BACKGROUND & AIMS: :The development of synthetic gene carriers has recently received much attention; however, they might lack the ability to control the transgene expression. The use of external stimuli for enhancement of the transgene expression may be a promising approach for the site-directed transfection in vivo. In this regard, a new technology of "photochemical internalization (PCI)" has recently been reported, in which the endosomal escape of gene carriers is assisted by photodamage of the endosomal membrane with co-incubating photosensitizers. To apply this technology for systemic gene delivery, the development of appropriate carrier systems for both the plasmid DNA (pDNA) and photosensitizer is of crucial importance. Also, the photocytotoxicity accompanied by the photochemical enhancement of the gene expression may need to be reduced. In this study, the combinational formulation of polymeric micelles incorporating pDNA and a dendrimer-based photosensitizer (DP) (dendrimer phthalocyanine (DPc)) was applied in the PCI-mediated transfection in vitro and then, estimating its potential utility for in vivo applications. The PCI using the polymeric micelle system achieved a remarkable photochemical enhancement of the transgene expression while maintaining an approximate 80% cell viability over a wide range of the DPc concentrations and light doses. Thus, this system may be promising for in vivo PCI-mediated gene delivery.

背景与目标： : 合成基因载体的发展最近受到了广泛关注; 但是，他们可能缺乏控制转基因表达的能力。使用外部刺激来增强转基因表达可能是体内定点转染的有前途的方法。在这方面，最近报道了一种 “光化学内在化 (PCI)” 的新技术，其中基因载体的内体逃逸是通过与共同孵育的光敏剂对内体膜的光损伤来辅助的。为了将该技术应用于系统基因传递，为质粒DNA (pDNA) 和光敏剂开发合适的载体系统至关重要。此外，可能需要降低伴随着基因表达的光化学增强的光细胞毒性。在这项研究中，结合了pDNA和基于树状大分子的光敏剂 (DP) (树状大分子酞菁 (DPc)) 的聚合物胶束的组合配方在体外PCI介导的转染中应用，然后估计其在体内应用的潜在效用。使用聚合物胶束系统的PCI实现了转基因表达的显著光化学增强，同时在广泛的DPc浓度和光剂量范围内保持近似80% 的细胞活力。因此，该系统可能有望用于体内PCI介导的基因递送。

BACKGROUND & AIMS: :The objective of this study was to investigate if the increase in apparent solubility induced by liposomalization or micellization of the poorly soluble drug hydrocortisone (HC) would lead to an enhancement of its permeability through biological membranes. For this purpose phosphatidylcholine liposome formulations as well as d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) micelle dispersions and polyvinylpyrrolidone (PVP) supersaturated solutions were prepared in order to increase the apparent solubility of HC. Both the apparent solubility of hydrocortisone (i.e. amount of drug entrapped plus non-entrapped in the carriers) as well as the concentration of molecularly dissolved drug (i.e. fraction non-entrapped into carriers, truly molecularly dissolved fraction) were characterized. Subsequently, the permeability of hydrocortisone was assessed for each type of formulation using the in vitro sheep nasal mucosa permeability assay. In all formulations where solubilizing agents are present, an enhanced flux of HC (compared to the pure drug powder suspension) is observed. The expected linear correlation between apparent solubilities and fluxes was not found, whereas, the concentrations of molecularly dissolved HC were found to be directly proportional to the respective fluxes. This is an experimental proof for the hypothesis that, of all the strategies to increase the apparent solubility of poorly soluble drugs, enhancement of the molecularly dissolved drug concentration (induction of true supersaturation) would lead to better permeation though membranes.

背景与目标： : 这项研究的目的是研究由难溶性药物氢化可的松 (HC) 的脂质体化或胶束化引起的表观溶解度的增加是否会导致其通过生物膜的渗透性增强。为此目的，制备磷脂酰胆碱脂质体制剂以及d-α-生育酚聚乙二醇1000琥珀酸酯 (TPGS) 胶束分散体和聚乙烯吡咯烷酮 (PVP) 过饱和溶液，以增加HC的表观溶解度。表征了氢化可的松的表观溶解度 (即被捕获的药物的量以及未捕获的药物在载体中的浓度) 以及分子溶解的药物的浓度 (即未捕获到载体中的组分，真正的分子溶解的组分)。随后，使用体外绵羊鼻粘膜通透性测定法评估每种制剂的氢化可的松通透性。在存在增溶剂的所有制剂中，观察到HC的通量增加 (与纯药物粉末悬浮液相比)。未发现表观溶解度和通量之间的预期线性相关性，而发现分子溶解的HC的浓度与各自的通量成正比。这是对以下假设的实验证明: 在增加难溶性药物的表观溶解度的所有策略中，分子溶解药物浓度的增强 (真正的过饱和诱导) 将导致膜更好的渗透。

BACKGROUND & AIMS: :To improve the in vivo stability of poly(-caprolactone)-b-poly(ethylene glycol) (PCL-PEG)-based micelles and cargo retention by π-π stacking interactions, pendant aromatic rings were introduced by copolymerization of -caprolactone with benzyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate (TMC-Bz). It was shown that the incorporation of aromatic rings yielded smaller micelles (18-30 nm) with better colloidal stability in PBS than micelles without aromatic groups. The circulation time of i.v. injected micelles containing multiple pendant aromatic groups was longer (t½-α: ~0.7 h; t½-β: 2.9 h) than that of micelles with a single terminal aromatic group (t½ < 0.3 h). In addition, the in vitro partitioning of the encapsulated photosensitizer (meta-tetra(hydroxyphenyl)chlorin, mTHPC) between micelles and human plasma was favored towards micelles for those that contained the pendant aromatic groups. However, this was not sufficient to fully retain mTHPC in the micelles in vivo, as indicated by similar biodistribution patterns of micellar mTHPC compared to free mTHPC, and unequal biodistribution patterns of mTHPC and the host micelles. Our study points out that more detailed in vitro methods are necessary to more reliably predict in vivo outcomes. Furthermore, additional measures beyond π-π stacking are needed to stably incorporate mTHPC in micelles in order to benefit from the use of micelles as targeted delivery systems.

背景与目标： : 为了通过 π-π 堆积相互作用提高聚 (-己内酯)-b-聚 (乙二醇) (PCL-PEG) 基胶束的体内稳定性和货物保留率，通过 -己内酯与5-甲基-2-氧代-1的共聚引入了侧芳环，3-二恶烷-5-羧酸盐 (tmc-bz)。结果表明，与没有芳族基团的胶束相比，芳族环的掺入产生了更小的胶束 (18-30 nm)，在PBS中具有更好的胶体稳定性。静脉注射的流通时间注射的含有多个侧位芳族基团的胶束比具有单个末端芳族基团的胶束 (t½-α: ~ 0.7 h; t½-β: 2.9 h) 更长 (t½ < 0.3 h)。此外，包封的光敏剂 (间四 (羟基苯基) 氯，mTHPC) 在胶束和人血浆之间的体外分配有利于胶束，因为其中含有侧芳基团。然而，这不足以将mTHPC完全保留在体内胶束中，如与游离mTHPC相比，胶束mTHPC的生物分布模式相似以及mTHPC和宿主胶束的生物分布模式不均匀所表明的那样。我们的研究指出，更详细的体外方法对于更可靠地预测体内结果是必要的。此外，除了 π-π 堆积之外，还需要采取其他措施来稳定地将mTHPC掺入胶束中，以便受益于使用胶束作为靶向递送系统。

BACKGROUND & AIMS: :Herein we describe the synthesis of gold nanoparticles (Au-NPs) in presence of sulphonated imidazolium salts [1,3-bis(2,6-diisopropyl-4-sodiumsulfonatophenyl)imidazolium (L1), 1-mesityl-3-(3-sulfonatopropyl)imidazolium (L2) and 1-(3-sulfonatopropyl)imidazolium (L3)] in water and in a confinement environment created by reverse micelles (RMs). The Au-NPs were characterized-with an excellent agreement between different techniques-by UV-vis spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential. In homogeneous media, the Au-NPs interact with the imidazolium ring and the sulphonate groups were directed away from the NPs' surface. This fact is responsible for the Au-NPs' stability-over three months-in water. Based on the obtained zeta potential values we assume the degree of coverage of the Au-NPs by the imidazolium salts. In n-heptane/sodium 1,4-bis (2-ethylhexyl) sulfosuccinate (AOT)/water RMs, the Au-NPs formed in presence of sulphonated imidazolium salts present different patterns depending on the ligand used as stabilizer. Interestingly, the Au-NPs are more stable in time when the salts are present in AOT RMs (three weeks) in comparison with the same RMs system but in absence of ligands (less than an hour). Clearly, the sulphonated imidazolium salts are very effective Au-NPs stabilizers in a different medium and this generates a plus to be able to use them for multiple purposes.

背景与目标： : 在本文中，我们描述了在磺化的咪唑鎓盐 [1,3-双 (2,6-二异丙基-4-磺基苯基) 咪唑鎓 (L1) 存在下金纳米颗粒 (Au-NPs) 的合成，在水中以及由反向胶束 (RMs) 产生的限制环境中的1-三甲基-3-(3-磺基丙基) 咪唑 (L2) 和1-(3-磺基丙基) 咪唑 (L3)]。通过UV-vis光谱对Au-NPs进行了表征-在不同技术之间具有出色的一致性，透射电子显微镜 (TEM) 、动态光散射 (DLS) 和 ζ 电位。在均匀介质中，au-NPs与咪唑环相互作用，磺酸盐基团被引导远离np的表面。这一事实是Au-NPs在水中三个月内的稳定性的原因。基于获得的 ζ 电位值，我们假设咪唑对Au-NPs的覆盖程度盐。在正庚烷/钠1中，4-双 (2-乙基己基) 磺基琥珀酸酯 (AOT)/水RMs，在磺化咪唑盐存在下形成的Au-NPs根据用作稳定剂的配体呈现不同的模式。有趣的是，与相同的均方根系统相比，当盐存在于AOT均方根 (三周) 时，Au-NPs在时间上更稳定，但没有配体 (不到一小时)。显然，磺化的咪唑鎓盐在不同的介质中是非常有效的Au-NPs稳定剂，这产生了一个加号，能够将它们用于多种用途。

BACKGROUND & AIMS: :The effect of attractive interaction between heparin and Pluronic co-polymer, two important macromolecules in biomedical applications, on the micellar state of Pluronic co-polymer was characterized. By the addition of heparin, the critical micellization temperature (CMT) of Pluronic solution decreased, indicating that heparin promoted micellization. Also, the Pluronic micelles were associated by the action of heparin, and the degree of aggregation became more pronounced by increasing the heparin amount. The association among Pluronic micelles by heparin enhanced the efficiency of chemical cross-linking of di-acrylated Pluronic solution by photo-polymerization, as well as the physical gelation by micelle packing. Thus, heparin can act as a sensitive modulator of Pluronic micelles in addition to its biological functions.

背景与目标： : 表征了肝素和Pluronic共聚物 (生物医学应用中的两个重要大分子) 之间的有吸引力的相互作用对Pluronic共聚物的胶束状态的影响。通过添加肝素，Pluronic溶液的临界胶束化温度 (CMT) 降低，表明肝素促进了胶束化。此外，多元胶束通过肝素的作用而结合，并且通过增加肝素量而使聚集程度更加明显。肝素与Pluronic胶束之间的结合通过光聚合增强了二丙烯酸酯化Pluronic溶液的化学交联效率，以及通过胶束堆积的物理凝胶化。因此，肝素除了具有生物学功能外，还可以充当多元胶束的敏感调节剂。

BACKGROUND & AIMS: :Polymeric micelles are ideally suited to exploit the EPR effect, and they have been used for the delivery of a range of anticancer drugs in preclinical and clinical studies. NK012 is an SN-38-loaded polymeric micelle constructed in an aqueous milieu by the self-assembly of an amphiphilic block copolymer, PEG-PGlu(SN-38). The antitumor activity was evaluated in several orthotopic tumor models including glioma, renal cancer, stomach cancer, and pancreatic cancer. Two independent phase I clinical trials were conducted in Japan and the USA. In the preclinical studies, it was demonstrated that NK012 exerted significantly more potent antitumor activity with no intestinal toxicity against various orthotopic human tumor xenografts than CPT-11. In clinical trials, predominant toxicity was neutropenia. Non-hematologic toxicity, especially diarrhea, was mostly Grade 1 or 2 during study treatments. Total 8 partial responses were obtained. According to data of preclinical studies, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent. Clinical studies showed that NK012 was well tolerated and had antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing in patients with colorectal cancer in Japan and in patients with triple negative breast cancer and small cell lung cancer in the USA.

背景与目标： : 聚合物胶束非常适合利用EPR效应，并且已在临床前和临床研究中用于一系列抗癌药物的递送。NK012是通过两亲性嵌段共聚物peg-pglu (SN-38) 的自组装在水性环境中构建的SN-38-loaded聚合物胶束。在几种原位肿瘤模型中评估了抗肿瘤活性，包括神经胶质瘤，肾癌，胃癌和胰腺癌。在日本和美国进行了两项独立的I期临床试验。在临床前研究中，已证明NK012对各种原位人类肿瘤异种移植物具有比CPT-11明显更有效的抗肿瘤活性，而对肠道无毒性。在临床试验中，主要毒性是中性粒细胞减少症。非血液学毒性，尤其是腹泻，在研究治疗期间主要为1级或2级。共获得8个部分响应。根据临床前研究的数据，NK012显示出增强的分布和延长的SN-38释放可能是理想的癌症治疗，因为SN-38的抗肿瘤活性是时间依赖性的。临床研究表明，NK012具有良好的耐受性，并具有抗肿瘤活性，包括部分反应和多种晚期难治性癌症的长期稳定疾病的发生。日本的结直肠癌患者和美国的三阴性乳腺癌和小细胞肺癌患者正在进行II期研究。

BACKGROUND & AIMS: :For folate receptor (FR) targeted anticancer therapy, novel folic acid (FA) conjugated cholesterol-modified glycol chitosan (FCHGC) micelles were synthesized and characterized by (1)H NMR, dynamic light scattering, transmission electron microscopy, and fluorescence spectroscopy. The degree of substitution was 1.4 FA groups and 7.7 cholesterol groups per 100 sugar residues of glycol chitosan. The critical aggregation concentration of FCHGC micelles in aqueous solution was 0.0169 mg/ml. The doxorubicin (DOX)-loaded FCHGC (DFCHGC) micelles were prepared by an emulsion/solvent evaporation method. The DFCHGC micelles were almost spherical in shape and their size increased from 282 to 320 nm with the DOX-loading content increasing from 4.53 to 11.4%. DOX released from DOX-loaded micelles displayed sustained release behavior. The targeted micelles encapsulated DOX showed significantly greater cytotoxicity against FR-positive HeLa cells than the nontargeted DOX-loaded micelles and free DOX. These results suggested that FCHGC micelles could be a potential carrier for targeted drug delivery.

背景与目标： 针对叶酸受体 (FR) 靶向抗癌治疗，合成了新型叶酸 (FA) 共轭胆固醇修饰的乙二醇壳聚糖 (FCHGC) 胶束，并通过 (1)H NMR，动态光散射，透射电子显微镜和荧光光谱对其进行了表征。取代度为1.4 FA组和7.7胆固醇组，每100糖残基乙二醇壳聚糖。FCHGC胶束在水溶液中的临界聚集浓度为0.0169 mg/ml。通过乳液/溶剂蒸发法制备了载有阿霉素 (DOX) 的FCHGC (DFCHGC) 胶束。DFCHGC胶束的形状几乎是球形的，并且它们的尺寸从282增加到320 nm，而DOX负载含量从4.53增加到11.4%。从载有DOX的胶束释放的DOX显示出持续释放的行为。与未靶向DOX负载的胶束和游离DOX相比，封装的DOX靶向胶束对FR阳性HeLa细胞显示出更大的细胞毒性。这些结果表明，FCHGC胶束可能是靶向药物递送的潜在载体。

BACKGROUND & AIMS: :An adenosine triphosphate (ATP)-fueled micellar system in the out-of-equilibrium state was constructed based on 4,5-diamino-1,3,5-triazine (DAT)-containing block copolymer. The block copolymer self-assembled into spherical micelles in equilibrium steady state at pH higher than its p Ka. The pendant DAT residues in protonated form acted as ATP catchers via hydrogen bonding and electrostatic interactions. Activated by ATP fuel, the polymeric micelles spontaneously disrupted into small aggregates of ATP/polymer hybrid complexes. The consumption of ATP energy via the enzymatic hydrolysis led to dissociation of the complexes and reversible formation of polymeric micelles. A transient self-assembly cycle, in which the assembly underwent autonomous division-fusion motion, was created using ATP fuel and enzyme; the switching of assembly structure was sustained by continuous supply of ATP fuel. This DAT-containing block copolymer have good biocompatibility, and drug-loaded micelles display ATP-responsive release behavior. It is expected that this ATP-fueled supramolecular assembly system will provide a functional platform for biomimic chemistry and therapeutic applications.

背景与目标： : 基于含4,5-二氨基-1,3，5-三嗪 (DAT) 的嵌段共聚物，构建了处于失衡状态的三磷酸腺苷 (ATP) 燃料胶束系统。嵌段共聚物在高于其p Ka的pH下以平衡稳态自组装成球形胶束。质子化形式的侧DAT残基通过氢键和静电相互作用充当ATP捕捉器。在ATP燃料的激活下，聚合物胶束自发地破裂成ATP/聚合物杂化复合物的小聚集体。通过酶水解消耗ATP能量导致复合物解离和聚合物胶束的可逆形成。使用ATP燃料和酶创建了一个瞬态自组装周期，其中组装经历了自主的分裂融合运动; 通过连续供应ATP燃料来维持组装结构的切换。这种含DAT的嵌段共聚物具有良好的生物相容性，载药胶束表现出ATP反应释放行为。预计这种以ATP为燃料的超分子组装系统将为生物化学和治疗应用提供功能平台。

BACKGROUND & AIMS: :Peptide amphiphile micelles (PAMs) are attractive vehicles for the delivery of a variety of therapeutic and prophylactic peptides. However, a key limitation of PAMs is their lack of preferential targeting ability. In this paper, we describe our design of a PAM system that incorporates a DNA oligonucleotide amphiphile (antitail amphiphile-AA) to form A/PAMs. A cell-targeting DNA aptamer with a 3' extension sequence (tail) complementary to the AA is annealed to the surface to form aptamer-displaying PAMs (Aptamer~A/PAMs). Aptamer~A/PAMs are small, anionic, stable nanoparticles capable of delivering a large mass percentage peptide amphiphile (PA) compared to targeting DNA components. Aptamer~A/PAMs are stable for over 4 h in the presence of biological fluids. Additionally, the aptamer retains its cell-targeting properties when annealed to the A/PAM, thus leading to enhanced delivery to a specifically-targeted B-cell leukemia cell line. This exciting modular technology can be readily used with a library of different targeting aptamers and PAs, capable of improving the bioavailability and potency of the peptide cargo.

背景与目标： 肽两亲胶束 (PAMs) 是用于递送各种治疗和预防肽的有吸引力的载体。然而，pam的一个关键限制是它们缺乏优先瞄准能力。在本文中，我们描述了我们的PAM系统的设计，该系统结合了DNA寡核苷酸两亲物 (antitail amphile-AA) 以形成a/PAMs。将具有与AA互补的3' 延伸序列 (tail) 的细胞靶向DNA适体退火到表面，以形成显示适体的PAMs (适体〜A/PAMs)。适体〜A/PAMs是小的，阴离子的，稳定的纳米颗粒，与靶向DNA成分相比，能够传递大质量百分比的肽两亲物 (PA)。适体〜A/PAMs在生物流体存在下稳定4小时以上。此外，当与A/PAM退火时，适体保留了其细胞靶向性，从而导致增强了对特异性靶向b细胞白血病细胞系的递送。这种令人兴奋的模块化技术可以很容易地与不同靶向适体和PAs的库一起使用，能够提高肽货物的生物利用度和效力。

BACKGROUND & AIMS: :Stimuli-responsive nanocarriers have demonstrated their potentials in optimizing chemotherapeutics and anticancer efficacy. In this study, a mixed micelle system (THSP) was prepared by combining reduction-sensitive hyaluronic acid-poly(lactide) (HA-ss-PLA) conjugates and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), with objective to achieve multiple functionalities of selective intracellular rapid release, active targeting capability and multidrug resistance reversal. The mixed micelle possessed desirable particle diameter of 124.32 nm and high entrapment efficiency at 87.97%. Importantly, the THSP mixed micelles demonstrated good stability in systemic circulation and rapidly released PTX in intracellular reductive environment. In vitro cellular uptake study and cytotoxicity assay indicated that the mixed micelles effectively increased drug accumulation in A549 cells and Taxol resistant A549/Taxol cells, and inhibited growth of tumor cells. In addition, the redox-responsive THSP micelles preferentially accumulated to the tumor site and improved anticancer drug activity in vivo, with a TIR of 69.08%. It was concluded that redox-sensitive mixed micelles THSP provided a potential vehicle for efficient anticancer drug delivery and enhancement in treating MDR tumor in the future.

背景与目标： : 刺激响应性纳米载体已证明其在优化化学疗法和抗癌功效方面的潜力。在这项研究中，通过结合还原敏感的透明质酸-聚丙交酯 (HA-ss-PLA) 缀合物和D-α-生育酚聚乙二醇丁二酸酯 (TPGS) 制备了混合胶束系统 (THSP)，目的是实现选择性细胞内快速释放的多功能，主动靶向能力和多药耐药逆转。混合胶束具有124.32  nm的理想粒径和87.97% 时的高截留效率。重要的是，THSP混合胶束在体循环中表现出良好的稳定性，并在细胞内还原环境中迅速释放PTX。体外细胞摄取研究和细胞毒性分析表明，混合胶束可有效增加A549细胞和紫杉醇耐药A549/紫杉醇细胞的药物积累，并抑制肿瘤细胞的生长。此外，氧化还原响应的THSP胶束优先积累到肿瘤部位并改善体内的抗癌药物活性，TIR为69.08%。结论是，氧化还原敏感的混合胶束THSP为将来有效的抗癌药物递送和增强MDR肿瘤的治疗提供了潜在的载体。

BACKGROUND & AIMS: :Targeted drug delivery systems (TDDS) have attracted wide attention for their reduced drug side effects and improved antitumor efficacy in comparison with traditional preparations. While targeting moieties in existing TDDS have principally focused on recognition of receptors on the surface of tumor cells, accumulation into tumor tissue only could be performed by enhanced permeability and retention effects and active transportation into tumor cells. Doxorubicin (DOX)-loaded sialic acid-dextran (Dex)-octadecanoic acid (OA) micelles (SA-Dex-OA/DOX) were designed for targeting hepatocellular carcinoma effectively. The synthesized conjugates could self-aggregate to form micelles with a critical micelle concentration of 27.6 μg·mL-1 and diameter of 54.53 ± 3.23 nm. SA-Dex-OA micelles incorporated with 4.36% DOX-loading content could prolong in vitro drug release to 96 h with 80% of final release. Cellular transportation studies revealed that SA-Dex-OA micelles mediated more efficient DOX delivery into Bel-7402 cells than those without SA modification. In vivo biodistribution testing demonstrated that SA-Dex-OA/ICG micelles showed 3.05-fold higher accumulation into Bel-7402 tumors. The recognition of overexpressed E-selectin in inflammatory tumor vascular endothelial cells led to a large accumulation of SA-Dex-OA/ICG micelles into tumor tissue, and the E-selectin upregulated on the surface of tumor cells contributed to active cellular transportation into tumor cells. Accordingly, SA-Dex-OA/DOX exhibited prior suppression of Bel-7402 tumor growth greater than that of Dex-OA/DOX micelles and free DOX (the tumor inhibition: 79.2% vs 61.0 and 51.3%). These results suggest that SA-functionalized micelles with dual targeting properties have high potential for liver cancer therapy.

背景与目标： : 与传统制剂相比，靶向药物递送系统 (TDDS) 因其降低的药物副作用和改善的抗肿瘤功效而受到广泛关注。尽管现有TDDS中的靶向部分主要集中在识别肿瘤细胞表面的受体上，但只能通过增强的渗透性和保留作用以及主动转运到肿瘤细胞中来完成向肿瘤组织的积累。设计了负载阿霉素 (DOX) 的唾液酸-葡聚糖 (Dex)-十八烷酸 (OA) 胶束 (SA-Dex-OA/DOX)，用于有效靶向肝细胞癌。合成的共轭物可以自聚成胶束，其临界胶束浓度为27.6 μ g·mL-1，直径为54.53 ± 3.23 nm。掺入4.36% DOX负载量的SA-Dex-OA胶束可将体外药物释放延长至96 h，最终释放80%。细胞运输研究表明，与没有SA修饰的相比，SA-Dex-OA胶束介导的DOX更有效地递送到Bel-7402细胞中。体内生物分布测试表明，SA-Dex-OA/ICG胶束在Bel-7402肿瘤中显示出3.05倍的高积累。在炎性肿瘤血管内皮细胞中过度表达的E-选择素的识别导致SA-Dex-OA/ICG胶束大量积聚到肿瘤组织中，并且在肿瘤细胞表面上调的E-选择素有助于细胞主动转运到肿瘤细胞中。因此，SA-Dex-OA/DOX表现出比Dex-OA/DOX胶束和游离DOX更大的先前对Bel-7402肿瘤生长的抑制 (肿瘤抑制: 79.2% 对61.0和51.3%)。这些结果表明，具有双重靶向特性的SA功能化胶束具有很高的肝癌治疗潜力。

BACKGROUND & AIMS: :Pluronics with different structural compositions and properties are used for several applications, including drug delivery systems. We developed a binary mixing system with two Pluronics, L121/P123, as a nano-sized drug delivery carrier. The lamellar-forming Pluronic L121 (0.1 wt%) was incorporated with Pluronic P123 to produce nano-sized dispersions (in case of 0.1 and 0.5 wt% P123) with high stability due to Pluronic P123 and high solubilization capacity due to Pluronic L121. The binary systems were spherical and less than 200-nm diameter, with high thermodynamic stability (at least 2 weeks) in aqueous solution. The CMC of the binary system was located in the middle of the CMC of each polymer. In particular, the solubilization capacity of the binary system (0.1/0.1 wt%) was higher than mono-systems of P123. The main advantage of binary systems is overcoming limitations of mono systems to allow tailored mixing of block copolymers with different physicochemical characteristics. These nano-sized systems may have potential as anticancer drug delivery systems with simple preparation method, high stability, and high loading capacity.

背景与目标： : 具有不同结构组成和性能的Pluronics用于多种应用，包括药物递送系统。我们开发了具有两个Pluronics L121/P123的二元混合系统，作为纳米级药物递送载体。将形成层状的Pluronic L121 (0.1重量 %) 与Pluronic P123掺入以产生纳米尺寸的分散体 (在0.1和0.5重量 % P123的情况下)，由于Pluronic P123具有高稳定性和Pluronic L121的高增溶能力。二元体系是球形的，直径小于200纳米，在水溶液中具有高热力学稳定性 (至少2周)。二元体系的CMC位于每种聚合物的CMC中间。特别地，二元体系的增溶能力 (0.1/0.1重量 %) 高于p123的单体系。二元体系的主要优点是克服了单体系的局限性，从而允许定制混合具有不同物理化学特性的嵌段共聚物。这些纳米系统可能具有制备方法简单，稳定性高和负载能力高的潜在抗癌药物递送系统。

BACKGROUND & AIMS: :Oxidative stress and inflammation are important mechanisms of cerebral ischemia reperfusion (IR) injury. Luteolin (Lu), one of the major active components in the classical Tibetan prescription, which has been used in the treatment of cardiovascular diseases since 700 BC, has potential for IR injury therapy. Its hydrophobicity has impeded its further applications. In this study, we first prepared Lu micelles (M-Lu) by self-assembling with an amphiphilic copolymer via the thin film hydration method to improve the dispersion of Lu in water. The obtained M-Lu was about 30 nm, with a narrow particle size distribution, and a 5% (w/w) of Lu. The bioavailability of the micelles was further evaluated in vitro and in vivo. Compared to free Lu, M-Lu had a better penetration efficiency, which enhanced its therapeutic effect in IR injury restoration. M-Lu further strengthened the protection of nerve cells through the nuclear factor-κ-gene binding κ (NF-κB) and mitogen-activated protein kinases (MAPK) pathways and inhibited the apoptosis of cells by adjusting the expression of B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in the case of oxidative stress damage. M-Lu induced stem cells to differentiate into neuron-like cells to promote the repair and regeneration of neurons. The results of in vivo pharmacodynamics of Lu on occlusion of the middle cerebral artery model further demonstrated that M-Lu better inhibited inflammation and the oxidative stress response by the down-regulation of the inflammatory cytokine, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, and the up-regulation of the activity of anti-oxidant kinase, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), which further ameliorated the degree of IR injury. The M-Lu could be a new strategy for IR injury therapy.

背景与目标： 氧化应激和炎症反应是脑缺血再灌注损伤的重要机制。木犀草素 (Lu) 是经典藏方的主要活性成分之一，自公元前700年以来一直用于治疗心血管疾病，具有潜在的IR损伤治疗潜力。它的疏水性阻碍了它的进一步应用。在这项研究中，我们首先通过薄膜水合方法与两亲共聚物自组装制备了Lu胶束 (M-Lu)，以改善Lu在水中的分散性。获得的M-Lu为约30 nm，具有窄的粒度分布，并且Lu的5% (w/w)。在体外和体内进一步评估了胶束的生物利用度。与游离Lu相比，M-Lu具有更好的穿透效率，增强了其在IR损伤修复中的治疗效果。M-Lu通过核因子-κ 基因结合 κ (NF-κ B) 和丝裂原活化蛋白激酶 (MAPK) 途径进一步加强对神经细胞的保护，并通过调节b细胞淋巴瘤-2 (Bcl-2) 和Bcl-2相关X蛋白的表达来抑制细胞凋亡 (Bax) 在氧化应激损伤的情况下。M-Lu诱导干细胞分化为神经元样细胞，促进神经元的修复和再生。Lu对大脑中动脉模型闭塞的体内药效学结果进一步表明，M-Lu通过下调炎性细胞因子，包括肿瘤坏死因子 (TNF)-α，白细胞介素 (IL)-1β 和IL-6，更好地抑制炎症和氧化应激反应，以及抗氧化激酶 (超氧化物歧化酶 (SOD) 和谷胱甘肽过氧化物酶 (GSH-px)) 活性的上调，进一步改善了IR的损伤程度。M-Lu可能是IR损伤治疗的新策略。

BACKGROUND & AIMS: :A new type of block copolymer micelles for pH-triggered delivery of poorly water-soluble anticancer drugs has been synthesized and characterized. The micelles were formed by the self-assembly of an amphiphilic diblock copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrophobic polymethacrylate block (PEYM) bearing acid-labile ortho ester side-chains. The diblock copolymer was synthesized by atom transfer radical polymerization (ATRP) from a PEG macro-initiator to obtain well-defined polymer chain-length. The PEG-b-PEYM micelles assumed a stable core-shell structure in aqueous buffer at physiological pH with a low critical micelle concentration as determined by proton NMR and pyrene fluorescence spectroscopy. The hydrolysis of the ortho ester side-chain at physiological pH was minimal yet much accelerated at mildly acidic pHs. Doxorubicin (Dox) was successfully loaded into the micelles at pH 7.4 and was released at a much higher rate in response to slight acidification to pH 5. Interestingly, the release of Dox at pH 5 followed apparently a biphasic profile, consisting of an initial fast phase of several hours followed by a sustained release period of several days. Dox loaded in the micelles was rapidly taken up by human glioma (T98G) cells in vitro, accumulating in the endolysosome and subsequently in the nucleus in a few hours, in contrast to the very low uptake of free drug at the same dose. The dose-dependent cytotoxicity of the Dox-loaded micelles was determined by the MTT assay and compared with that of the free Dox. While the empty micelles themselves were not toxic, the IC(50) values of the Dox-loaded micelles were approximately ten-times (by 24h) and three-times (by 48h) lower than the free drug. The much enhanced potency in killing the multi-drug-resistant human glioma cells by Dox loaded in the micelles could be attributed to high intracellular drug concentration and the subsequent pH-triggered drug release. These results establish the PEG-b-PEYM block copolymer with acid-labile ortho ester side-chains as a novel and effective pH-responsive nano-carrier for enhancing the delivery of drugs to cancer cells.

背景与目标： 合成并表征了一种新型的嵌段共聚物胶束，用于pH触发递送水溶性差的抗癌药物。胶束是通过两亲性二嵌段共聚物的自组装形成的，该两亲性二嵌段共聚物由亲水性聚 (乙二醇) (PEG) 嵌段和带有酸不稳定的邻酯侧链的疏水性聚甲基丙烯酸酯嵌段 (PEYM) 组成。通过PEG大分子引发剂通过原子转移自由基聚合 (ATRP) 合成二嵌段共聚物，以获得明确定义的聚合物链长。PEG-b-PEYM胶束在生理pH下的水性缓冲液中具有稳定的核壳结构，其临界胶束浓度较低，如质子NMR和pyr荧光光谱法测定。在生理pH下，原酯侧链的水解最小，但在轻度酸性pH下却大大加速。阿霉素 (Dox) 成功地在pH 7.4下加载到胶束中，并响应于轻微酸化至ph5以高得多的速率释放。有趣的是，在pH 5下Dox的释放显然遵循双相曲线，包括几个小时的初始快速阶段，然后是几天的持续释放期。在体外，人类神经胶质瘤 (T98G) 细胞迅速吸收了胶束中的Dox，并在溶酶体中积累，随后在几个小时内在细胞核中积累，而在相同剂量下游离药物的摄取非常低。通过MTT测定法确定了Dox负载的胶束的剂量依赖性细胞毒性，并将其与游离Dox的剂量依赖性细胞毒性进行了比较。虽然空胶束本身无毒，但载有Dox的胶束的IC(50) 值比游离药物低约十倍 (24小时) 和三倍 (48小时)。通过胶束中装载的Dox杀死多药耐药的人神经胶质瘤细胞的效力大大增强，这可能归因于高细胞内药物浓度和随后的pH触发的药物释放。这些结果建立了具有酸不稳定的邻酯侧链的PEG-b-PEYM嵌段共聚物，作为一种新型有效的pH响应纳米载体，可增强药物向癌细胞的递送。

BACKGROUND & AIMS: :We have investigated the responsiveness of micelle and bilayer surfaces to changes in bulk pH through titrations, and to changes in lipid packing through the application of high hydrostatic pressure using two fluorescent, pH-sensitive surface probes. In micelles, the surface is very sensitive to bulk pH while in phosphatidylcholine and phosphatidic acid bilayers the surface charge changed little through a large pH region. Application of pressure on micelles causes proton dissociation due to the volume reduction achieved from the contraction of water around the charges (electrostriction). However, in bilayers, the effect of electrostriction is greatly reduced, most likely due to the energy needed to expand and hydrate the surface. The sign and amount of change in dissociation the probe undergoes with pressure depend on the initial degree of probe dissociation, which is in turn dependent on the particular surface rather than the charge of the lipid head groups comprising the bilayer. This finding may limit the use of fluorescent probes to determine the exact surface potential. By assuming the change in delta V for proton dissociation from the probe is constant for a given pH, we can calculate the changes in local pH that occur under pressure relative to a neutral or uncharged system. In doing so, we find that the local pH around the probe in bilayers changes very little (approximately 0.1 pH unit or less) in the first 2000 bars. Also, if pressure data are coupled with titration curves, we can determine the change that the bulk pH must undergo to produce the observed change in dissociation seen under pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

背景与目标： : 我们使用两种荧光，pH敏感的表面探针研究了胶束和双层表面对滴定的整体pH变化以及通过施加高静水压力对脂质堆积变化的响应。在胶束中，表面对整体pH非常敏感，而在磷脂酰胆碱和磷脂酸双层中，表面电荷在较大的pH区域中变化很小。在胶束上施加压力会导致质子解离，这是由于电荷周围的水收缩 (电致伸缩) 引起的体积减小所致。但是，在双层中，电致伸缩的效果大大降低，这很可能是由于膨胀和水合表面所需的能量所致。探针随压力而发生的解离变化的符号和量取决于探针解离的初始程度，而初始程度又取决于特定表面而不是包含双层的脂质头基团的电荷。这一发现可能会限制使用荧光探针来确定确切的表面电势。通过假设质子解离探针的 Δ V变化对于给定的pH是恒定的，我们可以计算出相对于中性或不带电系统在压力下发生的局部pH变化。在这样做时，我们发现在前2000条中双层中探针周围的局部pH变化很小 (大约0.1 pH单位或更小)。此外，如果压力数据与滴定曲线相结合，我们可以确定主体pH必须经历的变化，以产生在压力下观察到的离解变化。(摘要截断为250字)