A structure-guided strategy to design Golgi apparatus-targeted type-I/II aggregation-induced emission photosensitizers for efficient photodynamic therapy.

The Golgi apparatus (GA) is a vital target for anticancer therapy due to its sensitivity against reactive oxygen species (ROS)-induced oxidative stress that could lead to cell death. In this study, we designed a series of aggregation-induced emission (AIE)-based photosensitizers (TPAPyTZ, TPAPyTC, TPAPyTM, and TPAPyTI) carrying different ROS with selective GA-targeted ability. The in vitro study showed that TPAPyTZ and TPAPyTC displayed strong AIE characteristics, robust type-I/II ROS production capabilities, specific GA-targeted, high photostability, and high imaging quality. The cell-uptake of TPAPyTZ was found primarily through an energy-dependent caveolae/raft-mediated endocytosis pathway. Remarkably, TPAPyTZ induced GA-oxidative stress, leading to GA fragmentation, downregulation of GM130 expression, and activation of mitochondria caspase-related apoptosis during photodynamic therapy (PDT). In vivo experiments revealed that TPAPyTZ significantly inhibited tumor proliferation under lower-intensity white light irradiation with minimal side effects. Overall, our work presents a promising strategy for designing AIEgens for fluorescence imaging-guided PDT. Additionally, it enriched the collection of GA-targeted leads for the development of cancer theranostics capable of visualizing dynamic changes in the GA during cancer cell apoptosis, which could potentially enable early diagnosis applications in the future. STATEMENT OF SIGNIFICANCE: AIE luminogens (AIEgens) are potent phototheranostic agents that can exhibit strong fluorescence emission and enhance ROS production in the aggregate states. In this study, through the precise design of photosensitizers with four different electron-acceptors, we constructed a series of potent AIEgens (TPAPyTZ, TPAPyTC, TPAPyTM, and TPAPyTI) with strong fluorescence intensity and ROS generation capacity. Among them, TPAPyTZ with an extended π-conjugation displayed the strongest ROS generation ability and anti-tumor activity, resulting in an 88 % reduction in tumor weight. Our studies revealed that the enhanced activity of TPAPyTZ may be due to its unique Golgi apparatus (GA)-targeted ability, which causes GA oxidative stress followed by effective cancer cell apoptosis. This unique GA-targeted feature of TPAPyTZ remains rare in the reported AIEgens, which mainly target organelles such as lysosome, mitochondria, and cell membrane. The successful design of a GA-targeted and potent AIEgen could enrich the collection of GA-targeted luminogens, providing a lead theranostic for the further development of fluorescence imaging-guided PDT, and serving as a tool to explore the potential mechanism and discover new GA-specific drug targets.

Programmable site-specific delivery of an alkaline phosphatase-activatable prodrug and a mitochondria-targeted cyclopeptide for combination therapy in colon cancer.

The design of advanced carriers that enable time- or stimulus-programmed drug release holds great promise to enhance the treatment efficacy in tumors. Here, hyaluronic acid (HA)-coated liposomes were designed to efficiently deliver multi-organelle-targeted and ALP/GSH dual-responsive prodrugs for combination therapy on colon tumors. In this system (designated CPTP/RA-HALipo), the unique natural cyclopeptide RA-V was linked covalently to a near-infrared (NIR) fluorophore through a disulfide linker, which was subsequently loaded in the cationic liposome core of CPTP/RA-HALipo, while the ALP-activatable phosphate CPT (CPTP) was encapsulated in the HA shell. In the tumor microenvironment, the HA shell of CPTP/RA-HALipo was partially degraded by HAase, thereby allowing the release of CPTP. The released phosphate prodrug CPTP was activated through hydrolysis of the phosphate esters by brush border-associated enzymes. The cationic liposome coated with the remaining HA could selectively enter CD44 overexpressed cells via receptor-mediated endocytosis into the lysosome, in which the acidic microenvironment degraded the liposomes to release the mitochondria-targeted theranostic agent RA-S-S-Cy. More significantly, the GSH-activatable NIR fluorescence of Cy5.5 made it possible to realize in vivo and in situ dynamic monitoring of drug release in a noninvasive manner. The organelle-specific and multi-stimuli responsive nanoparticles have shown precise control over drug delivery and release, leading to superior in vitro and/or in vivo anti-cancer efficacy. This approach represents a novel interactive drug delivery system that can synergistically differentiate the extracellular, cell membranal and intracellular targets to promote spatial and temporal control of drug release.

Improved fully convolutional neuron networks on small retinal vessel segmentation using local phase as attention.

Retinal images have been proven significant in diagnosing multiple diseases such as diabetes, glaucoma, and hypertension. Retinal vessel segmentation is crucial for the quantitative analysis of retinal images. However, current methods mainly concentrate on the segmentation performance of overall retinal vessel structures. The small vessels do not receive enough attention due to their small percentage in the full retinal images. Small retinal vessels are much more sensitive to the blood circulation system and have great significance in the early diagnosis and warning of various diseases. This paper combined two unsupervised methods, local phase congruency (LPC) and orientation scores (OS), with a deep learning network based on the U-Net as attention. And we proposed the U-Net using local phase congruency and orientation scores (UN-LPCOS), which showed a remarkable ability to identify and segment small retinal vessels. A new metric called sensitivity on a small ship (Sesv ) was also proposed to evaluate the methods' performance on the small vessel segmentation. Our strategy was validated on both the DRIVE dataset and the data from Maastricht Study and achieved outstanding segmentation performance on both the overall vessel structure and small vessels.

Arg-liposome-amplified colorimetric immunoassay for selective and sensitive detection of cystatin C to predict acute kidney injury.

Cystatin C (Cys C) has been considered as a novel biomarker of kidney disease, which is thought to be a better indicator of glomerular filtration rate than creatinine (Scr) in the prediction of acute kidney injury (AKI). Hence, there is strong need to develop a precise, rapid and simple detection method for Cys C. Here we reported a Arg-liposome-amplified colorimetric immunoassay for the detection of Cys C to predict AKI. Cys C antibodies are conjugated on the surface of magnetic beads (MBs) and arginine (Arg)-loaded liposomes to form Ab1-MBs and Ab2-Arg-liposomes, respectively. When Ab1-MBs captured Cys C, Ab2-Arg-liposomes are added and incubated to form the immuno-sandwich complex. After magnetic separation, the surfactant Triton ×100 is added to damage the liposomes, leading to the release of Arg which can induce the gold nanoparticles aggregation. Therefore, the discoloration can be used for visual and quantitative detection of Cys C. Notably, the method has a linear relation in the range of 10-100 µg/L for Cys C with a limit of detection 4.32 µg/L, which is lower than some of the previous reports. In addition, the AKI mice serum samples were tested by the developed method, which were in good agreement with ELISA results. More intriguingly, the results of cisplatin induced acute kidney injury in mice showed that the method could be used to evaluate the protective effect of astragalus membranaceus (AM) on AKI by detecting Cys C in serum, providing a new strategy for screening renal protective drugs. Accordingly, a rapid and highly sensitive Cys C detection system was established with great potential for clinical diagnostics.

Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy.

Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments, but its clinical implementation has been restricted by the low host antitumor response rate. Recently, chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication. The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism. Herein, a synergistic antitumor platform (designated as BMS/RA@CC-Liposome) was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug (RA-V) and PD-1/PD-L1 blockade inhibitor (BMS-202) to remarkably enhance antitumor immunity. In this study, the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem. To achieve the cell-specific targeting drug delivery, the combination therapy nanosystem was functionalized with cancer cell membrane camouflage. The biomimetic drug delivery system perfectly disguised as endogenous substances, and realized elongated blood circulation due to anti-phagocytosis capability. Moreover, the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells. The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response, RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells. Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically, demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.

Hyaluronic Acid Coated Liposomes Co-Delivery of Natural Cyclic Peptide RA-XII and Mitochondrial Targeted Photosensitizer for Highly Selective Precise Combined Treatment of Colon Cancer.

BACKGROUND: Natural cyclopeptide RA-XII, isolated from Rubia yunnanensis, is a promising chemotherapeutic agent for colon cancer. The photosensitizer protoporphyrin-IX attached with triphenylphosphonium (TPP) could possess mitochondria targeting capacity and exert photodynamic therapy (PDT) by inducing oxidizing damage to the mitochondria and cell apoptosis eventually. In this work, pH-sensitive liposomes were constructed to simultaneously deliver RA-XII as a chemotherapeutic drug and modified porphyrin as a mitochondria-targeting photosensitizer to treat colon cancer, and verified its mechanism of action and antitumor therapeutic efficacy. METHODS: The colon cancer targeting liposome nanoparticle RA/TPPP-Lip was synthesized using thin film hydration. The therapeutic effect and targeting ability of RA/TPPP-Lip was investigated in vitro. And use HCT116 cell allogeneic subcutaneous transplantation tumor model to investigate the anti-tumor and targeting effects of RA/TPPP-Lip in vivo. RESULTS: RA/TPPP-Lip gained the targeting ability through surface-modified HA to increase the accumulation of RA-XII and TPPP in colon cancer cells. A series of in vitro experimental results showed that TPPP produced cytotoxic ROS under laser irradiation to directly damage cell mitochondria and played a combined role with RA-XII, making RA/TPPP-Lip the best colon cancer cell growth inhibitory effect. Furthermore, in vivo antitumor experiments showed that the RA/TPPP-Lip substantially accumulated at the tumor site and efficiently repressed tumor growth in nude mice. CONCLUSION: We have successfully designed a new cancer-targeted nanomedicine platform (RA/TPPP-Lip) for the collaborative treatment of colon cancer, which can achieve the targeted continuous release of multiple therapeutic drugs. This work provides a new strategy for precise combination therapy, which may promote the further development of collaborative cancer treatment platforms.

New strategy for precise cancer therapy: tumor-specific delivery of mitochondria-targeting photodynamic therapy agents and in situ O2-generation in hypoxic tumors.

Besides tumor hypoxia and limitation of superficial lesions, the short lifetime of photoinduced reactive oxygen species (ROS) is another factor repressing photodynamic therapy (PDT) efficacy. To overcome these problems, this study developed newly designed mitochondria-specific, H2O2-activatable, and O2-producing nanoparticles to achieve highly selective and efficient PDT and self-sufficiency of O2 in hypoxic tumors. The newly designed nanoparticles (BDPP NPs) are composed of a mitochondria-targeting photosensitizer and catalase in the aqueous core and a black hole quencher and fluorescent tracker in the polymeric shell, and modified with the tumor-targeting cyclic pentapeptide c(RGDfK). Once taken up by αvß3 integrin-rich tumor cells, intracellular H2O2 easily penetrated the lipophilic shells into the aqueous cores of BDPP NPs, and it was catalyzed by catalase to quickly generate O2 gas, causing the rupture of the NPs to release the photosensitizer. Therefore in vivo tumor cell mitochondria targeting by BDPP can be realized together with the favorable hypoxia relief. In vitro and in vivo experiments demonstrate that the therapeutic efficiency was significantly improved by the mitochondria-specific feature and H2O2-controllable generation of 1O2. More importantly, BDPP NPs continuously generate O2 in the PDT process, which can be helpful for resolving the overconsumption of oxygen in PDT and enhancing the PDT efficiency of cancer chemotherapy. We anticipate that this work may provide new insight into the design of smart PDT systems to achieve highly selective in vivo PDT via targeting subcellular organelles and realize oxygen therapy in O2-deprived tumors.

Kidney targeted delivery of asiatic acid using a FITC labeled renal tubular-targeting peptide modified PLGA-PEG system.

Chronic kidney disease (CKD) is one of the leading public health problems worldwide and finally progresses to end-stage renal disease. The therapeutic options of CKD are very limited. Thus, development of drug delivery systems specific-targeting to kidney may offer more options. Here we developed an efficient kidney-targeted drug delivery system using a FITC labeled renal tubular-targeting peptide modified PLGA-PEG nanoparticles and investigated the intrarenal distribution and cell-type binding. We found that the modified nanoparticles with an approximate diameter of 200 nm exhibited the highest binding capacity with HK-2 cells and fluorescence and immunohistochemical analysis showed they mainly localized in renal proximal tubules by passing through the basolateral side. Furthermore, these kidney-specific nanoparticles could significantly enhance the therapeutic effects of asiatic acid, an insoluble triterpenoid compound as drug delivery carriers. In conclusion, these results suggest the potential of the peptide modified PLGA-PEG nanoparticles as kidneytargeted drug delivery system to proximal tubular cells in treatment of CKD.

Asiatic acid prevents renal fibrosis in UUO rats via promoting the production of 15d-PGJ2, an endogenous ligand of PPAR-γ.

Renal fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Recently, asiatic acid (AA), a triterpenoid compound from Chinese medicine Centella asiatica, has been found to attenuate renal fibrosis. In the current study, we explored the mechanisms underlying antifibrotic effect of AA on UUO model. SD rats and ICR mice were subjected to unilateral ureteral occlusion (UUO) surgery. Prior the surgery, rats were administered AA (10 mg·kg-1 per day, ig) for 7 days, whereas the mice received AA (15 mg·kg-1 per day, ig) for 3 days. UUO group displayed significant degree of renal dysfunction, interstitial fibrosis, oxidative stress, and activation of the TGF-ß/Smad and Wnt/ß-catenin signaling pathway in the kidney, these pathological changes were greatly ameliorated by pretreatment with AA. In addition, we found that co-treatment with GW9662, a selective PPAR-γ antagonist (1 mg·kg-1 per day, ip) for 7 days, abolished the protective effects of AA. We further revealed that AA pretreatment did not significantly change the expression levels of PPAR-γ in the kidney, but markedly increase the plasma levels of 15d-PGJ2, an endogenous ligand of PPAR-γ. In UUO mice, pretreatment with 15d-PGJ2 (24 µg·kg-1 per day, ip, for 7 days) produced similar protective effect as AA. Moreover, AA pretreatment upregulated the expression levels of active, nuclear-localized SREBP-1 (nSREBP-1), whereas fatostatin, a specific inhibitor of SREBP-1, decreased the expression of nSREBP-1, as well as the level of 15d-PGJ2. These results provide new insight into the antifibrotic mechanism of AA and endogenous metabolites might become a new clue for investigation of drug mechanism.

Programmed delivery of cyclopeptide RA-V and antisense oligonucleotides for combination therapy on hypoxic tumors and for therapeutic self-monitoring.

Chemotherapy is a dominant treatment modality for different types and stages of cancer. However, hypoxia is one of the undesirable limitations of chemotherapy, which reduces the therapeutic efficiency in cancer treatment, ultimately leading to failure of the treatment. Herein, an ideal chemosensitization system capable of attenuating the tumor hypoxia microenvironment and enhancing chemotherapy effects in tumors was designed. This system (designated as the RA/RX Liposome) uses for the first time a pH-sensitive liposome to co-deliver cyclopeptide RA-V as chemotherapeutic drugs and antisense oligonucleotides as HIF-1α inhibitors (RX-0047) for attenuating tumor hypoxia, as well as a caspase-8 activation probe for therapeutic self-monitoring. After modification with death receptor 5-specific antibodies (anti-DR5) on the surface of the liposome, the RA/RX Liposome can successfully deliver components targeting colon tumors in vivo. This work should synergistically enhance the therapeutic effects of the treatment by successfully down-regulating HIF-1α expression against tumor hypoxia during the RA-V-induced apoptotic process. More importantly, the RA/RX Liposome can be precisely applied for therapeutic self-monitoring with the light-up fluorescence of the caspase-8 probe.

Inhibition of fatty acid synthesis arrests colorectal neoplasm growth and metastasis: Anti-cancer therapeutical effects of natural cyclopeptide RA-XII.

Emerging evidence has shown that metabolism, in particular the synthesis of fatty acids, has great significance for growth and metastasis of colorectal neoplasm. The previous results showed that RA-XII, a natural cyclopeptide isolated from Rubia yunnanensis, inhibits tumor growth and metastasis by AMPK/mTOR/P70S6K pathway and PI3K/AKT/NF-κB pathway. But if or not lipid metabolism involves the antitumor mechanism of RA-XII is not clear. Herein the results indicated that RA-XII reduced the cell motility by decreasing the expressions of ß-catenin and ß-catenin dependent proteins CD44 and MMP7 in HCT116 cells. Then RA-XII effectively reduced fatty acids levels by decreasing the expression of SREBP-1 and inhibiting the expressions of de novo fatty acid synthesis proteins FASN and SCD. Moreover the decreased cell motility caused by RA-XII was attenuated with the SREBP-1 knockdown. In addition, the in vivo experiments also demonstrated that RA-XII inhibited tumor growth and metastasis via restraining lipogenesis in colorectal neoplasm mouse models. Taken together, these results indicated that RA-XII suppressed the colorectal neoplasm growth and metastasis by inhibition of lipogenesis depended on SREBP-1 suppression.

Redox Dual-Responsive and O2­Evolving Theranostic Nanosystem for Highly Selective Chemotherapy against Hypoxic Tumors.

Activatable theranostic agents, which combine fluorescent reporters with masked chemotherapeutic agents that are activated by tumor-associated stimuli, would be attractive candidates to improve the tumor selectivity of chemotherapy. This work reports a ROS/GSH dual-activatable and O2­evolving theranostic nanosystem (RA-S-S-Cy@PLGA NPs) for highly selective therapy against hypoxic tumors and in situ fluorescence-tracking of cancer chemotherapy. Methods: In this system, the newly designed theranostic agent (RA-S-S-Cy) is composed of a disulfide bond as a cleavable linker, a near infrared (NIR) active fluorophore as a fluorescent tracker, and a natural cyclopeptide RA-V as the active anti-cancer agent. Upon reaction with the high level of intracellular glutathione (GSH), disulfide cleavage occurs, resulting in concomitant active drug RA-V release and significant NIR fluorescence increase. To further improve the tumor targeting of RA-S-S-Cy and achieve redox dual-responsiveness, RA-S-S-Cy was incorporated into the c(RGDfK)-targeted PLGA nanoparticles together with an O2-generating agent (catalase) to produce RA-S-S-Cy@PLGA NPs. Results: The cell-specific and redox dual-activatable release of RA-V lead to enhanced therapeutic outcomes in vivo and in vitro. More significantly, the RA-S-S-Cy@PLGA NPs were successfully applied for monitoring of drug release and chemotherapeutic efficacy in situ by "turn-on" NIR fluorescence. Conclusions: RA-S-S-Cy@PLGA NPs would be efficient theranostic nanosystems for more precise therapy against hypoxic tumors and provides a potential tool for deeper understanding of drug release mechanisms.

Dimeric BODIPY-loaded liposomes for dual hypoxia marker imaging and activatable photodynamic therapy against tumors.

This work reports a dimeric BODIPY (BDP)-loaded liposome with conjugation of anti-HIF antibodies for dual hypoxia marker imaging and nitroreductase (NTR)-activatable photodynamic therapy (PDT) against hypoxic tumors. In this theranostic nanosystem (designated Ab-DiBDP NPs), the newly designed orthogonal BDP dimer has high 1O2 quantum yield, and the substitution of a nitro group at the meso-position leads to the NTR-controllable activation of phototoxicity and fluorescence. Both in vivo and in vitro experiments demonstrate that the NTR-activatable PDT liposome can efficiently destroy cancer cells and prevent damage to normal cells. More significantly, the fascinating advantage of the nanoprobe is the synergy between the Cy 7-marked anti-HIF-1α antibody and the NTR-activatable DiBDP, which significantly improves the accuracy of tumor hypoxia imaging by simultaneous detection of NTR and HIF-1α. Therefore, this work presents a new paradigm for NTR-triggered PDT against cancer cells and provides a new avenue for precise tumor hypoxia diagnosis.

Sequential Delivery of Cyclopeptide RA-V and Doxorubicin for Combination Therapy on Resistant Tumor and In Situ Monitoring of Cytochrome c Release.

A programmed drug delivery system that can achieve sequential release of multiple therapeutics under different stimulus holds great promise to enhance the treatment efficacy and overcome multi-drug resistance (MDR) in tumor. Herein, multi-organelle-targeted and pH/ cytochrome c (Cyt c) dual-responsive nanoparticles were designed for combination therapy on resistant tumor. In this system (designated DGLipo NPs), doxorubicin (Dox) was intercalated into the DNA duplex containing a Cyt c aptamer, which subsequently loaded in the dendrigraftpoly-L-lysines (DGL) cores of DGLipo NPs, while cyclopeptide RA-V was doped into the pH-sensitive liposomal shells. After dual modification with c(RGDfK) and mitochondria-penetrating peptide (MPP), DGLipo NPs could successively deliver the two drugs into lysosome and mitochondria of cancer cells, and achieve sequential drug release in virtue of the unique characteristic of these two organelles. The organelle-specific and spatiotemporally controlled release of Dox and RA-V led to enhanced therapeutic outcomes in MDR tumor. More significantly, the DGLipo NPs were successfully applied to monitor Cyt c release during mitochondria-mediated apoptotic process. This work represents a versatile strategy for precise combination therapy against resistant tumor with spatiotemporal control, and provides a potential tool for Cyt c-related apoptotic studies.

A New Approach to Sensitize Antitumor Monofunctional Platinum(II) Complexes via Short Time Photo-Irradiation.

Sensitizing the antitumor activity of monofunctional PtII complexes is a reliable approach to developing antitumor agents different from the classic Pt-based drugs. Considering the poor intracellular accumulation of monofunctional PtII complexes, in this study, the photosensitizing monofunctional PtII complex Pt-BA was derived from a weak BODIPY (boron-dipyrromethene)-derived photosensitizer BA, with the purpose to improve its antitumor cytotoxicity via enhancing its intracellular accumulation with a short time photo-irradiation. Photoinduced reactive oxygen species (ROS) determination indicated that the PtII center in Pt-BA is able to improve the photoinduced ROS production ability of BA, which makes Pt-BA a mild photosensitizer. Fluorescence imaging disclosed that dark incubation makes Pt-BA accumulate mainly on the surface of cell membrane, and the later short time photo-irradiation (5 min) promotes distinctly the intracellular accumulation of Pt-BA, which has been confirmed by inductively coupled plasma-mass spectrometry determination. Flow cytometric Annexin V-FITC assay indicated that the short time irradiation of Pt-BA induces in situ the cell membrane damage, which might finally enhance the intracellular accumulation of this monofunctional complex. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed that the short time photo-irradiation promotes distinctly the antitumor cytotoxicity of Pt-BA against MCF-7, SGC-7901, A549, and HeLa cell lines. The photopromoted antitumor activity of Pt-BA implies that modifying monofunctional PtII complex as a mild photosensitizer to promote its cell accumulation is a useful approach to sensitizing the antitumor activity of monofunctional PtII complex and renders the possibility of monofunctional PtII prodrugs for precise chemotherapy via only short time photoactivation.

Dual aptamer modified dendrigraft poly-l-lysine nanoparticles for overcoming multi-drug resistance through mitochondrial targeting.

A smart dendrigraft poly-l-lysine (DGL) nanoplatform for mitochondria-targeted chemotherapy was devised, which aims to achieve enhanced efficacy against drug resistant tumor cells. In this system, doxorubicin (Dox) was intercalated into the DNA duplex containing an ATP aptamer, which was subsequently condensed by DGL to form a nanoscaled controlled-release system. A nucleolin-specific binding aptamer, AS1411, and a cytochrome c aptamer were then incorporated into the system to give the nanoparticles (Dox/Mito-DGL) for biological evaluations. This dual modified system has been shown to selectively accumulate in the mitochondria of cancer cells and promptly release the loaded Dox in virtue of the high concentrations of ATP in mitochondria. The mitochondria-specific and spatiotemporally controlled release of Dox led to enhanced therapeutic outcomes both in vitro and in vivo. More significantly, Dox/Mito-DGL was successfully applied to improve the efficacy towards multi-drug resistant cancer cells by altering the mitochondrial membrane potential and bypassing the P-glycoprotein-mediated drug efflux. This work presents a paradigm for mitochondria-targeting therapy against mitochondria-associated diseases and provides a potential avenue for overcoming MDR in the treatment of solid tumors.

[Effects of Three Bioretention Configurations on Dissolved Nitrogen Removal from Urban Stormwater].

Multiple chemical forms of nitrogen in urban storm water make its management challenging. Three types of bioretention systems were constructed in 2015 with loamy sand as filter media, including a conventional freely drained bioretention (CB), a modified bioretetion incorporated a submerged zone (MB1), and a modified bioretention incorporating a submerged zone with woodchips addition (MB2). This study investigated the role of vegetation, the use of submerged zone and carbon addition in achieving co-optimized dissolved nitrogen removal in bioretention systems. Twelve bioretention columns were monitored over a 12-month period of dosing with synthetic storm water under varying hydrology and nitrogen loading rates. All the studied bioretention systems could achieve very good ammonia removal (more than 95%) at an average inflow ammonia concentration of (5.45±2.21) mg·L-1. The filter media sorption, nitrification and plants uptake were the main removal pathways for incoming ammonia. The effluent nitrate concentrations of the CB, MB1 and MB2 were (4.04±2.64)mg·L-1 (31.3%), (0.84±1.18) mg·L-1 (85.7%), and (0.26±0.48) mg·L-1 (95.6%), respectively, at the average inflow nitrate concentration of (5.88±2.32) mg·L-1. The use of the native species P. alopecuroides, a submerged zone and woodchips addition could effectively decrease the effluent nitrate concentration, reduce the washout and achieve high nitrate removal. Both plants uptake and denitrification were the two major pathways for removal of inflow nitrate. Inflow magnitude, antecedent dry days and inflow nitrate concentration were the main factors influencing the effluent nitrate concentrations for the three bioretention systems. The results highlighted that the bioretention design of the native species P. alopecuroides incorporated a submerged zone with 10% woodchips addition could consistently and effectively remove storm water nitrate under hydrological regime and nitrogen loading rates.

Glutathione boosting the cytotoxicity of a magnetic platinum(iv) nano-prodrug in tumor cells.

Superparamagnetic iron oxide nanoparticles (SPIONs) are potential vehicles for targeted drug delivery and viable contrast agents for magnetic resonance imaging (MRI). A PtIV prodrug (HSPt) derived from functionalization of cisplatin with hydroxyl and succinate is conjugated with a poly(ethylene glycol) (PEG)-modified SPION for cancer therapy and monitoring of therapeutic responses. The relaxivity of HSPt-PEG-SPIONs is larger than that of commercial contrast agent Feridex, and a tumor-selective negative contrast is observed in MRI in a magnetic field. HSPt-PEG-SPIONs can be dissociated and reduced into PtII species by glutathione (GSH). Instead of forming DNA-Pt crosslinks, the reduced product induces direct DNA single- or double-strand breaks, which is uncommon for Pt drugs. The cytotoxicity of HSPt-PEG-SPIONs is positively correlated with the GSH level of tumor cells, which is opposite to the scenario of current Pt drugs. HSPt-PEG-SPIONs are as cytotoxic as cisplatin against cancer cells but are almost nontoxic towards normal cells. Since the mechanism of action of the nanocomposite is different from the established paradigm for Pt drugs, it may become a special theranostic agent for cancer treatment.

H2O2-activatable and O2-evolving nanoparticles for highly efficient and selective photodynamic therapy against hypoxic tumor cells.

The low selectivity of currently available photosensitizers, which causes the treatment-related toxicity and side effects on adjacent normal tissues, is a major limitation for clinical photodynamic therapy (PDT) against cancer. Moreover, since PDT process is strongly oxygen dependent, its therapeutic effect is seriously hindered in hypoxic tumor cells. To overcome these problems, a cell-specific, H(2)O(2)-activatable, and O(2)-evolving PDT nanoparticle (HAOP NP) is developed for highly selective and efficient cancer treatment. The nanoparticle is composed of photosensitizer and catalase in the aqueous core, black hole quencher in the polymeric shell, and functionalized with a tumor targeting ligand c(RGDfK). Once HAOP NP is selectively taken up by α(v)ß(3) integrin-rich tumor cells, the intracellular H(2)O(2) penetrates the shell into the core and is catalyzed by catalase to generate O(2), leading to the shell rupture and release of photosensitizer. Under irradiation, the released photosensitizer induces the formation of cytotoxic singlet oxygen ((1)O(2)) in the presence of O(2) to kill cancer cells. The cell-specific and H(2)O(2)-activatable generation of (1)O(2) selectively destroys cancer cells and prevents the damage to normal cells. More significantly, HAOP NP continuously generates O(2) in PDT process, which greatly improves the PDT efficacy in hypoxic tumor. Therefore, this work presents a new paradigm for H(2)O(2)-triggered PDT against cancer cells and provides a new avenue for overcoming hypoxia to achieve effective treatment of solid tumors.

An H2O2-responsive nanocarrier for dual-release of platinum anticancer drugs and O2: controlled release and enhanced cytotoxicity against cisplatin resistant cancer cells.

Synergistic release of platinum anticancer drugs and O2 can be achieved in an H2O2-responsive nanocarrier incorporated with catalase. Such a system combines the advantages of chemotherapy and oxygen therapy and demonstrated improved therapeutic efficacy against cisplatin resistant cell lines which often appear to be in hypoxia.