To address the need for topical therapies with enhanced skin penetration and retention for infantile atopic dermatitis (AD), we screened esculetin (Esc), an active monomer from traditional Chinese medicine, in a cellular AD model. Esc demonstrated pronounced anti-inflammatory activity. Subsequently, a self-assembled nanogel delivery system, Esc@(HAP/PSI)-gel, was engineered using hydroxyapatite (HAP) and polysuccinimide (PSI) for sustained release. The optimized nanoparticles were spherical (Average diameter: 156 nm, zeta potential: −15.7 mV) with pH-responsive drug release. Compared with Esc-gel, Esc@(HAP/PSI)-gel significantly enhanced skin permeation and drug retention without inducing irritation. In AD mice, Esc@(HAP/PSI)-gel alleviated skin lesions, reduced ear swelling, lowered the spleen index, attenuated epidermal/dermal thickening, suppressed inflammatory cell infiltration, and modulated key cytokines (IL-6, TNF-α, IgE) more effectively than Esc-gel. Hence, the HAP/PSI-based nanogel delivery system enables the efficient and sustained delivery of Esc, enhances transdermal absorption, and demonstrates considerable therapeutic potential for AD.

To mitigate the dose-limiting toxicity of gemcitabine (GEM) in lung cancer therapy, we developed a targeted hyaluronic acid (HA)-based nanoplatform with sustained drug-release capabilities-GEM@HA-(HAP/PSI). The system consisted of a hydroxyapatite/polysuccinimide (HAP/PSI) composite core for efficient drug loading, with surface-conjugated HA serving as a CD44-targeting ligand. Following systematic optimization using response surface methodology, the resulting spherical nanoparticles (∼100-200 nm) exhibited pH-responsive drug release, good biocompatibility, and negligible hemolytic activity. In vitro studies using CD44-high A549 and CD44-low H358 cells confirmed that CD44-mediated active endocytosis was the predominant uptake pathway for the nanoplatform. Treatment with the optimized formulation (GEM@HA-(HAP/PSI)10) led to significantly greater cytotoxicity, inhibition of cell migration and colony formation, and apoptosis induction than treatment with a non-targeted control formulation. Importantly, in A549 xenograft mouse models, GEM@HA-(HAP/PSI)10 achieved superior tumor growth suppression relative to free GEM while also maintaining a favorable safety profile. Collectively, these findings indicate that the HA-targeted nanoplatform developed in this study enhances the precision and therapeutic efficacy of GEM delivery and holds promise for reducing its systemic toxicity.

To mitigate the adverse effects of doxorubicin (DOX) during the treatment of liver cancer, this study aimed to develop a novel DOX-encapsulated active-targeted nanodelivery system. The auxiliary materials hydroxyapatite (HAP), polysuccinimide (PSI), galactose-modified polyethylene glycol (Gal-PEG), PSI covalently linked with three different mole ratios of polyethylene glycol (PEG-PSIs), and galactose covalently linked with PEG-PSIs (Gal-PSIs) were synthesized and structurally characterized. The Box-Behnken and Three-Level Factorial Design response surface methodologies were employed to optimize the formulations and synthesis protocols for DOX@HAP/PSI (DOX@DC, where DC denotes the drug carrier), DOX@PEG-DCs, and DOX@Gal-DCs. The in vitro drug release and in vivo tissue distribution of each formulation were examined. Furthermore, in vitro studies were conducted to examine the effects of these formulations on the proliferation, apoptosis, and migration of Huh-7 liver cancer cells. The formulations and synthesis protocols for different DOX-based preparations were optimized. All nanoparticles gradually released DOX at pH levels >5, with the release rate increasing with the pH value. Among the tested formulations, DOX@Gal-DC20 (mole ratio of Gal-PEG to PSI = 1:20) showed the best hepatic targeting in mice in vivo. Furthermore, in vitro pharmacodynamic experiments indicated that Gal-DC20 had low cytotoxicity, could be taken up by cancer cells, and could significantly inhibit the proliferation of Huh-7 cells. Hemolysis experiments confirmed that none of the prepared formulations induced hemolysis. The novel nanodelivery system established in the study (DOX@Gal-DC) is simple to prepare and shows significant hepatic targeting.

Gene therapy offers an ideal potential treatment strategy for osteoarthritis (OA). However, the safe and efficient delivery of therapeutic genes remains highly challenging because of the inactivation in direct delivery of miRNA, low transfection efficiency, and a short half-life. This study introduced a gene therapy strategy using mesenchymal stem cells (MSCs) as a gene delivery platform and achieved the sustained delivery of therapeutic genes via engineered MSCs-derived extracellular vesicles (EVs). The miRNA-874-3p is combined with an exosome-targeting motif and transfected into bone marrow mesenchymal stem cells (BMSCs). The BMSCsmotif+miR874 are then seeded onto hydrogel microspheres, creating the BMSCmotif+miR874/MS system for OA treatment. In vitro experiments demonstrated that miRNA-874-3p not only alleviated inflammation and oxidative stress-induced damage to chondrocytes by downregulating the NF-κB signaling pathway, thereby rejuvenating chondrocytes, but also promoted chondrogenesis in the inflammatory microenvironment. Furthermore, the engineered BMSCs in the system demonstrated prolonged retention in vivo, thereby enabling the sustained delivery of the therapeutic gene, miRNA-874-3p, over an extended duration. In the rat OA model, BMSCmotif+miR874/MS successfully delivered miRNA-874-3p to the articular cartilage and effectively alleviated cartilage degeneration. In conclusion, this EVs-mediated therapeutic gene delivery approach enables miRNA-based gene therapy a viable alternative to surgery for OA treatment and provides a novel option for gene therapy.

In the original publication [...].

In this study, a nano drug delivery system for sustained release (PSI-HAP) with spherical or near-spherical particles and a negative zeta potential was established. PSI-HAP was prepared using polysuccinimide (PSI) as the coating material and hydroxyapatite (HAP) as the drug adsorption core. By simply mixing PSI and HAP in solution, uniformly size non-agglomerated nanoparticles could be generated rapidly via a facile preparation process. Herein, HAP was prepared using the micro-emulsion method (MEM), liquid phase reaction (LPR), precipitation method (PM), or hydrothermal method (HM). The effects of the HAP preparation process on PSI-HAP were investigated. The optimal formulations and preparation processes of PSI-HAP were determined using single-factor experiments and the Box-Behnken design (BBD) response surface method with different model drugs. Additionally, the drug-loading and release features of PSI-HAP preparations were measured, and the distribution of SCE-PSI-HAP (Schisandra chinensis extract, SCE) in vivo was determined. The in vitro drug release test showed that PSI-HAPs were pH-sensitive, showing complete drug release around pH 7. Meanwhile, in vivo experiment demonstrated that in animals, the retention time was significantly longer in the SCE-PSI-HAP preparation group than in the saline group, irrespective of whether the formulation was administered orally or injected. The findings showed that the proposed drug delivery system is easy to prepare and sterilize, making large-scale production feasible, which could be used clinically for multi-modal drug delivery. In this study, a nano drug delivery system for sustained release (PSI-HAP) with spherical or near-spherical particles and a negative zeta potential was established.

In this study, a nano drug delivery system for sustained release (PSI-HAP) with spherical or near-spherical particles (100–200 nm) and a negative zeta potential was established. PSI-HAP was prepared using polysuccinimide (PSI) as the coating material and hydroxyapatite (HAP) as the drug adsorption core. By simply mixing PSI and HAP in solution, uniformly size non-agglomerated nanoparticles could be generated rapidly via a facile preparation process. Herein, HAP was prepared using the micro-emulsion method (MEM), liquid phase reaction (LPR), precipitation method (PM), or hydrothermal method (HM). The effects of the HAP preparation process on PSI-HAP were investigated. The optimal formulations and preparation processes of PSI-HAP were determined using single-factor experiments and the Box-Behnken Design (BBD) response surface method with different model drugs. Additionally, the drug-loading and release features of PSI-HAP preparations were measured, and the distribution of SCE-PSI-HAP in vivo was determined. The in vitro drug release test showed that PSI-HAPs were pH-sensitive, showing complete drug release around pH 7. Meanwhile, in vivo experiment demonstrated that in animals, the retention time was significantly longer in the SCE-PSI-HAP preparation group than in the saline group, irrespective of whether the formulation was administered orally or injected. The findings showed that the proposed drug delivery system is easy to prepare and sterilize, making large-scale production feasible. PSI-HAP could be used clinically for multi-modal drug delivery and may also find use as a slow-release carrier for pesticides and fertilizers in green agriculture.

物理化学靶向制剂具有定向给药、药物生物利用度高、毒副作用低等优点,是靶向药物递送系统研究中的重要方向之一.充分了解物理化学靶向制剂的研发现状,有助于设计出更合理高效的递送系统.因此,本文对 2017-2022 年包括磁性靶向制剂、热敏靶向制剂、pH敏感靶向制剂和栓塞靶向制剂在内的4 种物理化学靶向制剂的研发进展进行了综述.

Tanshinol (Tan) has good therapeutic effects on osteoporosis, fracture, and bone trauma repair. However, it is easily oxidised, has low bioavailability and a short half-life. To solve these problems, the study aimed to develop a novel bone-targeted nano-sustained-release drug delivery system PSI-HAPs for the systemic administration of Tan. This proposed system has hydroxyapatite (HAP) as the core to load drug and polysuccinimide (PSI), PEG-PSI (Polyethylene glycol, PEG), and ALN-PEG-PSI (Alendronate sodium, ALN) as the coating materials to form nanoparticles. The article examines the various PSI-HAPs' entrapping efficiency (EE, %), drug loading capacity (DLC, %), and distribution to determine the best PSI-HAP formulation in vivo. The in vivo experiment showed that the ALN-PEG-PSI-HAP (ALN-PEG/PSI molar ratio = 1:20) was the best preparation due to its higher distribution on bone (120 h) and lower distribution in the other tissues. The determined preparation was a uniformly spherical or sphere-like nanoparticle with a negative zeta potential. Additionally, it exhibited pH-sensitive drug release in PBS based on an in vitro drug release test. The proposed PSI-HAP preparations were prepared in the water solution using a facile preparation process without ultrasound, heating, and other conditions, which can significantly affect the stability of drugs.

近年来,聚乙二醇(Polyethylene glycol,PEG)作为一种高分子化合物广泛应用于生物医药等领域,具有不错的发展前景.PEG修饰技术(PEGylation)是药物研究中里程碑式的创新,并已从实验室研究阶段走入了临床应用.本文简要介绍了PEG的生理化学特性和PEG修饰技术,并对近年来PEG修饰技术在药物研究领域的应用与研究进展,以及在临床应用中所遇到的困境,解决方案进行综述,为PEG修饰技术的研究提供参考.

目的 探讨纳米氧化镍(Nano NiO)亚慢性染毒对雄性SD大鼠内分泌功能的影响,并分析其对睾丸细胞毒作用与机制.方法 将无特定病原体级雄性SD大鼠随机分为5组,每组10只.采用非暴露式气管滴注法染毒,低、中、高剂量组大鼠分别予质量浓度为0.16、0.80、4.00g/L的Nano NiO混悬液,空白对照组大鼠予等体积0.9％氯化钠溶液,阳性对照组大鼠予质量浓度为4.00 g/L的微米氧化镍混悬液,每3天滴注1次,持续9周.染毒结束后,采用原子荧光光谱法测定血液和睾丸组织中镍的水平,采用酶联免疫吸附实验检测血清性激素水平,采用流式细胞术分析睾丸细胞倍体比值、细胞周期和细胞凋亡率,采用蛋白质印迹法检测睾丸组织中凋亡相关蛋白相对表达水平.结果 阳性对照组与3个剂量组大鼠血液和睾丸组织中镍水平均高于空白对照组(P值均＜0.05);中、高剂量组大鼠血液和睾丸组织中镍水平均高于阳性对照组(P值均＜0.05);血液与睾丸组织中镍水平呈正相关(P＜0.01).中、高剂量组大鼠血清睾酮、卵泡刺激素(FSH)和黄体生成素(LH)水平均低于空白对照组(P值均＜0.05);但各组大鼠血清促性腺激素释放激素水平比较,差异无统计学意义(P＞0.05).与空白对照组比较,中、高剂量组睾丸生殖细胞单倍体、二倍体细胞构成比和G0/G1期、S期细胞比值均下降(P值均＜0.05),睾丸细胞四倍体细胞构成比、G2/M期细胞比值和早期凋亡率均增加(P值均＜0.05).与空白对照组比较,中、高剂量组大鼠睾丸组织中B淋巴细胞瘤-2(BCL-2)蛋白相对表达水平和BCL-2/BCL-2相关X蛋白(BAX)比值均下降(P值均＜0.05),BAX和半胱氨酸天冬氨酸蛋白酶-3蛋白相对表达水平均升高(P值均＜0.05).与阳性对照组比较,高剂量组大鼠血液和睾丸组织中镍水平均升高(P值均＜0.05),睾丸细胞单倍体构成比和G0/G1期、S期比值以及睾丸组织中BCL2/BAX比值均下降(P值均＜0.05),四倍体构成比、G2/M期比值和睾丸细胞早期凋亡率、总凋亡率均升高(P值均＜0.05).结论 一定剂量的Nano NiO染毒可抑制雄性大鼠睾酮、FSH和LH的分泌;并可穿过血睾屏障,干扰睾丸细胞的增殖,通过线粒体凋亡途径诱导睾丸细胞凋亡,抑制单倍体精子细胞的形成,导致生精过程发生障碍.

目的 探讨基于PBL的对话教学模式在《社区预防与保健》课程中的教学效果,为基于PBL的对话教学模式的研究提供借鉴.方法 于2019年9-12月采用随机数字表将牡丹江医学院2015级全科医学专业131名学生采用随机数字表法随机分为对照组(63人)和研究组(68人).对照组采用传统的讲授式授课,研究组采用基于PBL的对话教学模式.课程结束后采用相同试卷考核且采用问卷调查评价教学效果、教学满意度、教学内容是否体现全科医学思维等.结果 研究组的理论考试成绩、实践技能考试成绩和总成绩均高于对照组(均P＜0.05);研究组对教学有助于培养全科医学思维与能力,培养临床预防服务的思维,增强临床筛检能力,以人群为基础的社区问题独立思考和分析处理能力,培养三级预防策略思维与能力,促进同学间的交流、沟通,增强团队合作等方面的评价优于对照组(均P＜0.05);研究组学生对教学方法的满意率为73.53％,对照组为53.97％,研究组对教学内容能体现全科医学思维的以健康为中心、群体为对象、个体群体兼顾的医疗,三级预防为导向的循证医疗,以家庭为单位的保健项目横向管理,慢性病管理的综合社区预防保健的评价优于对照组(均P＜0.05).结论 基于PBL的对话教学模式可以有效提高《社区预防与保健》课程的教学效果,激发全科学生了解基层卫生的兴趣,有利于学生全科医学思维与实践能力的培养.

Lung cancer seriously threatens the health of human beings, with non-small cell lung cancer (NSCLC) accounting for 80%. Nowadays, the potential position of nano-delivery in treating cancer has been the subject of continuous research. The present research aimed to prepare two molecular weight hyaluronic acid (HA)-modified kaempferol (KA)-loaded nanostructured lipid carriers (HA-KA-NLCs) by the method of melting ultrasonic and electrostatic adsorption, and to assess the antitumor effect of the preparations on A549 cells. The characterization and safety evaluation of the preparations illustrated that they are acceptable for drug delivery for cancer. Subsequently, differential scanning calorimetry (DSC) curve and transmission electron microscopy (TEM) images indicated that the drug was adequately incorporated in the carrier, and the particle appeared as a sphere. Moreover, HA-KA-NLC showed predominant in vitro antitumor effects, inhibiting proliferation, migration, and invasion, promoting apoptosis and increasing cellular uptake of A549 cells. Otherwise, the Western blot assay revealed that preparations could activate epithelial-mesenchymal transition (EMT)-related signaling pathways and modulate the expression of E-cadherin, N-cadherin, and Vimentin in A549 cells. Our present findings demonstrated that HA-KA-NLC could be considered as a secure and effective carrier for targeted tumor delivery and may have potential application prospects in future clinic therapy of NSCLC.

目的:优选参附滴丸的成型工艺.方法:采用单因素法分别考察了基质种类、参附提取物与基质的配比、熔融温度、冷却剂的种类、冷却柱的高度及冷却剂的温度对滴丸质量的影响,要满足2020版《中华人民共和国药典》规定的滴丸外观、重量差异、溶散时限的要求;在单因素研究基础上再选取熔融温度、冷却剂温度、参附提取物与基质的配比三个主要因素进行Box-Behnken响应面实验,以滴丸的质量变异系数、外观评价、溶散时限作为评价指标.结果:单因素考察显示选用聚乙二醇4000和聚乙二醇6000混合基质、参附提取物与聚乙二醇比例在1:2和1:3、熔融温度控制在80～100℃、冷却剂选择二甲基硅油、冷却柱的高度为40 cm、冷却剂的温度在10～20℃时制成的滴丸质量更好;Box-Behnken响应面实验结果显示参附提取物与聚乙二醇基质配比为1:2.5、熔融温度为90℃、冷却剂温度为15℃时参附滴丸成型效果较好.结论:Box-Behnken响应面法能够对原料液与基质的配比、熔融温度、冷却剂温度三个因素进行连续分析,找到最优化条件,故可用于参附滴丸成型工艺的优化,该工艺条件温和,适合工业化生产.

目的：优选参附汤的提取工艺条件，从而得到优质的参附汤的工艺。方法：选取水的用量、提取时间和提取次数3个因素，每个因素选取三个水平进行正交试验，以人参皂苷Re、乌头碱的含量以及浸膏得率为评定指标，用加权综合评分的方法筛选最佳工艺。结果：最佳工艺条件为水的用量为18倍，用水量单位不应该是克吗，如果是什么的18倍写清楚是参照哪个标准水量的18倍，不然很容易误解，提取时间为30min，提取次数为3。结论：该方法提取的参附汤合理可行，能有效提高活性成分提取率。

目的 本实验开发了多种人参总皂苷糖果制剂,为人参功能性产品市场增加新品种.方法 采用紫外分光光度法建立人参总皂苷糖果制剂质量检测标准.确定了压制糖果、硬糖和软糖的处方与制备工艺.以外观、硬度、干燥失重等作为考察指标,对人参总皂苷糖果制剂相关质量进行了检测.结果 人参总皂苷在235 nm处有最大吸收,浓度在0.0244～0.1920 mg/ml浓度范围内线性关系良好.所制备的不同种类糖果制剂外观、硬度、干燥失重等各项指标均符合要求.结论 本研究开发的人参总皂苷糖果制剂丰富了现有市场剂型.

羟基磷灰石是天然骨组织中无机质的主要成分,具有良好的生物相容性、亲和性及生物降解性.被广泛地用于骨组织替代材料、整形和整容外科材料,是一种无毒、无致癌、无副作用的生物活性材料.近年来,基于纳米羟基磷灰石颗粒的新型药物传递载体在药学研究领域十分活跃.因此,本文就近年来纳米级羟基磷灰石材料的常用制备方法及在不稳定药物传递系统方面的应用进行总结归纳.

阿德福韦酯是开环膦酸核苷酐类抗病毒药物,是阿德福韦的酯类前体药物,具有广谱的抗病毒活性.阿德福韦酯合成工艺中的酯化反应,质量不稳定,收率较低.在现有合成工艺路线文献报道的基础上,通过对反应温度、 反应时间、 投料比等因素的研究,重新优化合成工艺,并进行质量控制.采用正交设计法,重点考察反应温度(A)、 投料比(B)、 反应时间(C)3个因素对阿德福韦酯酯化反应的影响.通过实验研究,确定了阿德福韦酯酯化反应的最佳工艺条件为A2B1C1,提高了产品质量和收率.

目的 优选参附滴丸的最佳成型工艺.方法 选取基质的种类(A)、参附提取物与基质的配比(B)、溶药箱的温度(C)、冷却剂的温度(D)四个主要影响因素进行正交试验,以滴丸的质量变异系数、圆整度、溶散时限作为评价指标进行评价.结果 参附提取物与聚乙二醇4000按照1:1的比例在80℃条件下熔融,在温度为15℃的冷却箱中冷凝形成的参附滴丸成型效果较好.结论 该工艺可用于优化参附滴丸的生产.

目的 本文拟制备柠檬提取物泡腾制剂,用以防治龋齿的发生.方法 建立紫外分光度法,用于柠檬提取物含量测定;通过单因素考察与正2交实验设计,对柠檬提取物泡腾片辅料种类及用量进行考察;根据外观、硬度、脆碎度、重量差异等质量标准确定柠檬提取物泡腾片的最终处方及制备工艺并进行相关质量检测.结果 柠檬提取物在295 nm有最大吸收波长,2.0～8.0 mg/mL浓度范围内线性关系良好;最终确定了柠檬提取物泡腾剂处方及制备工艺,所制备的柠檬提取物泡腾片各项指标均符合质量标准.结论 本文成功制备了柠檬提取物泡腾制剂符合药典规定和相应标准,使用方便,便于储存与携带.