Polydopamine (PDA)-based Fenton agents attract increasing attention in tumor photothermal-enhanced chemodynamic therapy (CDT) due to their good biocompatibility and excellent loading capacity. However, PDA tends to eliminate the Fenton reaction-generated hydroxyl radical (∙OH) by its strong reducibility, which is an intractable hinder to the efficacy of CDT that need to be solved. Herein, a kind of mesoporous PDA-gold-manganese dioxide (MPDA-Au-MnO2, MPAM) nanoplatform was constructed for photothermal-enhanced CDT against tumor through the reducibility weakening strategy. The reducibility of original MPDA is effectively weakened by the oxidation role of HAuCl4 and KMnO4 during the preparation process, reducing the ∙OH scavenging ability of MPDA and benefiting the production of ∙OH. The MnO2 shell could react with GSH to release Mn2+, acting as the Fenton-like agent to generate ∙OH. The exposed Au NPs can further deplete GSH through the Au-S bond interaction. MPDA acts as the photothermal agent to generate hyperthermia under laser irradiation. MPAM shows excellent intracellular GSH scavenging ability and enhanced ∙OH production ability. After intravenous injection, MPAM can significantly suppress the growth of tumors under laser irradiation, meanwhile showing good biosafety. The developed MPDA-based nanoplatform can not only display good potential in further tumor treatments but also provide meaningful enlightenment for developing high-performance PDA or MPDA-based nanoplatforms in CDT-related applications.

BackgroundIn breast cancer (BC), tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment and are closely related to poor prognosis. A growing number of studies have focused on the role of TAMs in BC progression and therapeutic strategies targeting TAMs. As an emerging treatment, the application of nanosized drug delivery systems (NDDSs) in the treatment of BC by targeting TAMs has attracted much attention. AimsThis review is to summarize the characteristics and treatment strategies targeting TAMs in BC and to clarify the applications of NDDSs targeting TAMs in the treatment of BC by targeting TAMs. Materials & MethodsThe existing results related to characteristics of TAMs in BC, BC treatment strategies by targeting TAMs, and the applications of NDDSs in these strategies are described. Through analyzing these results, the advantages and disadvantages of the treatment strategies using NDDSs are discussed, which could provide advices on designing NDDSs for BC treatment. ResultsTAMs are one of the most prominent noncancer cell types in BC. TAMs not only promote angiogenesis, tumor growth and metastasis but also lead to therapeutic resistance and immunosuppression. Mainly four strategies have been used to target TAMs for BC therapy, which include depleting macrophages, blocking recruitment, reprogramming to attain an anti-tumor phenotype, and increasing phagocytosis. Since NDDSs can efficiently deliver drugs to TAMs with low toxicity, they are promising approaches for targeting TAMs in tumor therapy. NDDSs with various structures can deliver immunotherapeutic agents and nucleic acid therapeutics to TAMs. In addition, NDDSs can realize combination therapies. DiscussionTAMs play a critical role in the progression of BC. An increasing number of strategies have been proposed to regulate TAMs. Compared with free drugs, NDDSs targeting TAMs improve drug concentration, reduce toxicity and realize combination therapies. However, in order to achieve better therapeutic efficacy, there are still some disadvantages that need to be considered in the design of NDDSs. ConclusionTAMs play an important role in the progression of BC, and targeting TAMs is a promising strategy for BC therapy. In particular, NDDSs targeting TAMs have unique advantages and are potential treatments for BC.

背景:近红外发光碳点具备有蓝绿发光碳点不具备的组织穿透性,是理想的成像剂,但是由于其在体内易降解而无法到达靶点组织,实验将其与纳米粒相结合,使其能通过循环系统到达相应靶点,达到实时成像的目的.目的:制备具有成像能力且安全性高的近红外成像载碳点介孔有机-无机杂化二氧化硅纳米粒(mesoporous organosilica nanocapsules-carbon nanodots,MON-CDs).方法:利用胶束/前体共模板组装策略,以原硅酸四乙酯和双[3-(三乙氧基甲硅烷基)丙基]四硫化物为原材料、十六烷基三甲基氯化铵为模板剂、三乙醇胺为碱性催化剂成功制备了有机-无机杂化介孔二氧化硅纳米粒子,并将碳点加入到整个体系中制备MON-CDs.利用透射电镜与荧光光谱仪检测纳米粒的结构、形貌及其加载的荧光强度;利用光声成像仪、扫描激光共聚焦显微镜验证其体外成像能力,并在小鼠乳腺癌模型体内证明其体内光声成像能力;利用CCK-8实验检测不同质量浓度MON-CDs溶液的生物安全性.结果 与结论:①透射电镜显示,MON-CDs的粒径为(50.0±4.6)nm,呈球形,大小均一且具备良好的分散性,孔道清晰可见,碳点参杂其中;荧光检测显示碳点与介孔有机-无机杂化二氧化硅纳米粒子成功连接;②CCK-8检测显示,当MON-CDs溶液的质量浓度在200 mg/L以内时无明显的细胞毒性;③扫描激光共聚焦显微镜显示,当MON-CDs与MCF-7细胞共孵育1 h时,纳米粒已出现了细胞摄取,并且大部分集中于细胞膜附近;共孵育2 h时,纳米粒累积进入细胞内的量增加,纳米粒主要分布于细胞质中,并且大部分细胞内部均出现了纳米粒的摄入;④光声成像检测显示,随着MON-CDs溶液质量浓度的增加,体外光声信号强度增强;经尾静脉注射MON-CDs溶液6 h后,在乳腺癌小鼠肿瘤组织处观察到了明显的光声信号;⑤结果表明,MON-CDs具有很好的生物安全性且拥有近红外发光,在光声成像仪及激光共聚焦下展现了良好的成像能力.

Drug resistance is always a challenge in conquering breast cancer clinically. Recognition of drug resistance and enhancing the sensitivity of the tumor to chemotherapy is urgent. Herein, a dual-responsive multi-function “Matryoshka" nanosystem is designed, it activates in the tumor microenvironment, decomposes layer by layer, and release gene and drug in sequence. The cell is re-educated by NgBR siRNA first to regain the chemosensitivity through regulating the Akt pathway and inhibit ERα activation, then the drugs loaded in the core are controlled released to killing cells. Carbonized polymer dots are loaded into the nanosystem as an efficient bioimaging probe, due to the GE11 modification, the nanosystem can be a seeker to recognize and evaluate drug-resistance tumors by photoacoustic imaging. In the tumor-bearing mouse, the novel nanosystem firstly enhances the sensitivity to chemotherapy by knockdown NgBR, inducing a much higher reduction in NgBR up to 52.09%, then effectively inhibiting tumor growth by chemotherapy, tumor growth in nude mouse was inhibited by 70.22%. The nanosystem also can inhibit metastasis, prolong survival time, and evaluate tumor drug resistance by real-time imaging. Overall, based on regulating the key molecules of drug resistance, we created visualization nanotechnology and formatted new comprehensive plans with high bio-safety for tumor diagnosis and treatment, providing a personalized strategy to overcome drug resistance clinically.

本文将介孔有机二氧化硅纳米颗粒(MONs)与碳点(CDs)结合,制备新型负载碳点的介孔有机硅纳米粒子(CD@MONs).结果表明成功制备出负载碳点的介孔有机硅复合纳米粒子,详细表征显示产物呈球形,分散性较好,直径为40～60 nm,大小较为均一,孔道大,产物在415 nm激发下,荧光发射波长为670 nm,该复合材料既具有大于660 nm的发射波长荧光,可用于深部组织成像,且新型负载碳点的介孔有机硅纳米粒子可降解,低毒性,有良好的生物相容性及生物安全性,为生物医学成像及载药提供了一种新型纳米材料.

OBJECTIVES: To establish and verify a simple noninvasive model based on the left gastric vein (LGV) to predict the grade of esophageal varices (EV) and high-risk EV (HEV), to facilitate clinical follow-up and timely treatment. METHODS: We enrolled 320 patients with B-viral cirrhosis. All patients underwent endoscopy, laboratory tests, liver and spleen stiffness (SS), and ultrasonography. HEV were analyzed using the χ2 test/t test and logistic regression in the univariate and multivariate analyses, respectively. EV grades were analyzed using the variance/rank-sum test and logistic regression. A prediction model was derived from the multivariate predictors. RESULTS: In the training set, multivariate analysis showed that the independent factors of different EV grades were SS, LGV diameter, and platelet count (PLT). We developed the LGV diameter-SS to PLT ratio index (LSPI) and LGV diameter/PLT models without SS. The area under the receiver operating characteristic curve of the LSPI for diagnosis of small EV, medium EV, large EV, and HEV was 0.897, 0.899, 0.853, and 0.954, respectively, and that of the LGV/PLT was 0.882, 0.890, 0.837, and 0.942, respectively. For the diagnosis of HEV, the negative predictive value was 94.07% when LSPI < 19.8 and the positive predictive value was 91.49% when LSPI > 23.0. The negative predictive value was 95.92% when LGV/PLT < 5.15, and the positive predictive value was 86.27% when LGV/PLT > 7.40. The predicted values showed similar accuracy in the validation set. DISCUSSION: Under appropriate conditions, the LSPI was an accurate method to detect the grade of EV and HEV. Alternatively, the LGV/PLT may also be useful in diagnosing the varices when condition limited.