Mismatched Social Welfare Allocation and PM2.5-Related Health Damage along Value Chains within China.

Value chains have played a critical part in the growth. However, the fairness of the social welfare allocation along the value chain is largely underinvestigated, especially when considering the harmful environmental and health effects associated with the production processes. We used fine-scale profiling to analyze the social welfare allocation along China's domestic value chain within the context of environmental and health effects and investigated the underlying mechanisms. Our results suggested that the top 10% regions in the value chain obtained 2.9 times more social income and 2.1 times more job opportunities than the average, with much lower health damage. Further inspection showed a significant contribution of the "siphon effect"─major resource providers suffer the most in terms of localized health damage along with insufficient social welfare for compensation. We found that inter-region atmosphere transport results in redistribution for 53% health damages, which decreases the welfare-damage mismatch at "suffering" regions but also causes serious health damage to more than half of regions and populations in total. Specifically, around 10% of regions have lower social welfare and also experienced a significant increase in health damage caused by atmospheric transport. These results highlighted the necessity of a value chain-oriented, quantitative compensation-driven policy.

China's multi-sector-shared CCUS networks in a carbon-neutral vision.

China's carbon-neutral vision necessitates carbon capture, utilization, and storage (CCUS), which is still in its infancy due to inadequate infrastructure and indeterminate technology diffusion. To address the concerns, this study links spatially explicit CO2 source-sink matching with bottom-up energy-environment-economy planning to propose China's multi-sector-shared CCUS networks, with plant-level industrial transfer and infrastructure reuse considered. Nearly 19000-km trunk lines are needed by a capture of 1.74 Gt/yr in 2050, with 12-, 16-, 20-, and 24-inch pipelines enjoying the largest share of over 65%. Inspiringly, some CO2 routes accounting for 50% of the total length match well with the rights-of-way for oil and gas pipeline corridors. Regional cost-competitiveness improvement is observed given available offshore storage, with 0.2 Gt/yr redirected to the northern South China Sea. Furthermore, the interprovincial heterogeneity and intersectoral externality of CCUS scaling-up are unveiled, requiring a rational allocation of benefits and costs inherent in the value chains.

A nanotherapeutic strategy to overcome chemoresistance to irinotecan/7-ethyl-10-hydroxy-camptothecin in colorectal cancer.

Clinical development of 7-ethyl-10­hydroxy-camptothecin (SN38), the active metabolite of irinotecan (CPT-11), is hindered by its insolubility and poor stability. Another obstacle is that tumors could become resistant to SN38/CPT-11 through multiple mechanisms involving breast cancer resistance protein (BCRP). Herein one of the most potent and selective BCRP inhibitors, Ko143, is encapsulated into a recently constructed prodrug PEG-S-S-SN38 displaying a high and fixed drug loading, multiple intratumoral stimuli (oxidative stress, GSH and esterase)-responsive drug release and significant in vitro and in vivo superiorities over CPT-11. The obtained "combo" for simultaneous delivery of SN38 and Ko143, named as BI@PEG-SN38, has a high SN38 loading efficacy (14.85 wt.%) and a good Ko143 encapsulation efficacy (3.79%). Through generating panels of human colorectal cancer models expressing altered levels of BCRP via lentiviral transfection and CRISPR-Cas9, characteristics of different drug formulations are carefully evaluated. Impressively, BI@PEG-SN38 nanoparticles effectively reverse chemoresistance to CPT-11 (resistance index dropping from ∼274.00-456.00 to ∼1.70-4.68) and PEG-S-S-SN38 (resistance index dropping from ∼5.83-14.00 to ∼1.70-4.68) in three BCRP-overexpressing cancer cell lines. More importantly, reversal of BCRP-mediated chemoresistance to CPT-11 (P values lower than 0.001-0.0001) and PEG-S-S-SN38 (P values lower than 0.01-0.001) by BI@PEG-SN38 nanoparticles are further confirmed with two panels of colorectal cancer xenograft models in vivo. As the first nano-formulation of Ko143 and the first systemic co-delivery vehicle of SN38/CPT-11 and a BCRP inhibitor, BI@PEG-SN38 provides a new approach for resolving the bottlenecks for clinical translation of SN38 and numerous "chemosensitizers" like Ko143, and exhibits promising applicability in precision cancer medicine. STATEMENT OF SIGNIFICANCE: To resolve the bottlenecks in clinical application of anticancer agents SN38/CPT-11 and the most potent breast cancer resistant protein (BCRP) inhibitor Ko143, a "combo" nanotherapeutic simultaneously delivering SN38 and Ko143 was constructed and named as BI@PEG-SN38. By generating panels of colorectal cancer models, we demonstrate that BI@PEG-SN38 nanoparticles effectively and selectively reversed BCRP-mediated tumor resistance to SN38/CPT-11 in vitro and in vivo. As the first nano-formulation of Ko143 and the first systemic co-delivery vehicle of SN38/CPT-11 and a BCRP inhibitor, BI@PEG-SN38 provides a new strategy for clinical development of SN38 and numerous "chemosensitizers", and exhibits promising applicability in precision cancer medicine. Panels of cancer cell lines established here provides a useful platform for BCRP- and cancer-related research and technology development.

Non-invasive blood glucose measurement of 95% certainty by pressure regulated Mid-IR.

To fight against diabetes mellitus, from which more than 400 million people suffer in the world, the patients have to puncture their fingers 4-5 times a day for the blood glucose level checks when using a glucometer, causing invasive pain and the risk of infection. Therefore, non-invasive method has been urged for blood glucose monitoring, among which the mid-infrared spectroscopy (Mid-IR) response of interstitial fluid was found to be promising. However, despite the prolonged effort, the accuracy still falls below the FDA's requirement. To break this barrier which lasted for almost three decades, we discovered the finger contact pressure playing a critical role during the measurement, where the Mid-IR reading could be affected significantly by a small change of the finger posture. In addition, the Mid-IR absorption level was also found to be highly associated with individual, revealing the necessity of adjusting the calibration correlation for each patient. By imposing a certain contact pressure monitored by a pressure transducer, we were able to achieve over 95% certainty from the Mid-IR measurement of glucose concentration and 100% comparability to the "true" glucose concentration for the first time, which was mainly attributed to the morphological change of finger tissue under pressure. The previous works resulted in only about 70% accuracy on average, barely hitting 80 + %, whereas ours reaches 95%, finally exceeding the requirement of FDA.

Functionalized Nanoparticles Efficiently Enhancing the Targeted Delivery, Tumor Penetration, and Anticancer Activity of 7-Ethyl-10-Hydroxycamptothecin.

The enhanced permeability and retention (EPR) effect of tumors is much more complex than initially defined, and it alone is not sufficient for targeted delivery of nanosized agents. Meanwhile, poor tumor penetration is another major challenge for the treatment of solid tumors using nanoparticles. Development of delivery systems for SN38, the active metabolite of CPT-11 in human and a very potent anticancer molecule, has become an attractive research area. PEGx -p(HEMASN38)y (x and y are viable), a prodrug synthesized by using polyethylene glycol (PEG) as initiator and SN38 as monomer through atom transfer radical polymeration (ATRP) method, is previously reported. Using PEG2.4K -p(HEMASN38)3K as a model prodrug, herein an active-targeted strategy decorated with cys-arg-gly-asp-lys (CRGDK), a peptide specifically binds to neuropilin-1 overexpressed by tumor vessels and tumor cells, is successfully established to further improve the delivery and efficacy of SN38. CRGDK-functionalized PEG2.4K -p(HEMASN38)3K (C-SN38) nanoparticles and nonfunctionalized control (B-SN38) are prepared with two distinct sizes, 30 and 100 nm. Their physiochemical and biological characteristics are investigated in vitro and in vivo with multiple tumor models. It is demonstrated for the first time that CRGDK functionalization can be a promising strategy for efficient delivery of SN38, and C-SN38 is a potent drug candidate for the treatment of neuropilin-1 overexpressing tumors.

A multi-stimuli responsive nanoparticulate SN38 prodrug for cancer chemotherapy.

Modification of drug delivery systems (DDSs) with stimuli-responsive elements could significantly increase the tumor-specific delivery of anticancer drugs. Herein we synthesized a novel multiple stimuli-responsive SN38 prodrug, named PEG-S-S-SN38, by conjugating PEG (MW: 2000) and SN38 with disulfide bonds and carbonic ester linkages as linkers for efficient delivery of SN38. The amphiphilic PEG-S-S-SN38, with a high SN38 loading content, could self-assemble into nanoparticles (NPs) with a stable diameter of ∼73 nm. PEG-S-S-SN38 NPs release SN38 very slowly at physiological pH, while they quickly release SN38 in the presence of GSH, esterase and H2O2, all of which are abundant in the cytoplasm of cancer cells. PEG-S-S-SN38 NPs could be quickly internalized into tumor cells, achieve vesicular escape and nuclear localization, and exhibit remarkable in vitro anticancer activity similar to SN38. Encouragingly, PEG-S-S-SN38 NPs exhibit the same effects on cell cycle regulations as SN38 in vitro. Most importantly, the inhibition rate of tumor growth induced by PEG-S-S-SN38 NPs in a xenograft tumor model reached 72.49% ± 6.26%, which was nearly double that of the corresponding clinical drug CPT-11 (38.64% ± 13.04%) at a dosage equivalent to 10 mg kg-1 SN38. Our data suggest that the multi-stimuli responsiveness of PEG-S-S-SN38 NPs remarkably enhances their therapeutic activity against heterogeneous or mixed cell population in tumors, making this new DDS a promising alternative to CPT-11 for cancer treatment.

Self-Assembling Doxorubicin Prodrug Forming Nanoparticles and Effectively Reversing Drug Resistance In Vitro and In Vivo.

Doxorubicin (DOX) is a widely used chemotherapeutic drug to treat a range of cancers. However, its unfavorable effects, particularly the cardiotoxicity and the induction of multidrug resistance (MDR), significantly limit its clinical applications. Herein, a novel doxorubicin prodrug, PEG2K -DOX, is synthesized by conjugating a deprotonated doxorubicin molecule with the polyethylene glycol (PEG, MW: 2K) chain via pH-responsive hydrazone bond, and its potential as a better alternative than doxorubicin is evaluated. The data show that the amphiphilic PEG2K -DOX can self-assemble into stable nanoparticles with a high and fixed doxorubicin loading content (≈20 wt%), a favorable size of 91.5 nm with a narrow polydispersity (PDI = 0.14), good stability, and pH-dependent release behavior due to the acid-cleavable linkage between PEG and doxorubicin. Although doxorubicin hardly accumulates in MDR cells, PEG2K -DOX nanoparticles significantly increase the cellular uptake and cell-killing activity of doxorubicin in two MDR cancer cell lines MCF-7/ADR and KBv200, with the IC50 values dropped to 1.130% and 42.467% of doxorubicin, respectively. More impressively, PEG2K -DOX nanoparticles exhibit significantly improved plasma pharmacokinetics, increased in vivo therapeutic efficacy against MDR xenograft tumors, and better in vivo safety compared with doxorubicin. PEG2K -DOX nanoparticles hold the promise to become a better alternative than doxorubicin for cancer treatment, especially for MDR tumors.

Esterase-Activated Charge-Reversal Polymer for Fibroblast-Exempt Cancer Gene Therapy.

Selective gene expression in tumors via responsive dissociation of polyplexes triggered by intracellular signals is demonstrated. An esterase-responsive charge-reversal polymer mediates selective gene expression in the cancer cells high in esterases over fibroblasts low in esterase activity. Its gene therapy with the TRAIL suicide gene effectively induces apoptosis of HeLa cells but does not activate fibroblasts to secrete WNT16B, enabling potent cancer gene therapy with few side effects.