植物甾醇油酸酯的制备及其在负载虾青素的脂质体中的应用

为了探索植物甾醇酯构建脂质体的可行性,以植物甾醇和油酸为原料合成植物甾醇油酸酯并进行分离纯化,运用红外光谱法和核磁共振法对植物甾醇油酸酯进行表征。以大豆磷脂为主要膜材,运用薄膜-超声法构建虾青素-植物甾醇油酸酯复合脂质体,并对其粒径大小及分布、Zeta电位、包封率以及微观形貌性质进行研究。结果表明：制备的植物甾醇油酸酯经分离纯化后纯度为(96.51±0.93)%,构建的虾青素-植物甾醇油酸酯复合脂质体近似球形,形状规则且分散性好,平均粒径为(124.0±12.5)nm,多相分散系数(PDI)为0.37±0.01,平均Zeta电位为(-33.3±1.6)mV,包封率为(93.95±0.92)%。综上,采用植物甾醇油酸酯负载虾青素,包封率高,制备的复合脂质体稳定,分布均一,说明植物甾醇油酸酯可应用于负载脂溶性生物活性物质的脂质体的构建。     

Molecular Radiotherapy with 177Lu-Immunoliposomes Induces Cytotoxicity in Mesothelioma Cancer Stem Cells In Vitro

Malignant mesothelioma (MM) is a lethal tumor originating in the mesothelium with high chemotherapeutic resistance. Cancer stem cells (CSCs) persist in tumors and are critical targets responsible for tumor resistance and recurrence. The identification and characterization of CSCs may help develop effective treatment for MM. The objective of this study was to evaluate the therapeutic effect of molecular targeted radiotherapy by ¹⁷⁷Lu-labeled immunoliposomes (¹⁷⁷Lu-ILs) on CSCs of mesothelioma. MM CSCs were sorted based on CD26/CD24 expression level and their functional significances were established by small interference RNA. CSC potential of MM was evaluated for drug resistance, cell invasion, and cell growth rate in vitro. CSC metabolism was evaluated with the uptake of ¹⁸F-FDG. Therapeutic effects of ¹⁷⁷Lu-labeled immunoliposomes targeting CD26 and CD24 were evaluated in vitro through proliferation and apoptotic assays. CSCs sorted from H28 cells exhibited significant drug resistance and enhanced proliferative activity as well as increased metabolism indicated by higher ¹⁸F-FDG uptake. Treatment with ¹⁷⁷Lu-ILs, compared with ¹⁷⁷Lu-CL and ILs, showed enhanced therapeutic effects on inhibition of proliferation, up-regulation of apoptosis, and suppression of CD26 and CD24 expression. Thus, our results suggest that molecular radiotherapy targeting both CD26 and CD24 could be a promising approach for CSC-targeting therapy for MM.     

荞麦糖肽脂质体的制备及其稳定性和缓释研究

为提高荞麦糖肽(buckwheat glycopeptide,BG)的生物利用率,本研究首先对制备所得的BG进行稳定性分析,随后利用反向蒸发法制备荞麦糖肽脂质体(buckwheat glycopeptide liposomes,BGL),经响应面试验对包埋工艺进行优化,并探究其稳定性、体外缓释特性、α-葡萄糖苷酶(α-glucosidase,AGase)抑制活性和抗氧化活性。结果表明：温度(20~80 ℃)对BG的活性影响较小,碱性条件下BG极易失活。从五种磷脂中筛选出蛋黄卵磷脂制备BGL,响应面优化工艺条件为磷脂与胆固醇质量比为4.2:1,脂药比为7.5:1,水相体积为1 mL,此条件下,BGL包埋率为72.64%。BGL对高温(100 ℃)环境不耐受,在短时间(1 h)内具有广谱pH(2~10)稳定性,反复冻融5次对其渗漏率无显著影响(P＞0.05)。BGL在体外模拟胃、肠体系中表现出良好的缓释特性,24 h累计释放速率分别为（84.50±2.30）%和（60.17±1.42）%。脂质体包埋体系的建立有利于提高BG的稳定性,并对其AGase抑制和抗氧化活性表现出良好的保护作用,为荞麦糖肽脂质体开发应用提供理论依据。     

被动靶向药物载体的研究进展

近年来,为了提高药物载体的靶向性,国内外进行了广泛研究,被动靶向给药系统已成为给药系统研究的热点.主要介绍了被动靶向给药系统的机理、重要性及几种典型的被动靶向制剂,并对被动靶向药物载体:脂质体、毫微粒、乳剂、微泡的优缺点进行了详细的分析,提出了被动靶向制剂的发展趋势和前景.     

Design,preparation, and evaluation of liposomal gel formulations for treatment of acne: in vitro and in vivo studies

The study highlights the significance of co-application of bioactive components into liposomal gel formulations and their comparison to azithromycin for treatment of Acne. A Design of Experiments (DoE) approach was utilized to obtain optimized liposomal formulation encapsulating curcumin, with size and zeta potential of ～100?nm and ～14?mV, respectively, characterized by DLS, HR-TEM, FESEM, and AFM. The curcumin liposomal dispersion depicted excellent stability over the period of 60?days, which was further converted in gel form using Carbopol. Pharmacokinetics of curcumin-loaded liposomal gel showed that T_max for curcumin was achieved within 1?h of post application in both stratum corneum and skin, indicating quick penetration of nano-sized liposomes. Stratum corneum depicted C_max of 688.3?ng/mL and AUC_0-t of 5857.5?h?×?ng/mL, while the skin samples displayed C_max of 203.3?ng/gm and AUC_0-t of 2938.1?h?×?ng/gm. Lauric acid and azithromycin liposomal gel formulations were prepared as per the optimum parameters obtained by DoE. In antibacterial activity using agar diffusion assay, lauric acid gel formulation revealed ～1.5 fold improved antibacterial effect than curcumin gel formulation. Interestingly, their co-application (1:1) exhibited significantly enhanced antibacterial effect against both macrolide-sensitive (1.81 versus 1.25 folds) and resistant strains of P. acnes (2.93 versus 1.22 folds) than their individual counterparts. The in vivo studies in rat ear model displayed a ～2 fold reduction in comedones count and cytokines (TNF-α and IL-1β) on co-application with curcumin and lauric acid liposomal gel compared to placebo treated group.     

Targeting Fibronectin to Overcome Remyelination Failure in Multiple Sclerosis: The Need for Brain- and Lesion-Targeted Drug Delivery

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease with unknown etiology that can be characterized by the presence of demyelinated lesions. Prevailing treatment protocols in MS rely on the modulation of the inflammatory process but do not impact disease progression. Remyelination is an essential factor for both axonal survival and functional neurological recovery but is often insufficient. The extracellular matrix protein fibronectin contributes to the inhibitory environment created in MS lesions and likely plays a causative role in remyelination failure. The presence of the blood–brain barrier (BBB) hinders the delivery of remyelination therapeutics to lesions. Therefore, therapeutic interventions to normalize the pathogenic MS lesion environment need to be able to cross the BBB. In this review, we outline the multifaceted roles of fibronectin in MS pathogenesis and discuss promising therapeutic targets and agents to overcome fibronectin-mediated inhibition of remyelination. In addition, to pave the way for clinical use, we reflect on opportunities to deliver MS therapeutics to lesions through the utilization of nanomedicine and discuss strategies to deliver fibronectin-directed therapeutics across the BBB. The use of well-designed nanocarriers with appropriate surface functionalization to cross the BBB and target the lesion sites is recommended.     

Mechanism-Based Sonodynamic–Chemo Combinations against Triple-Negative Breast Cancer

Due to its noninvasive nature, site-confined irradiation, and high tissue penetrating capabilities, ultrasound (US)-driven sonodynamic treatment (SDT) has been proven to have broad application possibilities in neoplastic and non-neoplastic diseases. However, the inefficient buildup of sonosensitizers in the tumor site remarkably impairs SDT efficiency. The present work proposes a deep-penetrating sonochemistry nanoplatform (Pp18-lipos@SRA737&DOX, PSDL) comprising Pp18 liposomes (Pp18-lipos, Plipo), SRA737 (a CHK1 inhibitor), and doxorubicin (DOX) for the controlled formation of reactive oxygen species (ROS) and release of DOX and SRA737 upon US activation, therefore increasing chemotherapeutic effectiveness and boosting SDT efficacy. Therein, the antitumor activities of DOX have been attributed to its intercalation into the nucleus DNA and induction of cell apoptosis. CHK1 evolved to respond to DNA damage and repair the damage via cell cycle progression. SRA737 is a potent and orally bioavailable clinical drug candidate for inhibiting CHK1, demonstrating adjuvant anticancer effect in vitro and in vivo. It was interesting to find that SRA737 carried into Plipo@DOX could significantly alleviate G2/M cell cycle arrest and aggravate DNA double-strand injuries, resulting in significant cell death. The developed US-switchable nanosystem provides a promising strategy for augmenting sono-chemotherapy against breast cancer controllably and precisely.     

Interaction Between VLDL and Phosphatidylcholine Liposomes Generates New γ-LpE-like Particles

One of the subfractions of HDL involved in reverse cholesterol transport is γ-LpE. It has been assumed that, like preβ-LpAI, it can be generated during the interaction between phosphatidylcholine liposomes and lipoproteins and can contribute to more efficient cholesterol efflux after the introduction of liposomes to plasma. However, there has been no evidence concerning what the sources of these particles in plasma might be. Here, we determined whether the interaction of phosphatidylcholine liposomes with VLDL and the subsequent conversions of particles could be a source of new γ-LpE particles. We found that the interaction between liposomes and VLDL affected its lipid and protein composition. The content of phospholipids increased (~96 %) while the content of free cholesterol and apolipoprotein E decreased in VLDL during the reaction with liposomes (~100 and ~24 %, respectively). New particles which did not contain apolipoprotein B were generated. Heterogeneous HDL-sized populations of particles were generated, containing phospholipids and apolipoprotein E as the sole apolipoprotein, with densities from 1.063 to 1.21 g/ml, either with γ-mobility on agarose gel and Stokes diameters from 8.58 to 22.07 nm or with preβ-mobility and Stokes diameters from 9.9 to 21.08 nm. The obtained results contribute to the understanding of changes in lipoproteins under the influence of phosphatidylcholine liposomes, showing the formation of new (γ-LpE)-like and (preβ-LpE)-like particles, similar in mobility and size to plasma HDL-LpE. These newly generated particles can claim a share of the antiatherogenic effects of liposomes, observed in studies both in vitro and in vivo.     

Antioxidative activities of tocotrienols on phospholipid liposomes

Antioxidative activity of tocotrienol (Toc3) was studied in the oxidation of dilinoleoylphosphatidylcholine (DLPC) liposomes. The objective was to measure the differences in the antioxidative activities betweenα-Toc3 andα-tocopherol (α-Toc), and betweenγ-Toc3 andγ-Toc. When each antioxidant was added to the already prepared DLPC liposome solution, the antioxidative activity of Toc3 was larger than that of Toc. However, when incorporated into the liposomal membrane, the antioxidative activities of Toc3 and Toc were the same and were intermediate between those of the added Toc3 and Toc. When added to the liposome solution, the consumption of Toc3 during the induction period was larger than that of Toc. When incorporated into the liposomal membrane, the consumptions of Toc3 and Toc were the same and were intermediate between those of the added Toc3 and Toc. These results suggest that the reactions of Toc3 and Toc with phospholipid peroxide within the membrane are inhibited to a different degree depending on the dosing manner of Toc3 and Toc. Namely, the degree of inhibition decreases in the following order: Toc(added)> Toc(incorporated)= Toc3(incorporated)> Toc3(added).