TEVAR with fenestrations of all supra-aortic branches for traumatic aortic pseudoaneurysm: Case report and systematic review.

OBJECTIVES: Blunt thoracic aortic injuries (BTAIs) involving the aortic arch are a challenging condition. Thoracic endovascular aortic repair (TEVAR) with fenestration, which expands the proximal landing zone, is able to exclude the injury while preserving blood flow in supra-aortic branches. METHODS: Here we report a case of TEVAR with fenestrations of all supra-aortic branches for traumatic aortic pseudoaneurysm and perform a systematic review. RESULTS: A 24-year-old man suffering a blunt thoracic injury and a left femoral fracture was sent to our hospital. A pseudoaneurysm was found in the aortic arch between the brachiocephalic artery and the left common carotid artery. The patient underwent emergent TEVAR with fenestrations of all supra-aortic branches, which excluded the pseudoaneurysm and preserved the patency of all branches. The orthopedic team then treated the femoral fracture. The patient's recovery was unremarkable. We performed a systematic review on TEVAR with fenestrations for BTAI. Six patients (75%) received TEVAR with single fenestration, 1 patient (12.5%) received TEVAR with two fenestrations, and 1 patient (12.5%) had fenestrations of all supra-aortic branches. Except one patient died in the perioperative, other patients survived without stent-related complications in the short-term follow-up. CONCLUSIONS: TEVAR with fenestration is feasible for treating BTAI involving the aortic arch in selected patients.

Therapeutic implications of extracorporeal shock waves in burn wound healing.

Burns are a common type of trauma that seriously affect not only the physical health, but also the mental health and quality of life of the patient. Extracorporeal shock wave therapy (ESWT) is an emerging treatment that has been used in clinical treatment. It has many advantages, including safety, non-invasiveness, efficiency, short treatment duration, fewer complications, and relatively low prices. In clinical settings, ESWT has played an important role in the healing process of burns and the prevention of sequelae. This article reviews the history of ESWT, the mechanism of ESWT to promote burn healing, and the application of ESWT in burns. Current status of ESWT treatment for burns as well as future perspectives for research have been summarized and proposed. However, patients with burns cannot be considered recovered when the wounds have healed, we need some new technology to adjust to the challenges of the future.

An improved bi-level programming model for water resources allocation under multiple uncertainties.

Nowadays, with the scarcity of water resources, competition for water resources among different levels and water sectors is growing increasingly fierce. Furthermore, uncertainties are unavoidable in the water resources system. To address the aforementioned issues, a fuzzy max-min decision bi-level multi-objective interval programming model was proposed, which can not only focus on water conflicts at the same level or between different levels, but also pay attention to optimal allocation of water resources under uncertainty. The developed model was then applied to a case study in Wuwei City, Gansu Province, China, which selected fairness of water distribution and agricultural economic benefits as planning objectives. Based on the developed model, different water resources optimal allocation schemes under different representative hydrological years were provided. From the result, as representative hydrological years changed from wet (P = 25%) to dry (P = 75%), agricultural economic benefit and Gini coefficient of agriculture would vary from [35.19, 37.78] × 108 yuan to [31.12, 31.99] × 108 yuan and from [0.468, 0.429] to [0.505, 0.503], which indicates that as available water resources decrease, agricultural economic benefit would decrease and fairness of water distribution would also decrease. And the water distribution fairness of the upper bound water allocation scheme is higher than that of the lower bound water allocation scheme when in the same representative hydrological year. In addition, no matter what representative hydrological year, the results of the established bi-level programming model are always in the middle of the results of the upper and lower level individual objective, which means that the developed bi-level programming model has great advantage to deal with water competing conflict among different levels. Furthermore, based on the results of developed model, the reasonable water resources optimization schemes can be determined by the decision-makers when faced with multi-objective, bi-level and multiple uncertainties problems.

[Construction and Anti-tumor Effect Evaluation of a Dual-Responsive Hyaluronic Acid Carbon Quantum Dot-Gelatin Nano-Drug Delivery System].

OBJECTIVE: To construct a pH and matrix metalloproteinase (MMP) dual-responsive nano drug delivery system with adjustable particle size so as to synergistically enhance the retention and penetration of chemotherapeutic drugs in tumor tissues and improve tumor treatment effect. METHODS: Hyaluronic acid (HA) carbon quantum dots (CD) coupled with gelatin nanoparticle (GNP) were constructed, and were connected with doxorubicin (DOX), a chemotherapeutic drug, through pH-sensitive imine to produce GNP@HA-CD-DOX nanoparticles. The changes of particle size, drug release behavior, hemocompatibility, cell uptake and deep penetration of tumor spheroids, in vivo tumor targeting and therapeutic effect were analyzed. RESULTS: GNP@HA-CD-DOX nanoparticles had a particle size of (162.93±2.55) nm, which could be degraded to release HA-CD-DOX with a particle size of about 40 nm under the treatment of MMP. The drug loading of DOX was (4.94±0.22)%. DOX was released in the tumor microenvironment and lysosomes in response to the low pH. No obvious hemolysis was observed in GNP@HA-CD-DOX. GNP@HA-CD-DOX showed a reduction in particle size after co-incubation with MMP-2. The MMP-sensitive GNP@HA-CD-DOX had significantly improved cell uptake and better deep penetration in tumor spheres. GNP@HA-CD-DOX displayed better distribution in tumor and anti-tumor ability in tumor-bearing mice compared with the small particle size HA-CD-DOX group. In addition, it has better safety. CONCLUSION: The pH and MMP dual-sensitive nano-tech drug delivery system with adjustable particle sizes synergistically enhances the retention and deep penetration of drugs in tumors as well as the anti-tumor effect, suggesting new approaches to tumor treatment.

[Establishment of evaluation system on food safety management capacity for food production enterprises by Delphi method].

OBJECTIVE: To construct an evaluation indicator system on food safety management capacity for food production enterprises by Delphi method, and to provide a scientific theoretical framework for food safety management capacity for food enterprises.
 Methods: A framework for the evaluation system on food safety management capabilities was established and experts in relevant fields were invited to conduct 2 rounds of expert consultation. Indicators were selected and determined based on expert opinions and statistical analysis results. The hierarchical model was constructed by the analytic hierarchy process to determine the weight coefficients of each indicator.
 Results: The positive coefficients of the two rounds of expert consultation were 84% and 100%, and the coefficient of experts' authority was 0.826. The coordination coefficients of the indicators in the first round of consultation were 0.439, 0.323 and 0.324, and they were 0.607, 0.351, and 0.368 in the second round, respectively, with statistically significant differences (P<0.001). The evaluation index system of food safety management capacity for food production enterprises was established after the two rounds of expert consultation, and the system consisted of 5 indicators for the first level, 18 indicators for the second level and 32 indicators for the third level, with corresponding weights. 
 Conclusion: The enthusiasm, authority and concordance of experts during this consultation are good, and the selected indicators are reasonable and comprehensive, which can provide a basis for the evaluation of food safety management capabilities for food enterprises.

Crosstalk Between Cell Death and Spinal Cord Injury: Neurology and Therapy.

Spinal cord injury (SCI) often leads to neurological dysfunction, and neuronal cell death is one of the main causes of neurological dysfunction. After SCI, in addition to necrosis, programmed cell death (PCD) occurs in nerve cells. At first, studies recognized only necrosis, apoptosis, and autophagy. In recent years, researchers have identified new forms of PCD, including pyroptosis, necroptosis, ferroptosis, and cuproptosis. Related studies have confirmed that all of these cell death modes are involved in various phases of SCI and affect the direction of the disease through different mechanisms and pathways. Furthermore, regulating neuronal cell death after SCI through various means has been proven to be beneficial for the recovery of neural function. In recent years, emerging therapies for SCI have also provided new potential methods to restore neural function. Thus, the relationship between SCI and cell death plays an important role in the occurrence and development of SCI. This review summarizes and generalizes the relevant research results on neuronal necrosis, apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis after SCI to provide a new understanding of neuronal cell death after SCI and to aid in the treatment of SCI.

Mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation for ferroptosis after spinal cord injury.

Spinal cord injury is characterized by different aetiologies, complex pathogenesis, and diverse pathological changes. Current treatments are not ideal, and prognosis is generally poor. After spinal cord injury, neurons die due to various forms of cell death. Among them, ferroptosis causes dysfunction after spinal cord injury, and no existing traditional treatments have been indicated to block its occurrence. Meanwhile, emerging therapies using mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation therapy are promising for reversing spinal cord neuronal ferroptosis after spinal cord injury. However, no definitive studies have demonstrated the effectiveness of these approaches. This review summarizes the existing research on the mechanisms of ferroptosis; ferroptosis after spinal cord injury; treatment of spinal cord injury with mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation; and treatment of ferroptosis using mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation. Inhibiting ferroptosis can promote the reversal of neurological dysfunction after spinal cord injury. In addition, mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation can reverse adverse outcomes of spinal cord injury and regulate ferroptosis-related factors. Thus, it can be inferred that mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation have the potential to inhibit ferroptosis after spinal cord injury. This review serves as a reference for future research to confirm these conclusions.

Autophagy-Interfering Nanoboat Drifting along CD44-Golgi-ER Flow as RNAi Therapeutics for Hepatic Fibrosis.

The upregulated autophagy fuels the activation of hepatic stellate cells (HSCs) to promote hepatic fibrosis. However, the lack of specific inhibitors targeting autophagy and high requirements for cell targeting impede the application of antifibrotic therapy that targets autophagy. RNA interference (RNAi)-based short interfering RNA (siRNA) provides an approach to specifically inhibit autophagy. The therapeutic potential of siRNA, however, is far from being exploited due to the lack of safe and effective delivery vehicles. The cytoplasmic delivery of siRNA is essential for RNAi, and the intracellular trafficking pathway of vehicles determines the fate of siRNA. Unfortunately, the lysosomal degradation pathway, the intracellular fate of most gene vehicles, impedes RNAi efficiency. Inspired by the trafficking pathway of some viruses infecting cells, KDEL-grafted chondroitin sulfate (CK) was designed to alter the intracellular delivery fate of siRNA. The well-designed CD44-Golgi-ER trafficking pathway of CK was realized by triple cascade targeting including (1) CD44 targeting mediated by chondroitin sulfate, (2) Golgi apparatus targeting mediated by the caveolin-mediated endocytic pathway, and (3) endoplasmic reticulum (ER) targeting mediated by coat protein I (COP I) vesicles. CK was adsorbed on the complex of cationic liposomes (Lip) encapsulating siRNA targeting autophagy-related gene 7 (siATG7) to afford Lip/siATG7/CK. Lip/siATG7/CK functions as a drifting boat that follows the CD44-Golgi-ER flow and travels downstream to its destination (ER), bypassing the lysosomal degradation pathway and endowing HSCs with excellent RNAi efficiency. The efficient downregulation of ATG7 leads to an excellent antifibrotic effect both in vitro and in vivo.

A core-satellite micellar system against primary tumors and their lymphatic metastasis through modulation of fatty acid metabolism blockade and tumor-associated macrophages.

Lymph nodes (LNs) are the initial sanctuary of various metastatic tumor cells, and thus a precise lymphatic drug delivery strategy is necessary for the effective inhibition of metastasis. However, the complex biological barriers have restrained the drug delivery to tumor-draining lymph nodes (TDLNs). Metastatic tumor cells would undergo metabolic adaptation towards fatty acid oxidation (FAO) upon reaching the lipid-rich LNs. Herein, to inhibit primary tumors and their lymphatic metastasis, a core-satellite matrix metalloproteinase 2 (MMP-2) responsive micellar system was developed for sequential delivery of paclitaxel (PTX) and the metabolism-regulating drug etomoxir (ET) to tumors and TDLNs, respectively. Upon arrival at the tumor microenvironment (TME), the small satellite micelle encapsulating ET was detached from the core micelle in response to MMP-2, which not only drained to TDLNs via tumor-draining lymphatic vessels and inhibited the FAO of metastatic tumor cells, but also blocked M2-like macrophage polarization in the TME. Meanwhile, the core micelle containing PTX could largely accumulate in the TME and kill tumor cells. In an orthotopic 4T1 breast cancer model, the tumor and TDLN dual-targeted core-satellite micellar system effectively inhibited the growth of the primary tumor and alleviated immune suppression by blocking macrophage polarization. More importantly, tumor lymphatic metastasis was suppressed through FAO metabolic regulation. This strategy provides a promising approach for TDLN targeted therapy against breast cancer and its lymphatic metastasis.

Stationary distribution and extinction of a stochastic influenza virus model with disease resistance.

Influenza is a respiratory infection caused influenza virus. To evaluate the effect of environment noise on the transmission of influenza, our study focuses on a stochastic influenza virus model with disease resistance. We first prove the existence and uniqueness of the global solution to the model. Then we obtain the existence of a stationary distribution to the positive solutions by stochastic Lyapunov function method. Moreover, certain sufficient conditions are provided for the extinction of the influenza virus flu. Finally, several numerical simulations are revealed to illustrate our theoretical results. Conclusively, according to the results of numerical models, increasing disease resistance is favorable to disease control. Furthermore, a simple example demonstrates that white noise is favorable to the disease's extinction.

Inflammation-targeted cannabidiol-loaded nanomicelles for enhanced oral mucositis treatment.

One of the most common complications of cancer chemotherapy is oral mucositis (OM), a serious kind of oral ulceration, but its effective treatment remains a serious challenge. In this study, we used deoxycholic acid and fucoidan to prepare inflammation-targeting nanomicelles (FD), because fucoidan can target inflammation due to its high binding affinity for P-selectin. The hydrophobic anti-inflammatory drug cannabidiol (CBD) was then loaded into the hydrophobic core of FD. The resulting CBD-loaded FD micelles (CBD/FD) had uniform particle size and morphology, as well as favorable serum stability. Moreover, administration of the FD micelles via intravenous injection or in situ dripping in an OM mouse model enhanced the accumulation and retention of CBD. CBD/FD also showed a better anti-inflammatory effect compared to free CBD after local or systemic administration in vivo, while they accelerated OM healing and inhibited Ly6G inflammatory cell infiltration and NF-κB nuclear transcription. Our results show that CBD/FD nanomicelles are a promising agent for OM treatment.

Cellular Hypoxia Mitigation by Dandelion-like Nanoparticles for Synergistic Photodynamic Therapy of Oral Squamous Cell Carcinoma.

Hypoxia at the tumor site limits the therapeutic effects of photodynamic therapy (PDT) in oral squamous cell carcinoma (OSCC), which is an oxygen-consumption process. Inhibiting cellular oxygen consumption and reducing cellular ATP production are expected to enhance PDT. In this study, we designed and constructed dandelion-like size-shrinkable nanoparticles for tumor-targeted delivery of hypoxia regulator resveratrol (RES) and photodynamic agent chlorine e6 (CE6). Both drugs were co-encapsulated in small-sized micelles modified with EGFR targeting ligand GE11, which was further conjugated on hyaluronic nanogel (NG) to afford RC-GMN. After targeted accumulation in tumors mediated by GE11 and enhanced penetration and retention (EPR) effects, RC-GMN was degraded by hyaluronidase (HAase) and resulted in small-sized micelles, allowing for deep penetration and dual-receptor-mediated cellular internalization. Resveratrol inhibited cellular oxygen consumption and provided sufficient oxygen for PDT, which consequently activated PDT to produce reactive oxygen species (ROS). Notably, we found that autophagy was overactivated in PDT, which was further strengthened by the hypoxia regulator resveratrol, elevating autophagic cell death. The synergistic effects of resveratrol and CE6 promoted autophagic cell death and apoptosis in the enhanced PDT, resulting in stronger antitumor effects in the orthotopic OSCC model. Therefore, the facilitated delivery of hypoxia regulator enhanced PDT efficacy by elevating oxygen content in tumor cells and inducing autophagic cell death and apoptosis, which offers an alternative strategy for enhancing the PDT effects against OSCC.

Multifunctional self-delivery micelles targeting the invasion-metastasis cascade for enhanced chemotherapy against melanoma and the lung metastasis.

Metastasis is closely related to the high mortality of cancer patients, which is regulated by multiple signaling pathways. Hence, multiphase blocking of this biological process is beneficial for cancer treatments. Herein, we establish a multifunctional self-delivering system by synthesizing D-α-tocopheryl succinates (TOS)-conjugated chondroitin sulfate (CS) (CT NPs), which both serve as nanocarrier and antimetastatic agent that affects different phases of the metastatic cascade. TOS as the hydrophobic segment of CT NPs can inhibit the secretion of matrix metalloproteinase-9, while the hydrophilic segment CS targets B16F10 cells through CD44 receptors and reduces the interaction between tumor cells and platelets. The results show that CT NPs are able to inhibit metastasis successfully both in vitro and in vivo by interfering the multiphase of the metastatic cascade. Following encapsulating chemotherapeutic drug doxorubicin (DOX), the obtained micelles CT/DOX efficiently suppress both primary-tumor growth and metastases in B16F10 bearing mice. As a result, the rationally designed multifunctional NPs composing of biocompatible materials provide excellent therapeutic effects on solid tumors and metastases.

Shield and sword nano-soldiers ameliorate rheumatoid arthritis by multi-stage manipulation of neutrophils.

Rheumatoid arthritis (RA) is characterized by the outbreak of inflammation. Neutrophils, the main culprit of the outbreak of inflammation, are the first inflammatory cells to be recruited to inflamed joints and facilitate the recruitment of themselves by stimulating the release of chemokines. Here, based on neutrophils, a novel anti-inflammatory "shield and sword soldiers" strategy is established with LMWH-TOS nanoparticles (LT NPs). The hydrophilic fragment low molecular weight heparin (LMWH) acts as a shield which block the transvascular movement of neutrophils through inhibiting the adhesion cascade by binding to P-selectin on inflamed endothelium. Synergistically, MMP-9, which is secreted by the recruited neutrophils and degrade the main component of articular cartilage, is reduced by the hydrophobic fragment d-α-tocopheryl succinate (TOS), functioning as a sword. In collagen-induced arthritis (CIA) mouse model, LT NPs show significant targeting effect, and exhibit prominent therapeutic efficacy after enveloping the first-line anti-RA drug methotrexate. Our work proves that the multi-stage manipulation of neutrophils is feasible and effective, providing a new concept for RA treatment.

Phenylboronic acid modified nanoparticles simultaneously target pancreatic cancer and its metastasis and alleviate immunosuppression.

Pancreatic ductal adenocarcinoma is one of the most lethal malignant tumors, its drug resistance, immunosuppression and metastasis makes the traditional chemotherapy and immunotherapy inefficient. Here we confirmed a 3-aminophenylboronic acid-modified low molecular weight heparin-D-α-tocopheryl succinate micellar nanoparticle (PBA-LMWH-TOS NP, PLT NP) could inhibit orthotopic pancreatic tumor and its spontaneous metastases. The small particle size and high affinity of PBA to sialic acid residue (SA) made PLT/PTX NPs significantly targeted and accumulated in both pancreatic tumor tissues and metastases. The immunosuppressive microenvironment of pancreatic tumor was most caused by the infiltration of immunosuppressive cells, mainly myeloid-derived suppressor cells (MDSCs). We first reported that P-selectin glycoprotein ligand-1 (PSGL-1) was expressed on the surfaces of MDSCs in pancreatic tumor tissues. Meanwhile, we found that LMWH could inhibit the early stage of adhesion cascade between vascular endothelial cells (VECs) and MDSCs by interfering with P-selectin/PSGL-1 binding, thus inhibiting MDSC recruitment to pancreatic tumor tissues. The therapeutic results indicated that PLT/PTX NPs could significantly improve the immune microenvironment of pancreatic tumor and inhibit spontaneous metastases. This nanosystem provides a new immune microenvironment regulation mechanism based on carrier materials in pancreatic tumor, and has high clinical application potential.

Simultaneous inhibition of breast cancer and its liver and lung metastasis by blocking inflammatory feed-forward loops.

Inflammatory feed-forward loops including the steps of "inflammatory cell recruitment", "inflammatory signaling pathway activation" and "inflammatory factor production" are essential in the development of breast cancer and its metastasis. Herein, a doxorubicin-loaded micellar low-molecular-weight-heparin-astaxanthin nanoparticle (LMWH-AST/DOX, LA/DOX NP) was developed. The hydrophilic LMWH could decrease the recruitment of neutrophils in liver and myeloid-derived suppressor cells (MDSCs) in lung and tumor through P-selectin blockage. The hydrophobic AST could inhibit nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways. Therefore, LA/DOX NPs could block these loops and suppress the liver metastasis by inhibiting the formation of neutrophil extracellular traps (NETs), inhibit the lung metastasis and alleviate the inflammatory and immunosuppressive microenvironment in tumor. This is the first functional nanoparticle reported to shut down inflammatory feed-forward loops and the formation of NETs, which provides a promising therapeutic strategy for breast cancer and its liver and lung metastasis.

Rapid pH-responsive self-disintegrating nanoassemblies balance tumor accumulation and penetration for enhanced anti-breast cancer therapy.

The dilemma of tumor accumulation and deep penetration has always been a barrier in antitumor therapy. Stimuli-responsive size changeable drug delivery systems provide possible solutions. Nevertheless, the low size-shrinkage efficiency limited the antitumor effects. In this study, an instant pH-responsive size shrinkable nanoassemblies named self-aggregated DOX@HA-CD (SA-DOX@HA-CD) was formulated using small-sized hyaluronic acid modified carbon dots (HA-CD) as monomers, which could self-aggregate into raspberry-like structure via hydrophobicity force in neutral pH and rapidly disassemble into shotgun-like DOX-loaded CD monomer in simulated tumor microenvironment (pH 6.5), owing to the transformation in electrical charge and hydrophobicity/hydrophilicity of this system. The transmission electron microscopy showed that the clustered SA-DOX@HA-CD had a diameter of ~150 nm, and thoroughly disassembled into ~30 nm nanoparticles in response to acidic environment. The disassemble efficiency was approximately 100%. Attributed to this property, SA-DOX@HA-CD led to enhanced cellular internalization and accumulation in 4T1 cells in simulated tumor microenvironment, as well as deep tumor penetration in 3D tumor spheroid model. Besides, the imine bond between DOX and HA-CD endowed DOX with pH-responsive release profile in the acidic lysosome environment. Furthermore, in the orthotopic 4T1 tumor-bearing mouse model, SA-DOX@HA-CD demonstrated higher tumor accumulation than non-aggregated DOX-HA-CD. Meanwhile, in response to the acid tumor microenvironment, the dissociated DOX-HA achieved deep tumor penetration, which consequently resulted in 2.5-fold higher antitumor efficiency. The formulation of self-aggregated SA-DOX@HA-CD provides a simple and effective alternative to prepare pH-responsive size-shrinkable nanodrug delivery systems. STATEMENT OF SIGNIFICANCE: The heterogeneity of tumor vasculature and the high tumor interstitial pressure lead to the barriers in tumor accumulation and deep penetration, which calls for opposite properties (e.g. size) of drug delivery systems. To address this dilemma, various size changeable nanoparticles have been developed utilizing special features of tumor microenvironment, such as pH, enzyme and reactive oxygen species. Nevertheless, the current strategies face the problems of incomplete hydrolysis of chemical bonds or insufficient enzyme degradation, which result in only partial size shrinkage, hindering the tumor deep penetration effects. Here we developed a self-assembled nanocluster, which could respond to acidic pH rapidly and thoroughly disassemble into small nanodots due to the alteration of hydrophobicity/hydrophilicity/charge, leading to approximately 100% dissociation. This strategy provides a new concept for design of size changeable drug delivery systems.

A dual receptors-targeting and size-switchable "cluster bomb" co-loading chemotherapeutic and transient receptor potential ankyrin 1 (TRPA-1) inhibitor for treatment of triple negative breast cancer.

Oxidative-stress defense system stands for the vulnerability of tumor cells because of the stronger oxidative stress existing in tumor sites. TRPA-1 has been found to be overexpressed in various tumors, related to the tumor proliferation and metastasis, and promote reactive oxygen species (ROS) and chemotherapy tolerance through Ca2+-dependent anti-apoptotic pathway in recent studies, which provides a new anti-tumor approach to target oxidative-stress defense system. However, there are few studies on the mechanisms of TRPA-1 inhibition increasing the effectiveness of chemotherapy and inhibiting tumor metastasis. Here, in order to deliver drugs to the deep tumor where is full of stronger oxidative stress, a dual receptors-targeting and size-switchable "cluster bomb" co-loading doxorubicine (DOX) and TRPA-1 inhibitor AP-18 (DA-tMN) was designed. DSPE-PEG2000 micelles (M, ~10 nm) were connected to the master core of hyaluronic acid nanogels (N, ~100 nm) to realize HAase-responsive size-switchable and acquired targeting characteristics. Besides, tumor homing peptide tLyP-1 (t) was modified on the surface of micelles to further increase tumor accumulation. Our study showed that tLyP-1 modification enhanced tumor-targeting delivery of tLyP-1-modified micelles @ nanogels (tMN) in vitro and in vivo. Then, HAase responsive nanogel core realized the deep penetration of tMN in 4 T1 3D tumor spheres models and 4 T1 tumor-bearing mice models. In vitro anti-tumor and anti-metastasis mechanism studies indicated that AP-18 increased the sensitivity of tumor cells to DOX by inhibiting Ca2+ influx and AKT phosphorylation caused by DOX. Compared with DOX-loaded tLyP-1-modified micelles @ nanogels (D-tMN), DA-tMN had the enhanced anti-tumor and anti-metastasis effect in vitro and vivo. Furthermore, the further anti-metastasis mechanism studies showed that TRPA-1 inhibition downregulate the expression of N-cadherin and vimentin and upregulate the expression of E-cadherin, which suggested that metastases inhibition caused by TRPA-1 inhibition may be related to the inhibition of epithelial-mesenchymal transition (EMT) process.

Enhanced anti-tumor and anti-metastasis therapy for triple negative breast cancer by CD44 receptor-targeted hybrid self-delivery micelles.

Tumor growth and metastasis are multistep processes regulated by multiple signaling pathways. The successful treatment of cancer largely depends on the ability to inhibit metastatic process. Multiphase inhibition of metastasis is a promising approach. Here, we described a targeting delivery system which was constructed by mixing hyaluronic acid-d-α-tocopheryl succinate (HA-TOS, HT) and low molecular weight heparin-TOS (LMWH-TOS, LT) to form a stable hybrid micelle (HT-LT), encapsulating chemotherapeutic drug doxorubicin (DOX). The prepared HT-LT NPs was about 125 nm in diameter with high drug encapsulation rate and continuous drug release behavior. We confirmed that HT-LT NPs exhibited an effective targeting ability both in vitro and in vivo using a 4T1 model that was attributed to HA binding to CD44 receptors. In addition, HT-LT NPs acted on different phases of the invasion-metastasis cascade and inhibited tumor cell migration and invasion, thus inhibiting tumor metastasis. This combinatorial strategy provided an alternative approach for triple negative breast cancer therapy.

Size-adjustable micelles co-loaded with a chemotherapeutic agent and an autophagy inhibitor for enhancing cancer treatment via increased tumor retention.

Autophagy plays a key role in the stress response of tumor cells, which contributes to cancer cell survival and resistance to chemotherapy by degrading cytoplasmic proteins to provide energy and clear the hazardous substances. Therefore, combined treatment of chemotherapeutics and autophagy inhibitors is thought to obtain a desirable antitumor effect. Nanoparticles (NPs) show potential in tumor-targeting drug delivery because of the enhanced permeability and retention (EPR) effect. However, NPs with fixed particle size cannot achieve optimal delivery effect. Herein, a strategy based on Cu (I)-catalyzed click chemistry-triggered aggregation of azide/alkyne-modified micelles was developed for the co-delivery of the chemotherapeutic drug doxorubicin (Dox) and the autophagy inhibitor wortmannin (Wtmn). In vitro experiments showed that the size of micelles increased in a time-dependent manner, which enhanced micelle accumulation in both B16F10 and 4 T1 cells. The fluorescence resonance energy transfer (FRET) experiment and biodistribution study further demonstrated that the aggregation of micelles through click cycloaddition significantly improved the accumulation of drug-loading micelles at the tumor region. Furthermore, the decreased amount of autophagosomes observed by transmission electron microscopy (TEM), the declined expression of LC3-II, and the increased level of p62 by western blotting and immunohistochemistry (IHC) confirmed the obvious inhibition of autophagy induced by Dox/Wtmn co-loaded size-adjustable micelles, which had a synergistic effect in cancer suppression. In addition, the co-loaded size-adjustable micelles showed outstanding cytotoxicity and antitumor effect. Therefore, this strategy effectively suppressed melanoma and breast cancer in mice. STATEMENT OF SIGNIFICANCE: The therapeutic effects of chemotherapy can be limited by autophagy; hence, combined use of autophagy inhibitors with chemotherapeutics achieves desirable anticancer efficacy. In the present study, we designed size-adjustable micelles by modifying the click reaction substrate azide group and the alkyne group on the surface of micelles, and subsequently, the autophagy inhibitor wortmannin and the chemotherapeutic drug doxorubicin were co-loaded. The micelles could aggregate by click reaction at the tumor site when the catalysts were intratumorally injected. The results showed that the size-adjustable micelles achieved efficient drug delivery, penetration, and retention in tumors; through the combined effect of wortmannin-mediated autophagy inhibition and doxorubicin-mediated cytotoxicity, this strategy exerted significant anticancer effect in melanoma and breast cancer treatment.