Vulvovaginal candidiasis (VVC) co-infected with bacteria compromises the efficacy of traditional antifungal agents due to mixed biofilm and increased drug resistance. The physiological barrier posed by vaginal mucus and self-cleaning behavior further limit the application of existing clinical drugs. Conventional formulation design often combines different functional components, resulting in complex compositions. This complexity escalates with more demanding clinical needs, posing challenges for quality control and clinical translation. Extracellular vesicles (EVs), which combine physiological activity with carrier functions, offer new avenues to overcome multiple physiological barriers. This article develops an amphotericin B (AMB)-loaded thermosensitive gel system based on Lactobacillus gasseri-derived EVs (GEVs), named AMB/GEVs Gel. GEVs were selected for their favorable mucus-penetration and biological capabilities. Mechanistically, GEVs regulate the Ras1-cAMP-EFG1 pathway in C. albicans and the SarA system in S. aureus to exert anti-mixed-biofilm effects, and further modulate immune responses in macrophages and vaginal epithelial cells via the MAPK pathway, and these activities are associated with the GAPDH protein carried by GEVs. AMB/GEVs Gel demonstrates superior efficacy in eradicating mixed infection in vivo and in vitro, significantly reducing pro-inflammatory cytokines and promoting the restoration of a healthy vaginal microecology. In summary, this study provides foundational data supporting the use of GEVs-based gel system against vaginal C. albicans and S. aureus mixed infections, offering a potential strategy for combating vaginal infections.

The development and clinical application of KRASG12C inhibitors have made significant progress in recent years and some groundbreaking clinical results have been reported. However, overcoming resistance of KRASG12C-OFF covalent blockade remains a key focus in the fight against KRASG12C mutated cancers. Combination therapy may be one of the best treatment strategies to overcome the resistance. HJ-037 is an orally available, potent, and highly selective covalent KRASG12C inhibitor, which showed significantly superior inhibitory activities against NCI-H358 and Mia PaCa-2 cells to current marketed KRASG12C inhibitors, and favorable safety profile was observed in pre-clinical study, providing a good safety foundation for its combination with PD-1 inhibitor. In a Colon Cancer CT26-mKRASG12C cell line subcutaneous syngeneic model, animals treated with HJ-037 plus anti-PD-1 antibody showed complete tumor regression without recurrence. A proof-of-concept clinical trial combining HJ-037 with PD-1 inhibitor is currently ongoing, and preliminary data shows a positive trend in efficacy and safety profile. Preclinical study results indicate that the combination therapy of HJ-037 with PD-1 inhibitor could enhance the intensity and duration of antitumor activity compared to monotherapy, with satisfactory safety, therefore possessing a better potential for the treatment of cancer patients harboring KRASG12C mutation. Na Guo, Xiangyu Yang, Longjun Yang, Fengtian Du, Huiqiao Ling, Ke Xue, Lina Zhang, Jianxin Ji, Zhigang Wu. Preclinical evaluation of combination therapy of HJ-037 with anti-PD-1 antibody treating KRASG12C mutated tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3038.

The special physiological barriers of women, such as vaginal mucus and self-cleaning behavior, pose great challenges for the treatment of vulvovaginal candidiasis (VVC), and the drug resistance caused by fungal biofilms limits the application of existing antifungal drugs. Based on this, we designed a "three-in-one" thermosensitive gel system (AF/BP Gel) loaded with antibiofilm nanoparticles (AF NPs) and mucus penetration-assisting nanoparticles (BP NPs) to achieve vaginal adhesion while enhancing mucus and biofilm penetration. AF NPs were loaded with farnesol (FAR) and amphotericin B (AMB), and FAR is one of quorum sensing molecules which can interfere with biofilm-related genes such as ALS3, HWP1, RAS1, CPH1, EFG1, NRG1, TUP1, UME6, and disperse mature biofilm, thus playing a synergic antibiofilm role with AMB. BP NPs was loaded with bromelain (BRO), which cleared the mucus barrier for AF NPs and help it penetrate deep into the infection. These two kinds of nanoparticles use the thermosensitive gel matrix to reach the surface of the vaginal mucosa uniformly and persistently to overcome the obstacle of vaginal self-cleaning. AF/BP Gel showed great anti-candida albicans activity in vitro and in vivo, and greatly improved the inflammatory conditions in VVC mice. Overall, this "three-in-one" thermosensitive gel system can overcome multiple physiological barriers and resist different periods of biofilm, providing a new platform for treating vagina-associated infections.

BackgroundSLE is a complex autoimmune disease with deleterious effects on various organs. Accumulating evidence has shown abnormal vitamin B12 and one-carbon flux contribute to immune dysfunction. Transcobalamin II (TCN2) belongs to the vitamin B12-binding protein family responsible for the cellular uptake of vitamin B12. The role of TCN2 in SLE is still unclear.MethodsWe collected clinical information and blood from 51 patients with SLE and 28 healthy controls. RNA sequencing analysis, qPCR, and western blot confirmed the alteration of TCN2 in disease monocytes. The correlation between TCN2 expression and clinical features and serological abnormalities was analyzed. TCN2 heterozygous knockout THP1 cells were used to explore the effects of TCN2 dysfunction on monocytes. CCK-8 assay and EdU staining were used to detect cell proliferation. ELISA was conducted to assess vitamin B12, glutathione, and cytokines changes. UHPLC-MRM-MS/MS was used to detect changes in the intermediates of the one-carbon cycle. Flow cytometry is used to detect cell cycle, ROS, mitoROS, and CD14 changes.ResultsElevated TCN2 in monocytes was correlated positively with disease progression and specific tissue injuries. Using CD14+ monocytes and TCN2 genetically modified THP1 cell lines, we found that the TCN2 was induced by LPS in serum from SLE patients. TCN2 heterozygous knockout inhibited cellular vitamin B12 uptake and one-carbon metabolism, leading to cell proliferation arrest and decreased Toll-like receptor 4 (TLR4)-mediated CCL2 release. Methionine cycle metabolites, s-adenosylmethionine and homocysteine, rescued these effects, whereas folate treatment proved to be ineffective. Folate deficiency also failed to replicate the impact of TCN2 downregulation on THP1 inflammatory response.ConclusionOur study elucidated the unique involvement of TCN2-driven one-carbon flux on SLE-associated monocyte behavior. Increased TCN2 may promote disease progression and tissue damage by enhancing one-carbon flux, fostering monocyte proliferation, and exacerbating TLR4 mediated inflammatory responses. The inhibition of TCN2 may be a promising therapeutic approach to ameliorate SLE.

BackgroundChemotherapy resistance of osteosarcoma (OS) is still the crux of poor clinical curative effect.E3 ubiquitin-protein ligase Rad18 (Rad18) contributed to doxorubicin resistance in OS, which ultimately mediated DNA damage tolerance and led to a poor prognosis and chemotherapy response in patients.MethodsIn this study, doxorubicin was loaded in the process of Fe2+ and siRad18 forming nanoparticles(FSD) through coordination, chitosan modified with cell penetrating peptide (H6R6) was synthesized and coated on the surface of the NPs(FSD-CHR). FSD-CHR was then dispersed in thermosensitive hydrogel(PPP) for peritumoral injection of osteosarcoma in situ. Subsequently, the physicochemical properties and molecular biological characteristics of the drug delivery system were characterized. Finally, an osteosarcoma model was established to study the anti-tumor effects of multifunctional nanoparticles and the immunotherapy effect combined with αPD-L1.ResultsFSD-CHR has enhanced tumor tissue permeability, siRad18 can significantly reduce Dox-mediated DNA damage tolerance and enhance anti-tumor effects, and iron-based NPs show enhanced ROS upregulation. FSD-CHR@PPP showed significant inhibition of osteosarcoma growth in vivo and a reduced incidence of lung metastasis. In addition, siRad18 was unexpectedly found to enhance Dox-mediated immunogenic cell death (ICD).FSD-CHR@PPP combined with PD-L1 blocking significantly enhanced anti-tumor effects due to decreased PD-L1 enrichment.ConclusionHydrogel encapsulation of permeable nanoparticles provides an effective strategy for doxorubicin-resistant OS, showing that gene therapy blocking DNA damage tolerance can enhance treatment response to chemotherapy and appears to enhance the effect of ICD inducers to activate the immune system.

Alopecia areata affects over 140 million people worldwide and causes severe psychological distress. The Janus kinase (JAK) inhibitor, tofacitinib, shows significant potential in therapeutic applications for treating alopecia areata; however, the systemic adverse effects of oral administration and low absorption rate at the target site limit its application. Hence, to address this issue, we designed topical formulations of tofacitinib-loaded cationic lipid nanoparticles (TFB-cNLPs) with particle sizes of approximately 200 nm. TFB-cNLPs promoted percutaneous absorption and hair follicle targeting in an ex vivo pig ear model. TFB-cNLP decreased IFN-γ-induced alopecia areata symptoms in an in vitro follicle model by blocking the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. It also reduced the number of CD8+NKG2D+T cells in a C3H mouse model of alopecia areata in vivo, thereby inhibiting the progression of alopecia areata and reversing hair loss. These findings suggest that TFB-cNLP enhanced hair follicle targeting and has the potential for topical treatment or prevention of alopecia areata.

Background: CPT is a pentacyclic monoterpene alkaloid with a wide spectrum of antitumor activity. Its clinical application is restricted due to poor water solubility, instability, and high toxicity. We developed a new kind of multifunctional micelles to improve its solubility, reduce the side effecs, and obtain enhanced antitumor effects. Methods: We constructed HA-CPT nano-self-assembly prodrug micelles, which combined the advantages of pH-sensitivity, redox-sensitivity, and active targeting ability to CD44 receptor-overexpressing cancer cells. To synthesize dual sensitive HA-CPT conjugates, CPT was conjugated with HA by pH-sensitive histidine (His) and redox-sensitive 3,3′-dithiodipropionic acid (DTPA). In vitro, we studied the cellular uptake and antitumor effect for tumor cell lines. In vivo, we explored the bio-distribution and antitumor effects of the micelles in HCT 116 tumor bearing nude mice. Results: The dual-sensitive and active targeting HA-His-ss-CPT micelles was proved to be highly efficient in CPT delivery by the in vitro cellular uptake study. The HA-His-ss-CPT micelles escaped from endosomes of tumor cells within 4 h after cellular uptake due to the proton sponge effect of the conjugating His and then quickly released CPT in the cytosol by glutathione (GSH). In mice, HA-His-ss-CPT micelles displayed efficient tumor accumulation and conspicuous inhibition of tumor growth. Conclusions: The novel, dual-sensitive, active targeting nano-prodrug micelles exhibited high efficiency in drug delivery and cancer therapy. This “all in one” drug delivery system can be realized in an ingenious structure and avoid intricate synthesis. This construction strategy can illume the design of nanocarriers responding to endogenous stimuli in tumors.

研究珍珠岩基新型复合保温材料是开拓矿物材料应用领域的新课题.本工作研究了2种不同尺寸珍珠岩以及气相二氧化硅作为复合填料,分别以捏合工艺和直接混合工艺填充于乙烯基硅油或室温硫化硅橡胶,制备珍珠岩填充的复合硅橡胶保温板,通过检测不同产物的导热系数以及保温效果来评价其性能.结果表明:以捏合工艺制备的产品会降低珍珠岩的保温效果,主要原因是中空颗粒被捏合过程破碎;而以气相二氧化硅为主要填料制备的保温板不易成型,可成型产品最低导热系数为0.1728 W·m?1·K?1;当以珍珠岩+气硅粉在硅橡胶中的质量比为37.5％时,产品导热系数为0.0349 W·m?1·K?1,产物厚度为2.5 cm、250℃单侧加热4 min后,背面温度为67℃,基本满足在新型烟具等特种保温隔热应用要求.

Although oroxylin A, a natural flavonoid compound, suppressed progression of hepatocellular carcinoma, whether the tumor microenvironment especially the communication between cancer cells and immune cells was under its modulation remained obscure. Here we investigated the effect of extracellular vesicles from cancer cells elicited by oroxylin A on macrophages in vitro. The data shows oroxylin A elicits apoptosis-related extracellular vesicles through caspase-3-mediated activation of ROCK1in HCC cells, which regulates M1-like polarization of macrophage. Moreover, oroxylin A downregulates the population of M2-like macrophage and promotes T cells infiltration in tumor microenvironment, accompanied by suppression of HCC development and enhancement of immune checkpoint inhibitor treatment in mice model. Mechanistically, glycolytic proteins enriched in oroxylin A-elicited extracellular vesicles from HCC cells are transferred to macrophages where ROS-dependent NLRP3 inflammasome is activated, therefore contributing to anti-tumor phenotype of macrophage. Taken together, this study highlights that oroxylin A promotes metabolic shifts between tumor cells and immune cells, facilitates to inhibit tumor development, and improves immunotherapy response in HCC model.

目的 使用热熔挤出工艺,采用泊洛沙姆407作为凝胶基质连续化生产洛索洛芬钠凝胶.方法 使用粉末x射线衍射、流变学表征、质构分析和体外渗透试验等方法,将热熔挤出法与冷溶法制得的凝胶进行比较.结果 2种方法制备的洛索洛芬钠凝胶在黏弹性、黏度、硬度、黏附性等方面,在统计学上无显著性差异,药物均以分子形式分散于凝胶基质中.体外渗透试验过程中,热熔挤出凝胶与冷溶法凝胶的最大稳态渗透速率分别为(14.12±0.55)和(13.17±2.26)μg·cm-2·h-1,两者在统计学上无显著性差异.结论 用热熔挤出工艺可以快速,连续化地生产凝胶制剂,展示了该工艺在半固体制剂连续制造中的新应用.

Drug resistance represents one of the greatest challenges in cancer treatment. Cancer stem cells (CSCs) are thought to be the major cause of failure in cancer therapy due to their considerable resistance to most chemotherapeutic agents, resulting in tumor recurrence and eventually metastasis. Here, we report a treatment strategy for osteosarcoma using hydrogel-microspheres (Gel-Mps) complex mainly composed of collagenase (Col) and PLGA microspheres (Mps) carrying Pioglitazone (Pio) and Doxorubicin (Dox). Col was encapsulated in the thermosensitive gel to preferentially degrade tumor extracellular matrix (ECM), ensuring subsequent drug penetration, while Mps with Pio and Dox were co-delivered to synergistically inhibit tumor growth and metastasis. Our results showed that the Gel-Mps dyad functions as a highly biodegradable, extremely efficient, and low-toxic reservoir for sustained drug release, displaying potent inhibition of tumor proliferation and subsequent lung metastasis. Selective PPAR & gamma; agonist Pio reversed drug resistance to Dox by significantly down regulating the expression of stemness markers and P-glycoprotein (P-gp) in osteosarcoma cells. The Gel@ColMps@Dox/Pio exhibited advanced therapeutic efficacy in vivo , demonstrating its great potential to serve a novel osteosarcoma therapy, which not only inhibits the growth of, but also attenuates the stemness of osteosarcoma. The dual effects reinforce the sensitivity and efficacy of chemotherapy.

Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.

BACKGROUND:Acute myeloid leukemia (AML) showed limited clinical therapeutic efficiency with chemotherapy for its multi-distributed lesions and hard-to-kill leukemia cells deep in the bone marrow.RESULTS:Here, a biomimetic nanosystem (DR@PLip) based on platelet membrane (PM) coating and doxorubicin (DOX)/ginsenoside (Rg3) co-loading was developed to potentiate the local-to-systemic chemoimmunotherapy for AML. The PM was designed for long-term circulation and better leukemia cells targeting. The participation of Rg3 was proved to enhance the tumor sensitivity to DOX, thus initiating the anti-tumor immune activation and effectively combating the leukemia cells hiding in the bone marrow.CONCLUSIONS:In conclusion, the strategy that combining immediate chemotherapy with long-term immunotherapy achieved improved therapeutic efficiency and prolonged survival, which provided a new perspective for the clinical treatment of AML.

目的 建立离子色谱法测定枸橼酸钾缓释片中枸橼酸的含量.方法 采用Thermo Dionex IonPacAS11-HC(4mm×250mm,3μm)色谱柱,以 35 mmol·L-1KOH 作为淋洗液,流速为 1.0 mL·min-1,进样量为10μL;采用抑制电导检测方式,抑制电流:87mA,电导池温度:35℃.结果 枸橼酸在5～40 μg·min-1内线性关系良好(r=0.9998),低、中、高水平的枸橼酸平均回收率分别为101.3％、101.0％和100.4％,RSD分别为0.68％、0.60％和1.5％.结论 本方法专属性强,准确可靠,精密度良好,可用于测定枸橼酸钾缓释片中枸橼酸的含量.

以十一酸睾酮为模型药物,制备Ⅲ型脂质制剂,利用体外脂解模型评价各处方的体外脂解速率及脂解程度,并以光学显微镜和电导率等手段进一步研究其消化机制.结果 表明,在以蓖麻油为油相、Transcutol HP为助表面活性剂的十一酸睾酮Ⅲ型脂质制剂中,随着油相比例增加,脂解速率和脂解程度增加;表面活性剂比例过高,脂解过程中可观察到液晶相、脂解速率和脂解程度下降.含有不同表面活性剂的ⅢB型脂质制剂脂解速率排序为Labra-sol＞ Tween 80＞ Cremophor EL,而ⅢA型的排序在快速消化期和慢速消化期有所不同,但两者脂解程度排序均为Cremophor EL＞ Tween 80＞ Labrasol.研究结果提示,处方含油量、表面活性剂比例及其结构对Ⅲ型脂质制剂体外脂解速率和脂解程度均具有较大影响且相互交织,进行处方筛选时需综合考虑各方面因素对制剂体内消化的影响.

肝素是一种高度硫酸化的糖胺聚糖,目前主要作为抗凝剂应用于临床。肝素具有一定的抗肿瘤转移的作用,而基于肝素此项功能的抗肿瘤药物递送系统亦被广泛研究。在这类药物传递系统中,肝素一方面可增强抗肿瘤药物的抑瘤效果,同时亦可发挥自身的抗肿瘤转移功能,使药物及载体协同作用。基于肝素的抗肿瘤转移作用机理及肝素在药物递送系统中的应用,围绕相关的设计思路与方法展开综述,以期为相关领域的研究提供参考。

目的 分别制备速释、缓释和肠溶3种释药速率的卡马西平释药单元,按比例灌装胶囊以制备卡马西平缓释组合胶囊,并对其进行初步评价.方法 采用双螺杆挤出机通过热熔挤出法制备3种卡马西平固体分散体释药单元,以载药量、粒度、相似因子为指标,通过单因素法优化处方.结果 分别以VA64、EC 7CP、Eudragit L100-55为载体,制得载药量为33％、50％和20％的速释、缓释和肠溶释药单元.与市售制剂Carbatrol ?对比,3种释药单元的相似因子f2分别是55、56和62,自制组合胶囊制剂与市售制剂的f2为68.结论 采用热熔挤出制备卡马西平组合胶囊的技术简单易行,具有一定的产业化优势.

目的 制备一种不含肠溶包衣的双氯芬酸钠肠溶片.方法 以双氯芬酸钠(DS)为模型药物,以Eudragit L100-55为肠溶性材料,通过双螺杆挤出技术,制备双氯芬酸钠肠溶颗粒,随之压制成片;并以市售双氯芬酸钠肠溶片为参比制剂,考察自研制剂的溶出行为及体内药动学行为.结果 溶出结果显示自研制剂在胃内不溶,肠内以溶蚀型方式释放.家兔药动学实验结果显示,自研制剂的平均滞留时间和达峰时间长于参比制剂,血药浓度峰值略低于参比制剂,结合溶出结果可知,自制制剂在体内具有一定的缓释效果.结论 采用双螺杆挤出技术制备肠溶制剂,工艺简单、操作易行、可实现颗粒连续式生产,为肠溶制剂的制备提供了新思路.

The aim of this study was to prepare small-molecule camptothecin (CPT) prodrugs and evaluate their effectiveness in colorectal carcinoma therapy. Prodrug nanoparticles (NPs) were physicochemically characterized and evaluated for their cytotoxicity in human colon cancer (HCT116) cell lines. The antitumor efficacy of the NPs was evaluated in HCT116 tumor-bearing mice. The prepared NPs exhibited high drug loading capacity (32% of CPT w/w) and also kept a high active lactone fraction of CPT (>85%) during circulation. The NPs were internalized into tumor cells efficiently compared with free drug and significantly enhanced the drug's therapeutic efficacy. The developed small-molecule CPT prodrug NPs could be a promising strategy in the clinical therapy of colorectal carcinoma.

AIM:This work is to investigate the application characteristics of a new hot melt extrusion (HME) polymer (HME-grade hydroxypropyl methylcellulose, namely HPMC HME 15LV) in solid dispersion by HME.METHODS:Carbamazepine (CBZ) was chosen as the model drug. And two types of solid dispersion system was prepared by HME, that is, single carrier system which was composed of PVP VA64(VA64) or Soluplus (SOL), and binary carrier which was composed of HPMC HME 15LV and SOL. Phase analysis of the extrudates were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution, moisture absorption and thermal stability CBZ solid dispersion (CBZ-SD) were also investigated. In addition, the mechanism that affects the capsule dissolution was evaluated by the viscosity test and infiltration capability test.RESULTS:CBZ-SD was prepared by HME. DSC and PXRD results indicated that CBZ was amorphous in all solid dispersions. Unlike CBZ-SD powder with high dissolution, CBZ-SD capsules showed the variable gelatinization phenomenon during dissolution and different dissolution behaviors, which can be interpreted by the viscosity test and infiltration capacity test. Furthermore, compared with single carrier system, CBZ-SD made by binary carrier exhibited lower moisture absorption and better thermal stability, which is benefit to the long-term stability of CBZ-SD.CONCLUSION:HPMC HME 15LV, as a new HME carrier, has certain advantages in producing well CBZ-SD preparation. Its low viscosity can prevent the gelatinization phenomenon during capsule dissolution, as well as suitable Tg and low hygroscopicity were also benefit to the stability of CBZ-SD.