Self-Assembled Copper-Based Nanoparticles for Glutathione Activated and Enzymatic Cascade-Enhanced Ferroptosis and Immunotherapy in Cancer Treatment.

As an emerging cancer treatment strategy, ferroptosis is greatly restricted by excessive glutathione (GSH) in tumor microenvironment (TME) and low reactive oxygen species (ROS) generation efficiency. Here, this work designs self-assembled copper-alanine nanoparticles (CACG) loaded with glucose oxidase (GOx) and cinnamaldehyde (Cin) for in situ glutathione activated and enzymatic cascade-enhanced ferroptosis and immunotherapy. In response to GSH-rich and acidic TME, CACG allows to effectively co-deliver Cu2+ , Cin, and GOx into tumors. Released Cin consumes GSH through Michael addition, accompanying with the reduction of Cu2+ into Cu+ for further GSH depletion. With the cascade of Cu+ -catalyzed Fenton reactions and enzyme-catalyzed reactions by GOx, CACG could get rid of the restriction of insufficient hydrogen peroxide in TME, leading to a robust and constant generation of ROS. With the high efficiency of GSH depletion and ROS production, ferroptosis is significantly enhanced by CACG in vivo. Moreover, elevated oxidative stress triggers robust immune responses by promoting dendritic cells maturation and T cell infiltration. The in vivo results prove that CACG could efficiently inhibit tumor growth in 4T1 tumor-bearing mouse model without causing obvious systemic toxicity, suggesting the great potential of CACG in enhancing ferroptosis and immunotherapy for effective cancer treatment.

Colon-targeted bacterial hydrogel for tumor vascular normalization and improved chemotherapy.

The endogenous H2S plays an important role in the occurrence and development of colon cancer, and is related to the abnormal blood vessels. Here, we reported on a sulfhydryl hyaluronid-based hydrogel (HA-SH) synthesized by amide reaction and further obtained a bacterial hydrogel by loading Thiobacillus denitrificans to the hydrogel for targeting adhesion to the colon. It was found that the loaded bacteria in HA-SH hydrogel can scavenge excess H2S in colon cancer, then promote tumor vascular normalization and improve the delivery of chemotherapy drug CPT to inhibit tumor progression. Both in vivo and in vitro experiments show that the self-crosslinked bacterial hydrogel has satisfactory effects in inhibiting tumor progression and promoting tumor vascular normalization in colon cancer. This study presents an efficient method to target the colon and consume overexpressed H2S in colon cancer to inhabit tumor progression, providing a new way for oral drug treatment of colon cancer.

A heterogenic membrane-based biomimetic hybrid nanoplatform for combining radiotherapy and immunotherapy against breast cancer.

Radiotherapy is adopted to obliterate multiple malignant tumors clinically, which might also induce antitumor immune response. However, traditional radiotherapy is not enough to ablate tumors and activate long-term immunological response. Here, we developed a hybrid nanoplatform (MGTe) composed of GTe (glutathione (GSH) decorated Te nanoparticles) and fusing tumor cell membranes (TM) and bacterial outer membranes (BM). In this nanoplatform, GTe was designed for radiotherapy sensitization, concurrently the fusion of TM and BM was expected for amplifying antitumor immune. With a high-Z element, MGTe could enhance radiosensitivity by reactive oxygen species (ROS) production and cancer cell immunogenic death (ICD) under X-ray irradiation, which would also trigger antitumor immune. At meanwhile, TM and BM would further enlarge the immunological effects through antigen presenting cells (APCs) maturation and cytotoxic T lymphocytes (CTLs) stimulation. In this synergistic strategy, the combination of MGTe and X-ray showed significant tumor inhibition by radiation-driven immunotherapy, which will find great potential as an attractive clinical alternative to fight against tumor with reduced side effects.

Research progress in AIE-based crystalline porous materials for biomedical applications.

Crystalline porous materials (CPMs) not only present the precise integration of molecular building blocks into extensible structures with periodic frameworks and regular pores, but also provide limited molecular spaces for the interactions of guest molecules, electrons and photons. Incorporating aggregation-induced emission (AIE)-based units into crystalline porous frameworks can result in unique luminescent properties. AIE-based CPMs have widely tunable composition, high luminescent efficiency and good photo-stability, which make them useful for biomedical applications involving bio-sensing, bio-imaging and imaging-guided therapies. This review focused on structure design and luminescent property modulation of AIE-based CPMs with highlights on their applications in biomedical fields. The prospect and challenges in the development of AIE-based CPMs from chemistry, materials to biomedical applications were also discussed.

Progress of engineered bacteria for tumor therapy.

Recently, with the rapid development of bioengineering technology and nanotechnology, natural bacteria were modified to change their physiological activities and therapeutic functions for improved therapeutic efficiency of diseases. These engineered bacteria were equipped to achieve directed genetic reprogramming, selective functional reorganization and precise spatio-temporal control. In this review, research progress in the basic modification methodologies of engineered bacteria were summarized, and representative researches about their therapeutic performances for tumor treatment were illustrated. Moreover, the strategies for the construction of engineered colonies based on engineering of individual bacteria were summarized, providing innovative ideas for complex functions and efficient anti-tumor treatment. Finally, current limitation and challenges of tumor therapy utilizing engineered bacteria were discussed.

The clinical value of ultrasonic cardiac output monitor in very-low birth-weight and extremely-low-birth-weight infants undergoing PDA ligation.

BACKGROUND: Cardiorespiratory instability occurs very often in very-low-birth-weight (VLBW) and extremely-low-birth-weight (ELBW) infants undergoing patent ductus arteriosus (PDA) ligation during the early postoperative period. This study aimed to investigate ultrasonic cardiac output monitor (USCOM) as a bedside tool by evaluating the hemodynamic changes in preterm infants following PDA ligation and assessing factors that may influence these changes. METHODS: This was a single-center prospective observational study at a third-level neonatal intensive care unit. A total of 33 infants, including 21 VLBW and 12 ELBW infants, were involved. Hemodynamic measurements were performed in these infants using a USCOM preoperatively as well as 0-1 h, 8-10 h, and 24 h postoperatively. RESULTS: The PDA ligation was associated with reductions of the left ventricular cardiac output (LVCO) (P < 0.001), cardiac index (P < 0.001), flow time corrected (FTC) (P < 0.001), Smith-Madigan inotropy index (SMII) (P < 0.001), oxygen delivery (DO2) (P < 0.001), and oxygen delivery index (DO2I) (P < 0.001) and an increase of the systemic vascular resistance index (SVRI) (P < 0.001) at 0-1 h, 8-10 h, and 24 h post-ligation compared with the respective preoperative values. Compared with the respective values at 0-1 h post-ligation, there was no significant difference in the CI, SMII, or FTC at 8-10 h and 24 h post-ligation. However, the SVRI decreased at 8-10 h and 24 h post-ligation. Moreover, the DO2I increased at 8-10 h and 24 h post-ligation, and the LVCO and DO2 increased at 24 h post-ligation. CONCLUSION: Our study confirmed that the hemodynamic changes measured by the USCOM were similar to those measured by echocardiography in previous reports. Thus, USCOM is a useful and convenient bedside tool for assessing hemodynamic changes to guide the use of fluids, inotropic agents, and vasopressors and help modify the post-ligation course, and they may be a surrogate for repeated echocardiography during the early post-ligation period in preterm infants or a preliminary screening method.

The implications of an integrated management model of prenatal diagnosis/postnatal treatment for premature infants with critical congenital heart disease-a case-control study.

Background: The high death rate and medical costs of critical congenital heart disease (CCHD) in preterm infants has resulted in significant burdens on both countries and individuals. It is unclear how this affects the mortality of the integrated management model of prenatal diagnosis/postnatal treatment. This study explored the effects of the delivery classification scale for fetal heart and postnatal infants' CCHD on prenatal and postnatal integrated treatment strategies to improve the effectiveness of disease management in CCHD. Methods: This study was a case-control study, which retrospectively analyzed the clinical data of 79 preterm infants (<37 weeks) who underwent prenatal diagnosis and postpartum treatment in Guangdong Provincial People' s Hospital (China) from June 2017 to June 2019. According to the diagnostic and exclusion criteria, the subjects were divided into prenatal and postpartum diagnostic groups. The clinical characteristics and survival outcomes of patients were collected and compared. The delivery classification scale was used for risk stratification and patient management. Results: Among the 79 patients included in this study, 48 (60.76%) were diagnosed prenatally, and 31 (39.24%) were diagnosed postpartum. The prenatal diagnosis group was born slightly earlier during the gestation period [35.00 (33.29-35.86) vs. 35.57 (34.14-36.71) weeks, P<0.05], and their mothers were older (33.23±5.22 vs. 30.43±6.37 years, P<0.05). The difference in the admission age between the groups was statistically significant [0 (0-5.5) vs. 7 (5-16) days, P<0.001]. The median survival time of the prenatal diagnosis group was higher than the postnatal diagnosis group [48 months (95% CI: 40.78-57.29) vs. 39 months (95% CI: 34.41-44.32), P<0.05]. The 3-year survival rates of the classes I, II, and III were 92.31% (12/13), 59.09% (13/22), and 38.46% (5/13), respectively. The survival of class I as denoted in the delivery classification scale was better than classes II or III (class I vs. II, P<0.05; class I vs. III, P<0.05). Unexpectedly, the hospitalisation costs were lower and total in-hospital days were shorter in the postnatal diagnosis group. Conclusions: The results indicated that the integrated management of a prenatal diagnosis/postnatal treatment approach in premature infants may be effective. Furthermore, the delivery classification scale has a particular prognostic value for CCHD. The authors anticipate that their management model will be able to contribute to the shift from a reactive monodisciplinary system to a proactive, multidisciplinary and dynamic management paradigm in premature infants with CCHD in the near future.

Plasma membrane targeted photodynamic O2 economizer for hypoxic tumor therapy.

The development of photodynamic therapy (PDT) is severely limited by short half-life of singlet oxygen (1O2) and the hypoxic microenvironment. In this work, a plasma membrane targeted photodynamic O2 economizer (designated as P-POE) is developed to improve the subcellular delivery of photosensitizers and alleviate the tumor hypoxia for enhanced PDT effect. After self-assembly into nanomicelles, P-POE has a relatively high stability and a favorable photochemical performance, which are conducive to boosting the 1O2 production. Besides, the plasma membrane anchoring of P-POE contributes to enhancing the preferential retention and cellular accumulation of photosensitizers on tumor tissues and cells. More importantly, P-POE-induced mitochondrial respiratory depression is demonstrated to reduce the O2 consumption of tumor cells to relieve the hypoxia. Consequently, P-POE still exhibits a robust PDT effect against hypoxic tumors, which greatly inhibits the proliferation of breast cancer with low adverse reactions. This innovative combination of subcellular targeting and hypoxic alleviation would advance the development of individualized drug delivery systems for photodynamic therapy against hypoxic tumors.

Low toxicity and high immunogenicity of an inactivated vaccine candidate against COVID-19 in different animal models.

The ongoing COVID-19 pandemic is causing huge impact on health, life, and global economy, which is characterized by rapid spreading of SARS-CoV-2, high number of confirmed cases and a fatality/case rate worldwide reported by WHO. The most effective intervention measure will be to develop safe and effective vaccines to protect the population from the disease and limit the spread of the virus. An inactivated, whole virus vaccine candidate of SARS-CoV-2 has been developed by Wuhan Institute of Biological Products and Wuhan Institute of Virology. The low toxicity, immunogenicity, and immune persistence were investigated in preclinical studies using seven different species of animals. The results showed that the vaccine candidate was well tolerated and stimulated high levels of specific IgG and neutralizing antibodies. Low or no toxicity in three species of animals was also demonstrated in preclinical study of the vaccine candidate. Biochemical analysis of structural proteins and purity analysis were performed. The inactivated, whole virion vaccine was characterized with safe double-inactivation, no use of DNases and high purity. Dosages, boosting times, adjuvants, and immunization schedules were shown to be important for stimulating a strong humoral immune response in animals tested. Preliminary observation in ongoing phase I and II clinical trials of the vaccine candidate in Wuzhi County, Henan Province, showed that the vaccine is well tolerant. The results were characterized by very low proportion and low degree of side effects, high levels of neutralizing antibodies, and seroconversion. These results consistent with the results obtained from preclinical data on the safety.

Nitric Oxide Release Device for Remote-Controlled Cancer Therapy by Wireless Charging.

Traditional phototherapies face the issue that the insufficient penetration of light means it is difficult to reach deep lesions, which greatly reduces the feasibility of cancer therapy. Here, an implantable nitric oxide (NO)-release device is developed to achieve long-term, long-distance, remote-controllable gas therapy for cancer. The device consists of a wirelessly powered light-emitting diode (wLED) and S-nitrosoglutathione encapsulated with poly(dimethylsiloxane) (PDMS), obtaining the NO-release wLED (NO-wLED). It is found that NO release from the NO-wLED can be triggered by wireless charging and the concentration of produced NO reaches 0.43 × 10-6 m min-1 , which can achieve a killing effect on cancer cells. In vivo anticancer experiments exhibit obvious inhibitory effect on the growth of orthotopic cancer when the implanted NO-wLED is irradiated by wireless charging. In addition, recurrence of cancer can be prevented by NO produced from the NO-wLED after surgery. By illumination in the body, this strategy overcomes the poor penetration and long-wavelength dependence of traditional phototherapies, which also provides a promising approach for in vivo gas therapy remote-controlled by wireless charging.

PLA-PEG Micelles Loaded with a Classic Vasodilator for Oxidative Cataract Prevention.

The only treatment for cataract in clinic is the clouded lens removal combined with artificial lens implantation. In this study, nifedipine (NFP), a classic vasodilator, was loaded in a U.S. FDA-approved polymer PLA-PEG to form NFP-loaded PLA-PEG micelles as a novel eye drop to prevent oxidative cataract formation and progression at the early stage. The NFP-loaded PLA-PEG micelles not only showed satisfactory biocompatibility and bioavailability, but also efficiently improved the anticataract ability through the inhibition of extracellular calcium ions influx. This study may provide a new insight into the development of cataract treatment.

Comparison of decision-making in neonatal care between China and Japan.

BACKGROUND: Various differences between China and Japan in approaches to medical treatment have been noted, but a few studies have examined differences in medical decision-making, especially in neonatal care. The aim of this study was to clarify these differences by means of a questionnaire. METHODS: The subjects were physicians on the staff of NICUs in China and Japan. The study questionnaire consisted of three parts dealing with the general characteristics of the participants, questions about treatment strategies for hypothetical, critically ill infants, and general questions about the treatment of foreign patients. The Likert scale was used to assess the treatment strategies and the results were analyzed statistically. Subgroup analysis by age, sex, and medical and NICU experience was also performed. RESULTS: The proportion of respondents in the Chinese and Japanese groups was 26/26 (100%) and 26/31 (84%), respectively. There was a significant difference between the Chinese and Japanese groups for 8 of 75 questions; Chinese physicians chose the positive treatment or examination options for these eight questions unlike their Japanese counterparts. The responses of the younger, less experienced physicians in both countries were more similar to each other, and more positive than those of their older, more experienced colleagues. CONCLUSION: Chinese physicians showed a more positive attitude toward examination and treatment, whereas Japanese physicians showed a more cautious attitude.

[Spatial point patterns and their association dynamics of forest landscapes in Maoershan region, Northeast China between 1983 and 2016.] / 帽儿山地区1983­2016å¹´æ£®æž—æ™¯è§‚ç©ºé—´ç‚¹æ ¼å±€åŠå ¶å ³è”åŠ¨æ€æ€§.

Researches on the dynamics of spatial point patterns and their associations of forest landscape has important implications for maintaining forest stability and making forest management decisions. Based on the four period datasets of forest resource inventory in Maoershan region in 1983, 1993, 2004, and 2016, the O-ring statistics within Programita software (version 2010) was used to quantitatively analyze the dynamics of spatial point patterns and associations. The results showed that the cover percentage of soft-wood broadleaved mixed forest (SBM) significantly decreased, the percentage of natural Quercus mongolica (NMO) increased in the beginning, and then became lower. The percentage of hard broadleaved mixed forest (HBM), Larix gmelinii (RLG) and Pinus sylvestris var. mongolica (RPS) plantations increased dramatically from 1983 to 2016. During the study period, the scale of clumped distribution for the SBM, HBM, NMO all significantly decreased with the increasing spatial scale. The clumped distribution ranging from 0-7 km decreased to 0-3 km, and then tended to be random or uniform distribution with the further increases of spatial scale. The patterns of RLG showed aggregated distribution within the small scale and tended to be random or uniform distribution with the increasing scale. However, the range of scale of uniform distribution increased and random distribution decreased. The patterns of RPS showed clumped distribution within small scale (0-4 km) and the range of scale tended to be larger. On the whole, the spatial association between most of the landscape types within the small scale showed negative association. With the increases of scale, these landscape types gradually become non-association or positive association. However, only a few landscape types (e.g. RLG and RPS in 1983) showed positive association in a small scale. With the increases of scale, all the relationship tended to be non-association. The dynamics of the association of forest landscapes showed different regularity. The dynamics of spatial point patterns and associations of Maoershan region were the comprehensive results of the forest management during 1983 and 2016.

Versatile Supermolecular Inclusion Complex Based on Host-Guest Interaction for Targeted Gene Delivery.

A facile and targeted gene delivery system was prepared by conjugating ß-cyclodextrin modified polyethylenimine (PEI-CD) and adamantyl peptide (AdGRGDS) based on host-guest interaction. With the rational design between PEI-CD and AdGRGDS, the PEI-CD/AdGRGDS gene delivery system showed excellent DNA binding capability and exhibited good ability to compact DNA into uniform spherical nanoparticles. In vitro luciferase assay showed that gene expression transfected by PEI-CD/AdGRGDS was stronger than that by PEI-CD in HeLa cells, whereas gene expression transfected by PEI-CD/AdGRGDS and PEI-CD was similar to each other in COS7 cells. Internalization of complexes was qualitatively studied using a confocal laser scanning microscope (CLSM) and quantitatively analyzed by flow cytometry, respectively, and targeting specificity was also evaluated by CLSM. Results of CLSM and flow cytometry indicated that PEI-CD/AdGRGDS had good targeting specificity to tumor cells with integrin αvß3 overexpression. To further evaluate the targeting specificity and transfection efficiency in vivo, a rat model with murine hepatic carcinoma cell line H22 was used. PEI-CD/AdGRGDS showed stronger gene expression efficiency than PEI-CD via in vivo transfection of pORF-LacZ and pGL-3 plasmids after subcutaneous injection. Interestingly, PEI-CD/AdGRGDS also showed high targeting specificity and transfection distribution to tumor xenograft after tail-vein injection. In vitro and in vivo assays highlighted the importance of GRGDS targeting specificity to tumor cells with integrin αvß3 overexpression and demonstrated that the PEI-CD/AdGRGDS gene delivery system would have great potential for targeted tumor therapy.

Mitochondria-targeting "Nanoheater" for enhanced photothermal/chemo-therapy.

In this work, mitochondria-targeting gold nanostar (AuNS) and anticarcinogen DOX were co-encapsulated in hyaluronic acid (HA) protective shell for tumor-targeting synergistic photothermal/chemo-therapy. Cationic peptide R8 and mitochondria-targeting pro-apoptotic peptide TPP-KLA were co-decorated on AuNS to form AuNS-pep via Au-S bonds. Then, electronegative HA was further coated on the surface via electrostatic interaction for cancer cell targeting. During the coating process, DOX was also introduced via electrostatic interaction to obtain a versatile nanoplatform AuNS-pep/DOX@HA. It was found that the nanoplatform could be internalized into tumor cells via CD44 receptor-mediated recognition. Followed digestion by hyaluronidase (HAase), the therapeutic nanoplatform was able to release DOX for chemotherapy and mitochondria-targeting nanoheater AuNS-pep for near infrared (NIR) light triggered subcellular photothermal therapy (PTT). This tumor-targeting nanoplatform AuNS-pep/DOX@HA displayed prominent non-resistant or resistant tumor inhibition both in vitro and in vivo.

Gold Nanocluster Decorated Polypeptide/DNA Complexes for NIR Light and Redox Dual-Responsive Gene Transfection.

Endo/lysosomal escape and subsequent nuclear translocation are recognized as the two major challenges for efficient gene transfection. Herein, nuclear localization signal (NLS) peptide sequences and oligomeric lysine sequences were crosslinked via disulfide bonds to obtain glutathione (GSH) reducible polypeptide (pNLS). The pNLS could condense DNA into compact positive-charged complexes with redox sensitivity, and then gold nanoclusters (AuNC) were further decorated to the surface via electrostatic interactions obtaining versatile pNLS/DNA/AuNC complexes. The AuNC could generate reactive oxygen species (ROS) under NIR-irradiation and accelerate the endo/lysosomal escape of the complexes, and then the pNLS sequence degraded by GSH in cytoplasm would release the DNA and facilitate the subsequent nuclear translocation for enhanced gene transfection.

Cucurbit[8]uril Regulated Activatable Supramolecular Photosensitizer for Targeted Cancer Imaging and Photodynamic Therapy.

Activatable photosensitizers (aPSs) have emerged as promising photodynamic therapy (PDT) agents for simultaneous imaging and selective ablation of cancer. However, traditional synthetic aPSs are limited by complex design and tedious synthesis. Here, aPS regulated by cucurbit[8]uril (CB[8]) for targeted cancer imaging and PDT is reported. This system is based on the host-guest interaction between biotinylated toluidine blue (TB-B) and CB[8] to form 2TB-B@CB[8]. Moreover, a facile strategy to turn off/on the fluorescence and photodynamic activity of TB-B is developed through the reversible assembly/disassembly of 2TB-B@CB[8]. This established system can achieve selective accumulation in tumor, light-up cancer imaging, and enhanced anticancer behavior. Therefore, this work provides a novel and promising strategy for the aPS build via simple and facile regulation of supramolecular chemistry.

A redox-responsive drug delivery system based on RGD containing peptide-capped mesoporous silica nanoparticles.

In this paper, an intracellular glutathione (GSH) responsive mesoporous silica nanoparticle (MSN-S-S-RGD) was developed as a drug nanocarrier by immobilizing the gatekeeper (RGD containing peptide) onto MSNs using disulfide bonds. The antitumor drug, DOX was loaded onto the porous structure of the MSNs and the DOX@MSN-S-S-RGD system has been proved to be an effective nanocarrier. It was determined that most of the drug could be entrapped with only a slight leakage. After being accumulated in tumor cells via the receptor-mediated endocytosis, the surface peptide layer of DOX@MSN-S-S-RGD was removed to trigger the release of the entrapped drug to kill the tumor cell due to the cleavage of the disulfide bonds by intracellular GSH.

High length-diameter ratio nanotubes self-assembled from a facial cyclopeptide.

A six-residue facial cyclopeptide was designed with the following sequence: c-[D-Leu-L-Lys-D-Ala-L-Lys-D-Leu-L-Gln] (CP). Extensive hydrogen bonding between the cyclopeptide backbones mainly regulated CP to self-assemble into single-walled nanotubes. Simultaneously, the hydrophobic interaction among facial hydrophobic side chains of CP was introduced to stabilize the hydrogen bonding, resulting in the formation of the thick-walled nanotubes with high length­diameter ratios.

Fabrication of novel reduction-sensitive gene vectors based on three-armed peptides.

To address the inherent barriers of gene transfection, two reduction-sensitive branched polypeptides (RBPs) are synthesized and explored as novel non-viral gene vectors. The introduced disulfide linkages in RBPs facilitate glutathione-triggered intracellular gene release and reduce polymer degradation-induced cytotoxicity. Furthermore, the highly branched architecture concurrently realizes multivalency for strong DNA binding and elicits conformational flexibility for tight DNA compacting, which are beneficial for cellular entry. To increase the endosomal escape of plasmid DNA, pH-sensitive histidyl residues are incorporated into RBPs to improve buffer capacity in an acidic environment. In vitro study demonstrates that RBPs can efficiently mediate the DNA transfection and avoid apparent cytotoxicity in HeLa and COS7. The present gene delivery system offers a simple and flexible approach to fabricate microenvironment-specific branched gene vectors for gene therapy.