Association of at-home and out-of-home eating frequency with the estimated 10-year arteriosclerotic cardiovascular disease risk in rural population: the Henan Rural Cohort Study.

PURPOSE: Insufficient evidence currently exists regarding the relationship between eating frequency and arteriosclerotic cardiovascular disease (ASCVD). Thus, the objective of this study was to explore the association of at-home eating (AHE) and out-of-home eating (OHE) frequency with 10-year ASCVD risk. METHODS: A total of 23,014 participants were included from the Henan Rural Cohort Study. A face-to-face questionnaire was used to acquire data on the frequency of OHE and AHE. The relationship of OHE and AHE frequency with 10-year ASCVD risk was evaluated by logistic regression. Mediation analysis was conducted to evaluate whether BMI mediated the association of OHE and AHE frequency with 10-year ASCVD risk. RESULTS: The adjusted OR and 95% CI of 10-year ASCVD risk for participants who ate out 7 or more times a week was 2.012 (1.666, 2.429) compared with participants who had OHE 0 times. Compared to those who had AHE ≤ 11 times, the adjusted OR and 95% CI for the participants eating every meal at home (21 times) was 0.611 (0.486, 0.769). The relationship of OHE and AHE frequency with 10-year ASCVD risk was mediated by BMI, and the proportion of BMI explained was 25.3% and 36.6%. CONCLUSIONS: The OHE frequency was associated with increased 10-year ASCVD risk, while AHE was related to decreased 10-year ASCVD risk, and BMI may play a partial mediating role in the relationship. Implementing health promotion strategies that promote AHE and discourage frequent OHE may prove to be an effective approach to preventing and controlling ASCVD. TRIAL REGISTRATION NUMBER: ChiCTR-OOC-15006699 (2015-07-06).

The independent and combined association of napping and night sleep duration with stroke in Chinese rural adults.

BACKGROUND: Inappropriate sleep duration is a potential cause of stroke. But the effect of napping on stroke risk remains controversial and the interaction between night sleep and napping duration remains unclear. The objective of this study was to examine the independent and combined effects of napping and nocturnal sleep duration on stroke. METHODS: Subjects were derived from a rural cohort study in Henan. The Pittsburgh Sleep Quality Index (PSQI) was applied to identify nap duration and nocturnal sleep duration. Binary logistic regression was employed to indicate the dose-response relationships between naps, nocturnal sleep, total 24-h sleep duration, and stroke. RESULTS: Among the 37,341 participants (14,485 men), 2600 suffered from a stroke. The odds ratios (ORs) and 95% confidence level (CI) for stroke in the fully adjusted model were 1.37 (1.13-1.65) for men nappers compared to non-nappers. Compared to 7-8 h of sleep per day, night sleep durations < 6 h and ≥ 9 h and 24-h sleep duration ≥ 10 h were linked to increased odds of stroke in men. The ORs (95%CI) were 1.34 (1.06-1.69) in nocturnal sleep duration < 6 h, 1.30 (1.06-1.59) in nocturnal sleep duration ≥ 9 h, and 1.40 (1.15-1.71) in 24-h sleep duration ≥ 10 h in men. In addition, long naps and prolonged nocturnal sleep duration have a joint effect on stroke in the fully adjusted model. CONCLUSION: The napping duration and nocturnal sleep duration have independently and jointly effects on stroke in rural populations. More research is required to explore the underlying mechanisms for this relationship. CLINICAL TRIAL REGISTRATION: The Henan Rural Cohort Study has been registered on the Chinese Clinical Trial Register (Registration number: ChiCTR-OOC-15006699) ( http://www.chictr.org.cn/showproj.aspx?proj=11375 ).

Secular trends of age at menarche and the effect of famine exposure on age at menarche in rural Chinese women.

BACKGROUND: Over the past few decades, more studies have suggested that the age at menarche (AAM) has continued to decline. However, the AAM for women in resource-constrained areas is not clear. Moreover, the association between the Chinese famine and AAM is still unclear in rural regions. AIM: The study aimed to investigate the secular trends of AAM for women born between 1935 and 2000 and to further explore the effect of famine on AAM in rural China. SUBJECTS AND METHODS: The study included 23,444 women participants from the baseline study of the Henan Rural Cohort study. Changing AAM over time was analysed using linear regressions. Multinomial logistic regression was conducted to analyse the association between famine exposure and AAM subgroups. RESULTS: The age-standardised mean AAM was 14.74 years. The average AAM declined from 16.98 years for those born in 1935 to 13.87 years for those born in 2000, a decline of 0.077 years per 1 year and 0.729 years per decade. Compared to the reference group, women exposed to famine during foetal, early childhood, middle childhood, and late childhood were 1.376 (95% CI = 1.071-1.769), 1.848 (95% CI = 1.512-2.259), 2.084 (95% CI = 1.725-2.518), and 2.146 (95% CI = 1.788-2.576) times more likely to be ≥18 years AAM than women unexposed to famine, respectively. CONCLUSION: AAM showed a decreasing trend in rural China. Furthermore, both foetal and childhood famine exposure, especially in late childhood, were positively associated with increased AAM compared to unexposed famine.

Hyperthermic intraperitoneal chemotherapy for patients with gastric cancer based on laboratory tests is safe: a single Chinese center analysis.

PURPOSE: About 15%-40% of gastric cancer patients have peritoneal metastasis, which leads to poor prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) is considered to be an effective treatment for these patients. This study evaluated the efficacy and safety of HIPEC in patients with gastric cancer diagnosed from laboratory tests. METHODS: The clinical and pathological data of 63 patients with gastric cancer who underwent HIPEC in 2017-2021 were prospectively recorded. Fifty-five patients underwent cytoreductive surgery + HIPEC, and eight patients received HIPEC alone. The factors associated with HIPEC safety and efficacy were analyzed. The primary endpoint was overall survival. RESULTS: The average patient age was 54.84 years and 68.3% of patients were male. Moreover, 79.4% of patients had a peritoneal carcinoma index (PCI) score of ≤ 7 and 61.9% had a completeness of cytoreduction score of 0. Because of peritoneal metastasis, 29 patients (46.03%) were classified as stage IV. Laboratory tests showed no differences in pre-HIPEC blood test results compared to post-HIPEC results after removing the effects of surgery. HIPEC treatment did not cause obvious liver or kidney damage. Serum calcium levels decreased significantly after HIPEC (P = 0.0018). The Karnofsky performance status (KPS) score correlated with the patient's physical function and improved after HIPEC (P = 0.0045). In coagulation tests, FDP (P < 0.0001) and D-dimer (P < 0.0001) levels increased significantly and CA242 (P = 0.0159), CA724 (P < 0.0001), and CEA (P < 0.0014) levels decreased significantly after HIPEC. Completeness of cytoreduction score was an independent prognostic factor. HIPEC did not show a survival benefit in patients with gastric cancer (P = 0.5505). CONCLUSION: HIPEC is a safe treatment for patients with gastric cancer with peritoneal metastasis based on the laboratory tests. However, the efficacy of this treatment on gastric-derived peritoneal metastases requires further confirmation.

Plaintext-Related Dynamic Key Chaotic Image Encryption Algorithm.

To address the problems of the high complexity and low security of the existing image encryption algorithms, this paper proposes a dynamic key chaotic image encryption algorithm with low complexity and high security associated with plaintext. Firstly, the RGB components of the color image are read, and the RGB components are normalized to obtain the key that is closely related to the plaintext, and then the Arnold transform is used to stretch and fold the RGB components of the color image to change the position of the pixel points in space, so as to destroy the correlation between the adjacent pixel points of the image. Next, the generated sequences are independently encrypted with the Arnold-transformed RGB matrix. Finally, the three encrypted images are combined to obtain the final encrypted image. Since the key acquisition of this encryption algorithm is related to the plaintext, it is possible to achieve one key per image, so the key acquisition is dynamic. This encryption algorithm introduces chaotic mapping, so that the key space size is 10180. The key acquisition is closely related to the plaintext, which makes the ciphertext more random and resistant to differential attacks, and ensures that the ciphertext is more secure after encryption. The experiments show that the algorithm can encrypt the image effectively and can resist attack on the encrypted image.

Image Encryption Scheme with Compressed Sensing Based on a New Six-Dimensional Non-Degenerate Discrete Hyperchaotic System and Plaintext-Related Scrambling.

Digital images can be large in size and contain sensitive information that needs protection. Compression using compressed sensing performs well, but the measurement matrix directly affects the signal compression and reconstruction performance. The good cryptographic characteristics of chaotic systems mean that using one to construct the measurement matrix has obvious advantages. However, existing low-dimensional chaotic systems have low complexity and generate sequences with poor randomness. Hence, a new six-dimensional non-degenerate discrete hyperchaotic system with six positive Lyapunov exponents is proposed in this paper. Using this chaotic system to design the measurement matrix can improve the performance of image compression and reconstruction. Because image encryption using compressed sensing cannot resist known- and chosen-plaintext attacks, the chaotic system proposed in this paper is introduced into the compressed sensing encryption framework. A scrambling algorithm and two-way diffusion algorithm for the plaintext are used to encrypt the measured value matrix. The security of the encryption system is further improved by generating the SHA-256 value of the original image to calculate the initial conditions of the chaotic map. A simulation and performance analysis shows that the proposed image compression-encryption scheme has high compression and reconstruction performance and the ability to resist known- and chosen-plaintext attacks.

The role of Chinese medicine in COVID-19 pneumonia: A systematic review and meta-analysis.

INTRODUCTION: Chinese medicine (CM) has been used to treat Novel Coronavirus 2019 (COVID-19) pneumonia in China. This meta-analysis was conducted to evaluate the clinical efficacy and safety of CM in the treatment of COVID-19 pneumonia. METHODS: Randomized controlled trials (RCTs) involving CM in the treatment of COVID-19 pneumonia were identified from Cochrane Central Register of Controlled Trials, PubMed, EMBASE, Chinese National Knowledge Infrastructure, Chinese Biomedical Database, Wanfang Database and VIP Information Database. The methodological quality of trials was evaluated with Cochrane Hanadbook criteria, and the Cochrane Collaboration's Review Manager 5.3 software was used for meta-analysis. RESULTS: A total of 7 valid studies involving 681 patients were included. The meta-analysis exhibited in comparison to conventional treatment, CM combined with conventional treatment significantly improved clinical efficacy (RR = 1.21, 95% CI [1.08,1.36]), and significantly increased viral nucleic acid negative conversion rate (RR = 1.49, 95% CI [1.13,1.97]). CM also prominently reduced pulmonary inflammation (RR = 1.27, 95% CI [1.12,1.44]), and improved host immune function (WBC, MD = 0.92, 95% CI [0.07,1.76]; LYM, MD = 0.33, 95% CI [0.08,0.57]; LYM%, MD = 2.90, 95% CI [2.09,3.71]; CRP, MD = -12.66, 95% CI [-24.40, -0.92]). Meanwhile, CM did not increase the incidence of adverse reactions (RR = 1.17, 95% CI [0.39,3.52]). CONCLUSION: According to the allocated data, CM has demonstrated clinical efficacy and safety on COVID-19 pneumonia, which need to be confirmed by high quality, multiple-center, large sample randomized controlled trials.

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.

Facile Generation of Tumor-pH-Labile Linkage-Bridged Block Copolymers for Chemotherapeutic Delivery.

Successful bench-to-bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor-pH-labile linkage-bridged copolymers of clinically validated poly(D,L-lactide) and poly(ethylene glycol) (PEG-Dlink(m)-PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG-Dlink(m)-PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1% in comparison to 47.8% of the non-responsive control. Furthermore, PEG-Dlink(m)-PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG-b-PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.

Tumor Acidity-Sensitive Polymeric Vector for Active Targeted siRNA Delivery.

Although surface PEGylation of siRNA vectors is effective for preventing protein adsorption and thereby helps these vectors to evade the reticuloendothelial system (RES) in vivo, it also suppresses the cellular uptake of these vectors by target cells. This dilemma could be overcome by employing stimuli-responsive shell-detachable nanovectors to achieve enhanced cellular internalization while maintaining prolonged blood circulation. Among the possible stimuli, dysregulated pH in tumor (pHe) is the most universal and practical. However, the design of pHe-sensitive system is problematic because of the subtle differences between the pHe and pH in other tissues. Here, a simple acid-sensitive bridged copolymer is developed and used for tumor-targeted systemic delivery of siRNA. After forming the micelleplex delivery system, the corresponding nanoparticles (Dm-NP) might undergo several modifications as follows: (i) a poly(ethylene glycol) (PEG) corona, which is stable in the circulatory system and protects nanovectors from RES clearance; (ii) a pHe responsive linkage breakage, which induces PEG detachment at tumor sites and thereby facilitates cell targeting; and (iii) a cell-penetration peptide, which is exposed upon the removal of PEG and further enhances cellular uptake. Thus, Dm-NP achieved both prolonged circulation and effective accumulation in tumor cells and resulted in the safe and enhanced inhibition of non-small cell lung cancer growth.

Biocompatible conjugated polymer nanoparticles for efficient photothermal tumor therapy.

Conjugated polymers (CPs) with strong near-infrared (NIR) absorption and high heat conversion efficiency have emerged as a new generation of photothermal therapy (PTT) agents for cancer therapy. An efficient strategy to design NIR absorbing CPs with good water dispersibility is essential to achieve excellent therapeutic effect. In this work, poly[9,9-bis(4-(2-ethylhexyl)phenyl)fluorene-alt-co-6,7-bis(4-(hexyloxy)phenyl)-4,9-di(thiophen-2-yl)-thiadiazoloquinoxaline] (PFTTQ) is synthesized through the combination of donor-acceptor moieties by Suzuki polymerization. PFTTQ nanoparticles (NPs) are fabricated through a precipitation approach using 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000 ) as the encapsulation matrix. Due to the large NIR absorption coefficient (3.6 L g(-1) cm(-1) ), the temperature of PFTTQ NP suspension (0.5 mg/mL) could be rapidly increased to more than 50 °C upon continuous 808 nm laser irradiation (0.75 W/cm(2) ) for 5 min. The PFTTQ NPs show good biocompatibility to both MDA-MB-231 cells and Hela cells at 400 µg/mL of NPs, while upon laser irradiation, effective cancer cell killing is observed at a NP concentration of 50 µg/mL. Moreover, PFTTQ NPs could efficiently ablate tumor in in vivo study using a Hela tumor mouse model. Considering the large amount of NIR absorbing CPs available, the general encapsulation strategy will enable the development of more efficient PTT agents for cancer or tumor therapy.

[Study on acute toxicity of outlet water of new technology from a sewage treatment plant in Zhengzhou City].

OBJECTIVE: To study the acute toxicity of outlet water of new technology from a sewage treatment plant in Zhengzhou City, and provide scientific basis for safety evaluation of municipal sewage reuse. METHODS: Based on procedures and tests for toxicological evaluations of chemicals (GBZ/T 240-2011), the acute oral toxicity test, the acute dermal toxicity test, the acute eye irritation test, the skin irritation and sensitization tests were conducted on advanced treatment outlet water. RESULTS: The LD50 of outlet water of new technology in female mice and male mice were 6810 and 4220 mg/kg BW in the acute oral toxicity test respectively, and the former was actually no grade toxicity, the latter was low grade toxicity. The LD50 in female rats and male rats were 6810 and 5620 mg/kg BW in the acute dermal toxicity test respectively, and both were no grade toxicity. Advanced treatment outlet water could damage the rabbit cornea and conjunctiva differently, IAOI was 28, and MIOI was less than 20 after seven days, so advanced treatment outlet water had middle irritation for the rabbit cornea and conjunctiva. The mean value of skin irritation was 0, so it had no irritation for guinea pigs. The mean value of skin sensitization was 0, so it had no sensitization for guinea pigs. CONCLUSION: Outlet water of new technology is reused by reducing the chances of contracting it with the mouth and eyes, and has no skin irritation and skin sensitization.

Achieving a new controllable male contraception by the photothermal effect of gold nanorods.

During the process of human civilization, owning household pets has become increasingly popular. However, dogs and cats may be reservoirs or vectors of transmissible diseases to humans. Confronted with the overpopulation of pets, traditional contraception methods, surgical methods of sterilization, for animals are used, namely, ovariohysterectomy and orchidectomy. Therefore, a simple, nonsurgical, controllable, more effective and less expensive contraception method is highly desirable. In this study, we show that in situ testicular injection of methoxy poly(ethylene glycol)-modified gold nanorods with near-infrared irradiation in male mice can achieve short-lived or permanent male infertility. In a lower hyperthermia treatment, the morphology of testes and seminiferous tubules is only partly injured, and fertility indices are decreased to 10% at day 7, then recovered to 50% at day 60. In a higher hyperthermia treatment, the morphology of testes and seminiferous tubules are totally destroyed, and fertility indices are decreased to 0 at day 7. Overall, our results indicate a potential application of plasmonic nanomaterials for male contraception.

The Oncolytic virus VT1092M and an Anti-PD-L1 antibody synergize to induce systemic antitumor immunity in a murine bilateral tumor model.

This study investigated the synergistic potential of an oncolytic herpes simplex virus armed with interleukin 12 (VT1092M) in combination with immune checkpoint inhibitors for enhancing antitumor responses. The potential of this combination treatment to induce systemic antitumor immunity was assessed using bilateral subcutaneous tumor and tumor re-challenge mouse models. The antitumor efficacy of various OV and ICI treatment combinations and the underlying mechanisms were explored through diverse analytical techniques, including flow cytometry and RNA sequencing. Using VT1092M, either alone or in combination with an anti-PD-L1 antibody, significantly reduced the sizes of both the injected and untreated abscopal tumors in a bilateral tumor mouse model. The combination therapy demonstrated superior antitumor efficacy to the other treatment conditions tested, which was accompanied by an increase in T cell numbers and CD8+T cell activation. Results from the survival and tumor re-challenge experiments showed that the combination therapy elicited long-term, tumor-specific immune responses, which were associated with tumor clearance and prolonged survival. Immune cell depletion assays identified CD8+T cells as the crucial mediators of systemic antitumor immunity during combination therapy. In conclusion, the combination of VT1092M and PD-L1 blockade emerged as a potent inducer of antitumor immune responses, surpassing the efficacy of each monotherapy. This synergistic approach holds promise for achieving robust and sustained antitumor immunity, with potential implications for preventing tumor metastasis in patients with cancer.

Application of tumor pH/hypoxia-responsive nanoparticles for combined photodynamic therapy and hypoxia-activated chemotherapy.

Introduction: Cancer selectivity, including targeted internalization and accelerated drug release in tumor cells, remains a major challenge for designing novel stimuli-responsive nanocarriers to promote therapeutic efficacy. The hypoxic microenvironment created by photodynamic therapy (PDT) is believed to play a critical role in chemoresistance. Methods: We construct dual-responsive carriers (DANPCT) that encapsulate the photosensitizer chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) to enable efficient PDT and PDT-boosted hypoxia-activated chemotherapy. Results and discussion: Due to TAT masking, DANPCT prolonged payload circulation in the bloodstream, and selective tumor cell uptake occurred via acidity-triggered TAT presentation. PDT was performed with a spatially controlled 660-nm laser to enable precise cell killing and exacerbate hypoxia. Hypoxia-responsive conversion of the hydrophobic NI moiety led to the disassembly of DANPCT, facilitating TPZ release. TPZ was reduced to cytotoxic radicals under hypoxic conditions, contributing to the chemotherapeutic cascade. This work offers a sophisticated strategy for programmed chemo-PDT.

Strong Connection of Single-Wall Carbon Nanotube Fibers with a Copper Substrate Using an Intermediate Nickel Layer.

Lightweight carbon nanotube fibers (CNTFs) with high electrical conductivity and high tensile strength are considered to be an ideal wiring medium for a wide range of applications. However, connecting CNTFs with metals by soldering is extremely difficult due to the nonreactive nature and poor wettability of CNTs. Here we report a strong connection between single-wall CNTFs (SWCNTFs) and a Cu matrix by introducing an intermediate Ni layer, which enables the formation of mechanically strong and electrically conductive joints between SWCNTFs and a eutectic Sn-37Pb alloy. The electrical resistance change rate (ΔR/R0) of Ni-SWCNTF/solder-Cu interconnects only decreases ∼29.8% after 450 thermal shock cycles between temperatures of -196 and 150 °C, which is 8.2 times lower than that without the Ni layer. First-principles calculations indicate that the introduction of the Ni layer significantly improves the heterogeneous interfacial bond strength of the Ni-SWCNTF/solder-Cu connections.

The associations between sleep timing and night sleep duration with dyslipidemia in a rural population: The Henan Rural Cohort Study.

Evidence linking sleep timing and night sleep duration to dyslipidemia was limited and inconclusive, especially among low- and middle-income adults. The aims were to evaluate the associations between sleep timing, night sleep duration and dyslipidemia in a rural population. Based on the Henan Rural Cohort Study, a total of 37 164 participants were included. The Pittsburgh Sleep Quality Index was used to collect sleep information. Logistic regression and restrictive cubic splines were conducted to explore the associations. Of the 37 164 enrolled participants, 13881 suffered from dyslipidemia. Compared to the reference groups, people who went to sleep after 23:00 or woke up after 7:30 had higher prevalence of dyslipidemia, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs)were 1.30 (1.20-1.41) and 1.34 (1.19-1.50). The adjusted OR (95%CI) of participants in the Late-sleep/Late-rise category compared to the Early-sleep/Early-rise category was 1.55 (1.08-1.23). Compared to the reference (7~≤8 h), the adjusted OR (95%CI) was 1.11 (1.03-1.20) for longer (>9 h) night sleep duration. Moreover, the combined effects of sleep duration (>9 h) with sleep time (22:00~) (OR = 1.46, 95%CI: 1.16-1.84), sleep duration (>9 h) with wake-up time (≥7:30) (OR = 1.28, 95%CI: 1.08-1.51), and sleep duration (>9 h) with the Late-sleep/Late-rise category (OR = 1.41, 95%CI: 1.14-1.75) increased the prevalence of dyslipidemia. Accordingly, our results indicate that delayed sleep timing and longer night sleep duration had independent and joint effects on higher risks of dyslipidemia in rural population.

Rational design of ROS-responsive nanocarriers for targeted X-ray-induced photodynamic therapy and cascaded chemotherapy of intracranial glioblastoma.

Glioblastoma (GBM) is the most lethal primary intracranial tumor because of its high invasiveness and recurrence. Therefore, nanocarriers with blood-brain barrier (BBB) penetration and transcranial-controlled drug release and activation are rather attractive options for glioblastoma treatment. Herein, we designed a multifunctional nanocarrier (T-TKNPVP) that combined targeted X-ray-induced photodynamic therapy (X-PDT) and cascaded reactive oxygen species (ROS)-boosted chemotherapy. The T-TKNPVP loaded with verteporfin (VP) and paclitaxel (PTX) was self-assembled from an angiopep-2 (Ang) peptide, functionalized Ang-PEG-DSPE and ROS-sensitive PEG-TK-PTX conjugate. After systemic injection, the T-TKNPVP efficiently crossed the BBB and targeted the GBM cells via receptor-mediated transcytosis. Upon X-ray irradiation, they can generate a certain amount of ROS, which not only induces X-PDT but also locoregionally activates PTX release and action by cleaving the TK bridged bonds. As evidenced by 9.4 T MRI and other experiments, such nanocarriers offer significant growth inhibition of GBM in situ and prolong the survival times of U87-MG tumor-bearing mice. Taken together, the designed T-TKNPVP provided an alternative avenue for realizing transcranial X-PDT and X-ray-activated chemotherapy for targeted and locoregional GBM treatment in vivo.

Tumor pH-Responsive Nanocarriers With Light-Activatable Drug Release for Chemo-Photodynamic Therapy of Breast Cancer.

Developing bioresponsive nanocarriers with particular tumor cell targeting and on-demand payload release has remained a great challenge for combined chemo-photodynamic therapy (chemo-PDT). In this study, an intelligent nanocarrier (DATAT-NPCe6) responded to hierarchical endogenous tumor pH, and an exogenous red light was developed through a simple mixed micelle approach. The outside TAT ligand was masked to prevent an unexpected interaction in blood circulation. Following the accumulation of DATAT-NPCe6 in tumor tissues, tumor acidity at pH ∼6.5 recovered its targeting ability via triggering DA moiety degradation. Furthermore, the cascaded chemo-PDT was accomplished through light-stimulated nanocarrier disassembly and doxorubicin (DOX) release. Taking advantage of stability and controllability, this work provides a facile approach to designing bioresponsive nanocarriers and represents a proof-of-concept combinatorial chemo-PDT treatment.

Tumor acidity/redox hierarchical-activable nanoparticles for precise combination of X-ray-induced photodynamic therapy and hypoxia-activated chemotherapy.

With the advantages of deep tissue penetration and controllability, external X-ray-induced photodynamic therapy (X-PDT) is highly promising for combined cancer therapy. In addition to the low efficiency of photosensitizer (PS) delivery to tumor sites, however, the radiation- and drug-resistance of hypoxic cells inside the tumor after X-PDT also limit its benefits. Herein, we develop a combined therapeutic modality based on an intelligent nanosized platform (DATAT-NPVT) with tumor acidity-activated TAT presenting and redox-boosted release of tirapazamine (TPZ) for more precise and synchronous X-PDT and selective hypoxia-motivated chemotherapy. After DATAT-NPVT has accumulated in tumor tissues via decreased blood clearance by masking of the TAT ligand, its targeting ability is reactivated by tumor pH (∼6.8), which enhances tumoral cellular uptake. Upon low-dose X-ray irradiation, the encapsulated verteporfin (VP) generates reactive oxygen species (ROS) to carry out X-PDT against MDA-MB-231 breast tumors. As a result of the abundant GSH-triggered degradation of ditelluride bridged bonds, the cascaded TPZ release and activation in the hypoxic environment following X-PDT would produce highly cytotoxic radicals to serve as antitumor agents to kill the remaining hypoxic tumor cells. This concept provides new avenues for the design of hierarchical-responsive drug delivery systems and represents a proof-of-concept combinatorial tumor treatment.