in thin-film passive accumulation

A sensitive and free interference method for the determination of total and labile fractions of Cd, Pb, Cu and Zn in soil after DGT passive accumulation and detection by optical emission spectrometry with an Ar microplasma was validated.

Validation of microwave acid digestion, diffusive gradients in thin-film preconcentration and inductively coupled plasma optical emission spectrometry methodology for the determination of REEs in natural zeolites.

The determination of rare earth element (REE) content in different natural minerals is of high interest due to their extensive use in modern and sustainable technologies. The REEs occurring in natural zeolites are specific to each deposit. This study presents the validation and evaluation of the measurement uncertainty for the determination of REEs (Ce, Dy, Er, Eu, Gd, La, Lu, Nd, Pr, Sm, Y, and Yb) in natural zeolites using microwave-assisted acid digestion and inductively coupled plasma optical emission spectrometry (ICP-OES) after diffusive gradients in thin-film preconcentration. A mixture of HNO3 : HCl : HF of 3 : 9 : 2 (v/v/v) and microwave digestion provided suitable recoveries for the analysis of two certified reference materials, CRM BCS-CRM 375/1 and CRM OREAS 460. Good linearity over the calibration range of 0-2 μg mL-1, with correlation coefficients of 0.9995-1.0000, was obtained for each REE by ICP-OES. The limits of quantification (LOQS), calculated considering the instrumental LOQs and the sample preparation by microwave digestion, were in the range of 0.20-0.60 mg kg-1. A supplementary step of preconcentration/matrix separation based on the passive sampling by diffusive gradients in thin-films (DGT) technique improved the LOQs by about 20 times after three days of passive accumulation, allowing the measurement of the concentrations of all studied REEs in natural zeolite samples. The proposed methodology is a suitable approach for the measurement of REEs at low concentrations in natural zeolite samples by ICP-OES, and it can be extended to other geological samples. The measurement uncertainty was calculated based on the validation data. The proposed method provides reliable results for the measurement of REEs in natural zeolites and was used to measure the specific concentrations of REEs in natural zeolite samples from three Romanian quarries. The REE concentration can be used as a fingerprint for each deposit.

Synchronous Intravital Imaging and Cavitation Monitoring of Antivascular Focused Ultrasound in Tumor Microvasculature Using Monodisperse Low Boiling Point Nanodroplets.

Focused ultrasound-stimulated microbubbles can induce blood flow shutdown and ischemic necrosis at higher pressures in an approach termed antivascular ultrasound. Combined with conventional therapies of chemotherapy, immunotherapy, and radiation therapy, this approach has demonstrated tumor growth inhibition and profound synergistic antitumor effects. However, the lower cavitation threshold of microbubbles can potentially yield off-target damage that the polydispersity of clinical agent may further exacerbate. Here we investigate the use of a monodisperse nanodroplet formulation for achieving antivascular effects in tumors. We first develop stable low boiling point monodisperse lipid nanodroplets and examine them as an alternative agent to mediate antivascular ultrasound. With synchronous intravital imaging and ultrasound monitoring of focused ultrasound-stimulated nanodroplets in tumor microvasculature, we show that nanodroplets can trigger blood flow shutdown and do so with a sharper pressure threshold and with fewer additional events than conventionally used microbubbles. We further leverage the smaller size and prolonged pharmacokinetic profile of nanodroplets to allow for potential passive accumulation in tumor tissue prior to antivascular ultrasound, which may be a means by which to promote selective tumor targeting. We find that vascular shutdown is accompanied by inertial cavitation and complex-order sub- and ultraharmonic acoustic signatures, presenting an opportunity for effective feedback control of antivascular ultrasound.

Preference of Silicon Accumulation on the Shade Foliage of Tree Crown and its Implication in Juniperus chinensis L.

PurposeThe passive accumulation of silicon (Si) generally depends on the regulation of plant transpiration rates after its uptake. It is challenging to comprehend how plants use Si to adapt to shady habitats where they have low transpiration rates and photothermal energy. Therefore, we speculated that Si accumulation is not entirely dependent on the transpiration rate.MethodsTo test this speculation, the concentrations of Si and total minerals and water status at various positions of shady shoots (stems and their foliage) and stems within the crown of Juniperus chinensis L. were examined to determine whether shady shoots or stems had a preferred allocation to resist shade.ResultsThe concentrations of total minerals and Si in the shoots were consistently higher in shady areas than in areas within the same crown, regardless of the position within the crown or shoot age. However, shoot Si accumulation displayed a greater dependence on available light or photothermal supply, which is linked to crown orientation. Additionally, stem Si accumulation displayed a weak dependence on available light. Compared with the bound water content, the water potential and free water content of shady shoots were higher than those of sunny shoots. In light of the fact that water prefers to move readily towards regions with low water potential, these results demonstrate that the movement of minerals and water is not fully coupled in the same crowns.ConclusionTherefore, the accumulation of Si and minerals in shady foliage is partially independent of water flow, which helps to offset the low-carbon supply due to the photothermal decrease in the shady crown area.

Cyclodextrin-loaded nanobubbles reduce cholesterol and atherosclerosis in vivo

Abstract Background Ischemic heart disease (IHD) is the leading cause of mortality and morbidity worldwide. Atherosclerosis, a chronic inflammatory disease, is the main contributor to IHD. However, atherosclerosis is commonly left undiagnosed and untreated. Our study aims to create a theranostic nanobubbles (NBs), with ultrasonic properties for diagnostic imaging and at the same time for the delivery of 2-Hydroxypropyl-beta-cyclodextrin (CD), an FDA-approved drug to dissolve cholesterol crystals. Methods and Results Using polybutlycyanoacrylate, we created polymeric NBs. The incorporation of near-infrared dye (IR780) resulted in a multimodal contrast NB, which allows in vitro and in vivo visualization on both ultrasound and optical imaging. Furthermore, these NBs can be triggered by ultrasonic bursts to release their dye/drug payload. The safety profile of the NBs, post-incorporation of CD (CDNBs), demonstrated excellent biocompatibility in vitro using cell culture and in human blood. Cellular uptake of CP increased by 2.4x when using CPNBs compared to free CD (p<0.00001). In vivo biodistribution demonstrated that the NBs circulate in blood plasma for 48 hours, with a peak at 1-hour post-injection. In a mouse model of atherosclerosis, ApoE-/- mice on high-fat diet, we intravenously injected CDNBs, free CD or NBs only fortnightly for 8 weeks. En face Oil Red O-staining showed a significant reduction in total plaque area in the CDNB-treated group, as compared to the control animals treated with free CD and with NBs only (p>0.01). There was also a significant reduction in blood plasma cholesterol for the CDNBs-treated mice as compared to the control mice (p>0.01). Conclusion We demonstrated the ability to load CDs into NBs. These CDNBs are taken up by immune cells. The passive accumulation of CDNPs in the atherosclerotic lesions, resulted in the release of CD and the reduction of total plaque area in the entire aorta. These CDNBs treated mice also have a reduced cholesterol level in their plasma. CDNBs represent a novel theranostic nanocarrier with a high potential of clinical translation and ultimately major benefits to patients with atherosclerosis.

Biomineralized nanomedicine for enhanced cancer therapy through in situ toxification and amplified Ca2+ overload

Disulfiram (DSF), an FDA-approved drug for alcoholism, has demonstrated promising anti-tumor effects combined with Cu2+. This combination is achieved through the metabolism of DSF into dithiocarbamate (DTC), which chelates with Cu2+ to form the active form of DTC-copper complexes (CuET). Interestingly, our investigation revealed that Ca2+ can serve as another amplifier to enhance the efficacy of DSF by inducing calcium overload in tumor cells. Building upon this finding, we developed biomineralized nanoparticles (CuCaP@DTC) capable of controlled release of DTC, Cu2+, and Ca2+ in response to the acidic tumor microenvironment. These nanoparticles exhibited stability in the bloodstream for prolonged circulation, enabling their passive accumulation in tumors while efficiently releasing Ca2+ and Cu2+/DTC to facilitate CuET generation within tumor cells. The combined effect of in-situ CuET generation and calcium overload resulted in amplified anti-tumor effects. This research underscores the potential of synergistically combining DSF, copper, and calcium as a promising approach for improving treatment outcomes. Furthermore, it emphasizes the importance of rational design in delivery carrier systems based on a comprehensive understanding of the therapeutic mechanisms to enhance the drug efficacy.

A Self-Assembled Organic Probe with Activatable Near-Infrared Fluoro-Photoacoustic Signals for In Vivo Evaluation of the Radiotherapy Effect.

Early evaluation and prediction of the radiotherapy effect against tumors are crucial for effective radiotherapy management. The clinical approach generally relies on anatomical changes in tumor size, which is unable to promptly reflect clinical outcomes and guide a timely adjustment of therapy regimens. To resolve it, we herein develop a self-assembled organic probe (dCyFFs) with caspase-3 (Casp-3)-activatable near-infrared (NIR) fluoro-photoacoustic signals for early evaluation and prediction of radiotherapy efficacy. The probe contains an NIR dye that is caged with a Casp-3-cleavable substrate and linked to a self-assembly initiating moiety. In the presence of Casp-3, the self-assembled probe can undergo secondary assembly into larger nanoparticles and simultaneously activate NIR fluoro-photoacoustic signals. Such a design endows a superior real-time longitudinal imaging capability of Casp-3 generated by radiotherapy as it facilitates the passive accumulation of the probe into tumors, activated signal output with enhanced optical stability, and retention capacity relative to a nonassembling small molecular control probe (dCy). As a result, the probe enables precise prediction of the radiotherapy effect as early as 3 h posttherapy, which is further evidenced by the changes in tumor size after radiotherapy. Overall, the probe with Casp-3-mediated secondary assembly along with activatable NIR fluoro-photoacoustic signals holds great potential for evaluating and predicting the response of radiotherapy in a timely manner, which can also be explored for utilization in other therapeutic modalities.

The transportosome system as a model for the retrotransport of soluble proteins

The classic model of action of the glucocorticoid receptor (GR) sustains that its associated heat-shock protein of 90-kDa (HSP90) favours the cytoplasmic retention of the unliganded GR, whereas the binding of steroid triggers the dissociation of HSP90 allowing the passive nuclear accumulation of GR. In recent years, it was described a molecular machinery called transportosome that is responsible for the active retrograde transport of GR. The transportosome heterocomplex includes a dimer of HSP90, the stabilizer co-chaperone p23, and FKBP52 (FK506-binding protein of 52-kDa), an immunophilin that binds dynein/dynactin motor proteins. The model shows that upon steroid binding, FKBP52 is recruited to the GR allowing its active retrograde transport on cytoskeletal tracks. Then, the entire GR heterocomplex translocates through the nuclear pore complex. The HSP90-based heterocomplex is released in the nucleoplasm followed by receptor dimerization. Subsequent findings demonstrated that the transportosome is also responsible for the retrotransport of other soluble proteins. Importantly, the disruption of this molecular oligomer leads to several diseases. In this article, we discuss the relevance of this transport machinery in health and disease.

Trash or treasure: Rhizome conservation during drought

Abstract The role of storage carbohydrates in plant carbon economy is currently disputed as possibly passive accumulation when other resources are limiting growth, or part of a conservative growth strategy as insurance for regrowth and stress response. One indication may be the fate of carbohydrates in senescing rhizomes, as either translocated to be retained in the live and growing end of the rhizome or kept within the senescing rhizome end and lost into the soil for it to decompose. To examine carbohydrate storage in senescing rhizomes, eight rhizomatous species were grown in a split‐pot design with one compartment containing the forward‐growing and younger end of the rhizome and another containing the older end. Both compartments were either watered (control) or the older one was left un‐watered (drought treatment) to trigger rhizome senescence and potential carbohydrate translocation. Plant growth, root traits, and non‐structural carbohydrate types and concentrations were assessed in four sequential harvests. Drought treatment plants had higher rhizome dry matter content. Younger rhizome parts produced higher new rhizome and above‐ground biomass than older rhizome parts. Carbohydrate concentrations in rhizomes remained consistent for both treatments, younger and older rhizome parts, and all harvests, probably because of the translocation of water from the watered to the dry compartment to prevent senescence and rhizome loss. Contrary to expectations, the experimental treatment did not trigger rhizome senescence: plants responded by conserving the rhizome and resources within, rather than by losing their older parts. The invariant composition and concentration of carbohydrates within the rhizome suggest that rhizomes are essential plant organs and the storage carbohydrates they contain are necessary for regrowth after stress. Read the free Plain Language Summary for this article on the Journal blog.