载阿霉素星型多臂PLGA-PEG嵌段共聚物纳米胶束的构建

目的 利用星型多臂端氨基聚乙丙交酯/聚乙二醇[4s-( PLGA-PEG-NH2)]两亲性嵌段共聚物作为载体材料,构建抗肿瘤药物阿霉素纳米胶束载药体系.方法 合成聚合物4s-( PLGA-PEG-NH2),通过核磁共振氢谱(1H NMR)和凝胶渗透色谱(GPC)对其组成、结构及相对分子质量进行表征;采用溶剂挥发法制备阿霉素(DOX)聚合物纳米胶束,并通过透射电子显微镜(TEM)、粒径分析仪及荧光分析法对载药纳米胶束进行表征;对阿霉素载药纳米胶束在HeLa细胞中的摄取及细胞毒性进行了初步评价.结果 1H NMR与GPC测定结果表明:合成的共聚物符合设计的4s-( PLGA-PEG-NH2)结构;能成功物理包埋DOX药物分子在水溶液中自组装成核-壳结构的纳米胶束,载药量约为7.5％,包埋率约为75.2％,Zeta电位为-17.6 mV;体外细胞实验显示:载阿霉素星型4臂聚合物纳米胶束[DOX-loaded 4s-(PLGA-PEG-NH2)micelles]比载阿霉素线性聚合物纳米胶束[DOX-loaded linear-( PLGA-PEG-PLGA)micelles]可更有效地被HeLa细胞摄取,并对HeLa细胞的毒性更强.结论 4s-( PLGA-PEG-NH2)阿霉素载药纳米胶束可有效提高HeLa细胞的摄取率以及对HeLa细胞的杀伤率,提示其可作为一类新型的抗肿瘤药物递送载体.     

利用负载吲哚菁绿/姜黄素的聚合物胶束进行光热-化学联合抗菌可行性研究

目的 构建一种具有近红外光（NIR）刺激响应性姜黄素@聚乙二醇-硫代缩酮-吲哚菁绿聚合物胶束（Cur@PEGTK-ICG PMs）,对其结构进行表征,评估其载药、释药行为,并研究其生物相容性与体外抗菌效果。方法 通过两步简单的酰胺化反应制备得到两亲性聚合物,即聚乙二醇-硫代缩酮-吲哚菁绿（PEG-TK-ICG）,使用溶剂交换法在两亲性聚合物自组装过程中负载疏水药物姜黄素,获得负载姜黄素的聚合物胶束Cur@PEG-TK-ICG PMs。通过核磁共振氢谱、透射电子显微镜对胶束进行结构、形貌表征;通过紫外-可见光吸收光谱对其载药、释药行为进行评估;使用细胞毒性实验cell counting kit-8细胞活性计数对载药胶束的生物相容性进行评价;采用菌落的平板克隆法和光密度600法评估其体外抗菌效果。结果 两亲性聚合物可自组装形成尺寸约为90 nm的均一球形胶束纳米粒。姜黄素的包载效率为93.75%,经NIR照射的Cur@PEG-TK-ICG PMs可在30 min内完成100%药物释放。Cur@PEG-TK-ICG PMs浓度达到800μg/m L时,细胞生存率仍保持在90%以上。NIR照射...     

体外研究聚合物P(DLLA-co-TMC)的降解性能与释药行为

目的 研究P(DLLA-co-TMC)聚合物的体外降解性能与释药行为,且探讨该聚合物作为长效避孕释放载体的可行性.方法 以PBS溶液为溶媒研究P(DLLA-co-TMC)的降解性能;以P(DLLA-co-TMC)聚合物为载体制备含孕二烯酮的载药片,并通过蒸馏水浸泡载药片研究载药体系的体外释药行为.结果 P(DLLA-co-TMC)聚合物前期降解较慢,第30天和第90天失重率分别为10.0%和12.3%,后期降解速率较快,第120天的失重率为59.3%;P(DLLA-co-TMC)的载药片前期释药速率较大,出现"暴释现象",后期释药速率减缓并逐渐趋于平稳,第100天时累计释放率为5.64%.结论 P(DLLA-co-TMC)聚合物降解性能良好、释药效果明显,有望通过体内研究使含孕二烯酮的P(DLLA-co-TMC)聚合物载药系统应用于长效埋植避孕.     

白藜芦醇聚合物胶束的制备及质量评价

目的制备白藜芦醇(RES)聚合物胶束并对其进行质量评价。方法采用薄膜分散法,以聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(SPS)和D-α生育酚聚乙二醇1000琥珀酸酯(TPGS)为载体材料,制备白藜芦醇聚合物胶束(RES-SPS-TPGS-PMs);采用纳米粒度分析仪、差示扫描量热法(DSC)及傅立叶变换红外光谱法(FTIR)对其进行表征;采用高效液相色谱法测定聚合物胶束的包封率和载药量;采用动态膜透析法考察载药胶束的体外释放特性。结果制备的胶束平均粒径为(52.4±0.66)nm,多分散指数为0.06±0.01,包封率为(97.12±9.08)%,载药量为(2.37±0.22)%。白藜芦醇在聚合物胶束中可能以无定型或分子的形式存在,且白藜芦醇与载体材料之间形成了氢键。体外释放结果表明白藜芦醇聚合物胶束具有明显的缓释效果。结论该胶束制备工艺简单,其粒径、包封率、载药量可控,具有缓释作用。     

核交联聚(N-异丙基丙烯酰胺-co-N,N-二甲基丙烯酰胺)-b-聚己内酯胶束及紫杉醇的温敏控制释放行为(英文)

背景:高分子纳米胶束是近几年正在发展的一类新型药物载体,其载药范围广、结构稳定、具有优良的组织渗透性,体内滞留时间长,能使药物有效地到达靶点。而使其带有智能靶向性以及减弱其初期爆发释放行为成为了最近研究的热点。目的:得到一种低临界溶液浓度在40℃左右的智能靶向药物载体,可以通过对温度的改变而改变其药物释放行为,并进一步通过核交联改善胶束的稳定性以及其药物释放行为。方法:通过N-异丙基丙烯酰胺(NIPAAm)和N,N-二甲基丙烯酰胺(DMAAm)的自由基共聚,合成端羟基聚(N-异丙基丙烯酰胺-co-N,N-二甲基丙烯酰胺)(P(NIPAAm-co-DMAAm))。通过调节巯基乙醇和单体的比例,以及NIPAAm和DMAAm的比例,调节P(NIPAAm-co-DMAAm)的相对分子质量和低临界溶液温度。然后在异辛酸亚锡的催化下,利用P(NIPAAm-co-DMAAm)端羟基引发己内酯开环聚合,得到端羟基P(NIPAAm-co-DMAAm)-b-PCL两亲性嵌段共聚物。该嵌段共聚物再与丙烯酰氯反应得到末端带有不饱和双键的两亲性嵌段共聚物。用透析法制备具有不同核交联程度的纳米载药胶束,并对其释放行为进行研究。结果与结论:得到了温敏段相对分子质量为3600、PCL段相对分子质量为1600的两亲性嵌段共聚物,其低临界溶液浓度为42℃。采用不同比例端羟基和端羧基P(NIPAAm-co-DMAAm)-b-PCL混合,制备得到具有不同核交联程度的温敏性纳米载药胶束。胶束的药物释放速度在43℃快于37℃,随着核交联程度的增高,紫杉醇的释放速度变慢。结果提示以低临界溶液浓度在40℃左右的温敏性P(NIPAAm-co-DMAAm)-b-PCL所制备的胶束,具有一定的温敏控制释放行为,药物释放速度可进一步通过核交联程度来控制。     

多西他赛共聚物纳米胶束的制备及性能研究

目的制备一种包载多西他赛的聚乳酸羟基乙酸-聚乙二醇-聚乳酸羟基乙酸(PLGA-PEG-PLGA)三嵌段共聚物纳米胶束,并考察其相关性能。方法采用开环聚合法合成共聚物,直接溶解法制备载多西他赛共聚物纳米胶束,荧光光谱法测定临界胶束浓度,高效液相色谱检测载药胶束的包封率与载药率,透析法测定载药胶束体外释放情况,扫描电镜观察纳米胶束的形态,激光粒径仪测量共聚物纳米胶束粒径及分布,改良寇氏法测定载药胶束的半数致死量。结果直接溶解法制备的共聚物纳米胶束的临界胶束浓度为4.5×10-3 g/L,多西他赛与共聚物投料比为1∶20制备的载多西他赛共聚物纳米胶束的包封率为98.20%,载药率达4.68%,在体外平稳释放时间约3 d。扫描电子显微镜观察载多西他赛共聚物纳米胶束呈类圆形,分散良好,平均粒径为30.8 nm,多元分散系数0.42。载多西他赛共聚物纳米胶束静脉注射小鼠的半数致死量为273.5 mg/kg。结论采用直接溶解法可制备一种载多西他赛的PLGA-PEG-PLGA三嵌段共聚物纳米胶束,包封率高,体外释药平稳,毒副作用小,具有潜在的临床应用价值。     

载药敷料体外细胞毒性及释药性评价

目的评价载药敷料体外细胞毒性和释药性。方法按国标GB/T14233.2-2005,规定的MTT法操作,通过光学倒置显微镜观察L929细胞形态和增殖状况定性分析载药敷料体外细胞毒性,通过吸光度(OD)值计算细胞相对增殖率定量分析载药敷料体外细胞毒性等级;以磷酸盐缓冲液(PBS7.4)为溶出介质,(32±5)℃模拟人体表皮温度,于1/6、1/2、1、3、16、24、36和48h不同时间点取样,采用紫外分光光度法测定载药敷料体外累积释放性能。结果该载药敷料浸提原液中的细胞形态正常,贴壁生长良好,细胞平均相对增殖率(RGR)为91.25%,毒性为1级。载药敷料的释药动力学符合Higuchi方程:拟合方程为Mt/M∞=0.3271t0.239。结论该载药敷料细胞相容性良好,并具有一定的缓释性能。     

9-硝基喜树碱叶酸聚合物胶束肿瘤靶向给药系统的表征及体外药效评价

背景：近年来,两亲性聚合物胶束作为难溶性药物载体和叶酸介导的肿瘤细胞靶向给药系统在药剂学研究领域受到极大的关注。 目的：制备包载9-硝基喜树碱的叶酸聚合物胶束并进行理化表征及体外药效评价。 方法：采用薄膜-水化法制得载药胶束,利用激光粒度分析仪检测胶束粒径大小,反相高效液相层析法检测载药量,透析法进行体外释放试验;利用肿瘤细胞摄取及体外生长抑制试验,对叶酸聚合物胶束作体外药效评价。 结果与结论：制得的9-硝基喜树碱叶酸聚合物胶束粒径为24~26 nm,载药量为3.24%,24 h累积释放百分率约90%。叶酸修饰的聚合物胶束对肿瘤细胞的亲和性及抗肿瘤活性显著高于普通胶束。提示叶酸修饰的聚合物胶束可为难溶性药物提供一种具有良好应用前景的肿瘤主动靶向纳米载药系统。     

成骨生长肽壳聚糖-海藻酸钠微球的制备及体外检测

背景：成骨生长肽体外注射可以刺激外周血和骨髓细胞数增加,增加动物的骨量,加速骨折愈合,但因多肽不稳定性及注射应用不方便,限制了其临床应用。 目的：应用乳化交联法制备成骨生长肽壳聚糖-海藻酸钠缓释微球,并对其粒径、载药、体外释药、理化特性进行检测。 方法：以戊二醛作为交联剂,应用乳化交联法制备具有控制释放功能的负载成骨生长肽壳聚糖-海藻酸钠微球,显微镜及扫描电镜观察微球的形态和粒径;利用酶联免疫吸附实验动态检测成骨生长肽壳聚糖-海藻酸钠微球的载药率、包封率和缓释规律。 结果与结论：乳化交联法制备的壳聚糖-海藻酸钠微球,球形良好,球体表面有较多微孔,具有较高的包封率(>72%)。体外药物释放实验表明,成骨生长肽可以从壳聚糖-海藻酸钠微球中缓慢释放,整个释放过程可达49 d,累积释放率>85%。提示应用乳化交联法制备的负载成骨生长肽壳聚糖-海藻酸钠缓释微球,具有很好的控制释放成骨生长肽的能力。     

体外研究聚合物P（DLLA—co—TMC）的降解性能与释药行为

目的 研究P（DLLA—CO-TMC）聚合物的体外降解性能与释药行为,且探讨该聚合物作为长效避孕释放载体的可行性。方法以PBS溶液为溶媒研究P（DLLA-CO-TMC）的降解性能;以P（DLLA—CO—TMC）聚合物为载体制备含孕二烯酮的载药片,并通过蒸馏水浸泡载药片研究载药体系的体外释药行为。结果P（DLLA-CO-TMc）聚合物前期降解较慢,第30天和第90天失重率分别为10．0％和12．3％,后期降解速率较快,第120天的失重率为59．3％;P（DLLA-CO-TMC）的载药片前期释药速率较大,出现“暴释现象”,后期释药速率减缓并逐渐趋于平稳,第100天时累计释放率为5．64％。结论P（DLLA-co-TMC）聚合物降解性能良好、释药效果明显,有望通过体内研究使含孕二烯酮的P（DLLA—CO—TMC）聚合物载药系统应用于长效埋植避孕。     

纳米羟基磷灰石/胶原药物载体的制备

以湿法制备出平均粒径为50nm的羟基磷灰石粉体，并采用超声分散，将纳米羟基磷灰石分散在酸溶的胶原稀溶液中。测试结果显示，羟基磷灰石在胶原溶液中形成了稳定的分散体系，该分散体系的稳定性与体系的pH值以及羟基磷灰石和胶原的相对浓度有关。     

Electrospun biphasic drug release polyvinylpyrrolidone/ethyl cellulose core/sheath nanofibers

The capability of core/sheath nanofibers prepared using coaxial electrospinning to provide adjustable biphasic drug release was investigated. Using ketoprofen (KET) as the model drug, polyvinylpyrrolidone as the sheath polymer, and ethyl cellulose as the core matrix, the coaxial process could be conducted smoothly and continuously without spinneret clogging. Scanning electron microscopy and transmission electron microscopy revealed linear nanofibers with homogeneous and clear core/sheath structures. Differential scanning calorimetry and X-ray diffraction verified that the core/sheath nanofibers were nanocomposites, with the drug present in the polymer matrix in an amorphous state. Attenuated total reflectance–Fourier transform infrared spectra demonstrated that the sheath polymer and core matrix were compatible with KET owing to hydrogen bonding. In vitro dissolution tests showed that the core/sheath nanofibers could provide typical biphasic drug release profiles consisting of an immediate and sustained release. The amount of drug released in the first phase was tailored by adjusting the sheath flow rate, and the remaining drug released in the second phase was controlled by a typical diffusion mechanism. The present study shows a simple and useful approach for the systematic design and fabrication of novel biomaterials with structural characteristics for providing complicated and programmed drug release profiles using coaxial electrospinning.     

PTEN/Akt/mTOR通路增加K562/ADM细胞化疗敏感性

目的 探讨K562/ADM细胞系中PTEN/Akt/mTOR信号通路对不同化疗药物敏感性的影响.方法 K562/ADM细胞分为未转染组、转染野生型PTEN组(Ad-PTEN-GFP)、转染空载体组(Ad-GFP),并与不同浓度雷帕霉素或三氧化二砷( As2 03)联合作用.通过MTT法检测细胞增殖,流式细胞术检测细胞凋亡率,荧光定量PCR检测PTEN、mTOR、BCL-2及BAXmRNA水平,Western blot检测PTEN及Akt、p-Akt蛋白水平.结果 野生型PTEN对K562/ADM细胞最大增殖抑制率为32.3％,与未转染组及Ad-GFP组相比,Ad-PTEN-GFP组mTOR mRNA和p-Akt蛋白明显减低;雷帕霉素与As2 03联合应用后细胞增殖明显受抑,凋亡率(28.61％±1.46％)明显高于单药作用组(P＜0.05),BCL-2 mRNA表达降低,BAX mRNA表达增加,以联合干预组最为明显.结论 PTEN/Akt/mTOR信号传导通路能够增加K562/ADM细胞对雷帕霉素及As2 03的敏感性.     

Efficient nuclear drug translocation and improved drug efficacy mediated by acidity-responsive boronate-linked dextran/cholesterol nanoassembly

The present study reported a lysosome-acidity-targeting bio-responsive nanovehicle self-assembled from dextran (Dex) and phenylboronic acid modified cholesterol (Chol-PBA), aiming at the nucleus-tropic drug delivery. The prominent advantage of this assembled nanoconstruction arose from its susceptibility to acidity-labile dissociation concurrently accompanied with the fast liberation of encapsulated drugs, leading to efficient nuclear drug translocation and consequently favorable drug efficacy. By elaborately exploiting NH₄Cl pretreatment to interfere with the cellular endosomal acidification progression, this study clearly evidenced at a cellular level the strong lysosomal-acidity dependency of nuclear drug uptake efficiency, which was shown to be the main factor influencing the drug efficacy. The boronate-linked nanoassembly displayed nearly no cytotoxicity and can remain structural stability under the simulated physiological conditions including 10% serum and the normal blood sugar concentration. The cellular exposure to cholesterol was found to bate the cellular uptake of nanoassembly in a dose-dependent manner, suggesting a cholesterol-associated mechanism of the intracellular internalization. The in vivo antitumor assessment in xenograft mouse models revealed the significant superiority of DOX-loaded Dex/Chol-PBA nanoassembly over the controls including free DOX and the DOX-loaded non-sensitive Dex-Chol, as reflected by the more effective tumor-growth inhibition and the better systematic safety. In terms of the convenient preparation, sensitive response to lysosomal acidity and efficient nuclear drug translocation, Dex/Chol-PBA nanoassembly derived from natural materials shows promising potentials as the nanovehicle for nucleus-tropic drug delivery especially for antitumor agents. More attractively, this study offers a deeper insight into the mechanism concerning the contribution of acidity-responsive delivery to the enhanced chemotherapy performance.     

抗骨肉瘤药物纳米载体的研究进展

骨肉痛是最常见的恶性骨肿瘤,病死率较高。而生物医用纳米材料是纳米材料和生物材料交叉的一个全新领域,在生物医学上有着十分诱人的、广泛的应用前景。本文对纳米无机生物材料、纳米高分子生物材料、纳米复合生物材料作为抗骨肉瘤药物载体的研究进展作了较全面的综述。     

Strain-induced crack formations in PDMS/DXA drug collars

Drug-eluting systems are currently used in cardiac leads in order to reduce inflammation and fibrosis at the lead–tissue interface. Drug release from these drug delivery systems can be modulated by the manufacturing processes used to create the drug systems and assemble them onto the cardiac lead. In this study, scanning electron microscopy, atomic force microscopy and Raman microscopy are employed to explore the material characteristics of a polydimethylsiloxane–dexamethasone acetate drug collar used on cardiac leads when varying the strain during collar assembly on the lead. A novel test fixture was created in order to investigate these drug collars under simulated stresses. Measurements of the collar while fitted to a rod revealed microcracks that are hypothesized to affect the drug release performance, resulting in increased drug elution. It was found that the strain that occurs during assembly of the collar onto the lead is a key factor in the formation of these microcracks. Results also suggest that cracks tend to form in areas of high drug particle density, and propagate between drug particles.     

MBG/PLGA composite microspheres with prolonged drug release

Mesoporous bioactive glass (MBG) and composite microspheres with MBG particles embedded in biodegradable poly(D,L-lactide-co-glycolide) (PLGA) matrix have been prepared and used to load gentamicin (GS). The in vitro drug release experiments from both MBG and composite microspheres were conducted in distilled water and phosphate buffered saline (PBS) solution at 37 degrees C for more than 30 days. In both water and PBS, GS release from the MBG was very fast with about 60 wt % of the loaded drug released in the first 24 h, and more than 80 wt % released in two days. MBG/PLGA composite microspheres showed an initial release of about 33 wt % in the first day, and 48 wt % in 2 days, and a subsequent sustained release lasting for more than 4 weeks in PBS. MBG/PLGA composite microspheres may be used as an alternative drug release system, especially as a bone void filler for bone repair due to their combined advantages of sustained release of antibiotics and apatite-forming ability.     

An imaging-guided platform for synergistic photodynamic/photothermal/chemo-therapy with pH/temperature-responsive drug release

To integrate biological imaging and multimodal therapies into one platform for enhanced anti-cancer efficacy, we have designed a novel core/shell structured nano-theranostic by conjugating photosensitive Au₂₅(SR)₁₈ – (SR refers to thiolate) clusters, pH/temperature-responsive polymer P(NIPAm-MAA), and anti-cancer drug (doxorubicin, DOX) onto the surface of mesoporous silica coated core–shell up-conversion nanoparticles (UCNPs). It is found that the photodynamic therapy (PDT) derived from the generated reactive oxygen species and the photothermal therapy (PTT) arising from the photothermal effect can be simultaneously triggered by a single 980 nm near infrared (NIR) light. Furthermore, the thermal effect can also stimulate the pH/temperature sensitive polymer in the cancer sites, thus realizing the targeted and controllable DOX release. The combined PDT, PTT and pH/temperature responsive chemo-therapy can markedly improve the therapeutic efficacy, which has been confirmed by both in intro and in vivo assays. Moreover, the doped rare earths endow the platform with dual-modal up-conversion luminescent (UCL) and computer tomography (CT) imaging properties, thus achieving the target of imaging-guided synergistic therapy under by a single NIR light.