Tumor therapeutic efficacy is determined, to a great extent, by the delivery efficiency of therapeutic drugs to their final targets. The cell nucleus has been proven to be the main interaction site ...for most therapeutic agents such as anticancer drugs, genes, free radicals, and heat. Therefore, it is highly expected that cell nucleus-targeting or nuclear membrane-penetrating nanotherapeutics would provide a more effective strategy than ordinary cell membrane-targeting ones for benefiting precise nanomedicine in humans' battles against cancer. This tutorial review presents a summary of the most recent progress achieved in the design, synthesis, and application of cell nucleus-targeting nanotherapeutics. We first discuss a number of design principles involved in cell nucleus-targeting nanotherapeutics, including size control, shape regulation, and surface modification. Next, we demonstrate the diverse applications of cell nucleus-targeting nanotherapeutics ranging from chemotherapy, gene therapy, photodynamic therapy, photothermal therapy to synergistic therapy. Moreover, a number of typical nanotherapeutics designed for enhanced therapeutic efficacy by targeting other subcellular organelles (such as mitochondria, lysosomes, and endoplasmic reticulum) are also briefly discussed. Finally, perspectives and challenges in this research field are proposed, in the hope of accelerating their translation into the clinic.
Recent advances in the chemical design and synthesis of nuclear-targeted nanotherapeutics for combating tumors are summarized and highlighted.
Mesoporous silica nanoparticles functionalized with peptides are developed for sequential drug delivery. The RGD peptide is used for vasculature/cell membrane targeting and the TAT peptide for ...nuclear targeting. Using this delivery strategy, a tumor in a murine xenograft model is successfully regressed.
Abstract The development of multidrug resistance (MDR) in cancer cells is one of major obstacles to the effective cancer chemotherapy. In this report we demonstrate the effective circumvention of ...multidrug resistance in cancer cells by an active nuclear-targeted drug delivery system that was constructed by conjugating TAT peptide onto the surface of mesoporous silica nanoparticles (MSNs-TAT). The conjugation of TAT peptide facilitated the intranuclear localization of MSNs-TAT and the release of the encapsulated drugs directly within the nucleoplasm. The direct intranuclear drug delivery of doxorubicin (DOX) in multidrug resistant MCF-7/ADR cancer cells was capable of increasing the intracellular as well as intranuclear drug concentrations much more effectively than free DOX or delivered by MSNs in the absence of TAT peptide. With the nuclear drug delivery fashion, DOX-MSNs-TAT presents a promising strategy in overcoming MDR in cancer cells and improving the therapeutic index of currently available chemotherapeutics by enhancing therapeutic efficacy and reducing side effects.
In this study, we used a 224Ra mass balance model to evaluate the importance of submarine groundwater discharge (SGD) for the budgets of biogenic elements in two major Chinese estuaries: the Pearl ...River Estuary (PRE) and the Changjiang River Estuary (CRE). The apparent water age in the PRE was estimated to be 4.8 ± 1.1 days in the dry season and 1.8 ± 0.6 days in the wet season using a physical model based on the tidal prism. In the dry season, the water age in the CRE was estimated to be 11.7 ± 3.0 days using the 224Ra/223Ra activities ratios apparent age model. By applying the 224Ra mass balance model, we obtained calculations of the SGD flow in the PRE of (4.5–10) × 108 m3 d−1 (0.23–0.50 m3 m−2 d−1) and (1.2–2.7) × 108 m3 d−1 (0.06–0.14 m3 m−2 d−1) in the dry season and wet season, respectively, and the estimated SGD flux was (4.6–11) × 109 m3 d−1 (0.18–0.45 m3 m−2 d−1) in the dry season of the CRE. In comparison with the nutrient fluxes from the rivers, the SGD-derived nutrient fluxes may play a vital role in controlling the nutrient budgets and stoichiometry in the study areas. The large amount of dissolved inorganic nitrogen and phosphorus fluxes together with high N: P ratios into the PRE and CRE would potentially contribute to eutrophication and the occurrence of red tides along the adjacent waters.
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•Physical model and 224Ra/223Ra were used to estimate water ages in the Pearl River Estuary and Changjiang River Estuary.•Submarine groundwater discharge (SGD) was evaluated using a 224Ra mass balance model.•SGD is important for hydrology and nutrient budgets in the Pearl River Estuary and Changjiang River Estuary.
Iron oxide nanoparticle (IONP)-based magnetic resonance imaging (MRI) contrast agents have been widely used for the diagnosis of hepatic lesions. However, current IONP-based liver-specific MRI ...contrast agents rely on single-phase contrast enhancement of the normal liver, which is not sensitive enough to detect early stage small hepatocellular carcinomas (HCCs). We herein report i-motif DNA-assisted pH-responsive iron oxide nanocluster assemblies (termed RIAs), which provide an inverse contrast enhancemt effect to improve the distinction between normal liver and target HCC tissues. The acidic pH of the tumor microenvironment triggers the disassembly of the RIAs, which leads to a drastic decrease in their relaxivity ratio (r 2/r 1), thus converting the RIAs from a T2 to T1 contrast agent. This inverse contrast enhancement of normal liver darkening and HCC brightening under T1 imaging mode was validated on an orthotopic HCC model. Our design provides a novel strategy for the exploitation of the next-generation intelligent MRI contrast agents.
Local hypoxia in tumors is an undesirable consequence of photodynamic therapy (PDT), which will lead to greatly reduced effectiveness of this therapy. Bioreductive pro‐drugs that can be activated at ...low‐oxygen conditions will be highly cytotoxic under hypoxia in tumors. Based on this principle, double silica‐shelled upconversion nanoparticles (UCNPs) nanostructure capable of co‐delivering photosensitizer (PS) molecules and a bioreductive pro‐drug (tirapazamine, TPZ) were designed (TPZ‐UC/PS), with which a synergetic tumor therapeutic effect has been achieved first by UC‐based (UC‐) PDT under normal oxygen environment, immediately followed by the induced cytotoxicity of activated TPZ when oxygen is depleted by UC‐PDT. Treatment with TPZ‐UC/PS plus NIR laser resulted in a remarkably suppressed tumor growth as compared to UC‐PDT alone, implying that the delivered TPZ has a profound effect on treatment outcomes for the much‐enhanced cytotoxicity of TPZ under PDT‐induced hypoxia.
Synergetic therapy: Strong hypoxia created by upconversion photodynamic therapy (UC‐PDT) activates bioreductive pro‐drugs co‐delivered to form cytotoxic species, thereby potentiating the synergetic anticancer efficacy of UC‐PDT. This process was accomplished by using upconversion‐based nanoparticles designed to simultaneously deliver photosensitizer molecules and bioreductive pro‐drugs in silica layers.
Freeze-thaw cycle is one of the main distresses of asphalt pavement, and the law of freeze-thaw damage has always been an important topic. In this paper, X-ray computed tomography (CT) of asphalt ...mixture before and after freezing and thawing was carried out, and its two-dimensional (2D) digital image was recognized. Firstly, the eigenvalues of internal voids of asphalt mixture are extracted. Then the distribution of internal voids was analyzed. Finally, the evolution law of internal voids was summarized. The research results show that the characteristic mean value of the 9th cycle is the irreversible limit of freeze-thaw damage, and the non-resilience after the large void area increases is the fundamental reason for the accumulation of freeze-thaw damage. The source of void damage shifts from large voids to small voids, and the middle-stage is a critical stage of freeze-thaw damage. This work quantitatively evaluates the internal freeze-thaw damage process of asphalt mixture, and a morphological theory of the evolution of void damage based on an equivalent ellipse is proposed, which is helpful for better understanding the freezing-thawing damage law of asphalt pavement.
•Water ages, SGD, and associated nutrients on different scales of Xiangshan Bay were evaluated using radium-based model.•SGD fluxes in XSB Channel and three inner embayments are at least 1–2 orders ...of magnitude higher than river discharge.•SGD is primarily regulated and modulated by ocean dynamics and anthropogenic activities.•SGD rates and associated nutrient rates in the XSB were comparable to those in other global mariculture regions.
Submarine groundwater discharge (SGD) is a predominant component of chemical fluxes in the solute budgets in coastal ecosystems because of its large flux and the corresponding concentrated constituents. A quantitative study regarding the mass balance model of 226Ra and 228Ra was performed to assess SGD and associated nutrient inputs in Xiangshan Bay (XSB), a typical Chinese aquaculture bay. Based on these mass balance models, the SGD rates in the XSB Channel were 8.9–13.2 cm d−1. The SGD rates in the three corresponding embayments were 3.5–3.7 cm d−1 in Embayment I, 5.6–5.8 cm d−1 in Embayment II, and 4.5–5.8 cm d−1 in Embayment III. Significant spatial variabilities in SGD rates were observed in the different XSB districts, reflecting that ocean dynamics and anthropogenic activities play significant roles at different scales. SGD-derived nutrient fluxes in XSB were the dominant sources of nutrient loading, and their magnitudes were approximately 1–2 orders larger than those of riverine input. SGD rates in the XSB Channel were approximately three times higher than those in the three embayments, but the SGD-derived nutrient rates in the XSB Channel were comparable with those in the three embayments, even significantly lower than that for NO3-N in the inner regions of the embayment. These results imply that aquaculture activities and urbanization jointly influence SGD. When combined with the results of other studies, our observations demonstrate the significant comprehensive effects of multiple factors on SGD, a critical but overlooked nutrient source.
Abstract To achieve the accurate diagnosis and efficient in situ therapy of malignant tumors is encouraging but still remains a big challenge. The integration of upconversion nanoparticles and ...mesoporous silica that can combine the diagnostic/therapeutic functions within a single platform, may provide a more advanced way for the efficient theranostics of cancer. In this study, sub-80 nm rattle-structured multifunctional Gd-UCNPs core/mesoporous silica shell nanotheranostics (UCMSNs) were successfully constructed for the co-delivery of a radio-/photo-sensitizer hematoporphyrin (HP) and a radiosensitizer/chemodrug docetaxel (Dtxl). Upon NIR excitation and X-ray irradiation, the complete tumor elimination has been achieved by the synergetic chemo-/radio-/photodynamic tri-modal therapy under the assistance of simultaneous magnetic/upconversion luminescent (MR/UCL) bimodal imaging. To the best of our knowledge, this study is the first example of achieving tri-modal synergetic therapy in one single nanotheranostic system, and we anticipate that it may serve as a particularly useful platform for the clinical diagnosis and efficient treatment of cancer from bench to beside.
Surgical resection, one of the main clinical treatments of intracranial glioblastoma, bears the potential risk of incomplete excision due to the inherent infiltrative character of the glioblastoma. ...To maximize the accuracy of surgical resection, the magnetic resonance (MR) and fluorescence imaging are widely used for the tumor preoperative diagnosis and intraoperative positioning. However, present commercial MR contrast agents and fluorescent dyes can only function for single mode of imaging and are subject to poor blood–brain barrier (BBB) permeability and nontargeting-specificity, resulting in the apparent risks of inefficient diagnosis and resection of glioblastoma. Considering the unique MR/upconversion luminescence (UCL) bimodal imaging feature of upconversion nanoparticles (UCNPs), herein, we have developed a dual-targeting nanoprobe (ANG/PEG-UCNPs) to cross the BBB, target the glioblastoma, and then function as a simultaneous MR/NIR-to-NIR UCL bimodal imaging agent, which showed a much enhanced imaging performance in comparison with the clinically used single MRI contrast (Gd-DTPA) and fluorescent dye (5-ALA). Moreover, their biocompatibility, especially to brains, was systematically assessed by the histological/hematological examination, indicating a negligible in vivo toxicity. As a proof-of-concept, the ANG/PEG-UCNPs hold the great potential in MR diagnosis and fluorescence positioning of glioblastoma for the efficient tumor surgery.
