RGD肽修饰的pH响应型中空介孔二氧化硅纳米粒子的制备与评价

以聚多巴胺(PDA)为反应平台,对中空介孔二氧化硅纳米粒子(HMSN)进行RGD肽和聚(2-乙基-2-噁唑啉)(PEOz)双重修饰,构建了RGD肽和PEOz共同修饰的中空介孔二氧化硅纳米载体(HMSN-PEOz-RGD),以盐酸阿霉素(DOX)为模型药物构建载药体系DOX@HMSN-PEOz-RGD,用红外光谱法(FTIR)对载体进行结构表征,考察载药体系的载药量、包封率及载体的形态、粒径及Zeta电位,通过体外释药实验研究载药体系在不同pH值下的响应性释放,以人乳腺癌细胞MCF-7为模型,考察载体的生物相容性及载药体系的细胞毒性及细胞摄取过程。结果表明,HMSN-PEOz-RGD的平均粒径为(256.1±26.5) nm,粒径分布较均匀;DOX@HMSN-PEOz组和DOX@HMSN-PEOz-RGD组的体外释药都表现出明显的pH依赖性,即酸性(pH值5.0)条件下药物快速释放,而在生理pH值(pH值7.4)条件下药物释放缓慢;生物相容性实验结果显示,各载体在2.5～80μg·mL~(-1)的浓度范围内,与MCF-7细胞共培养24 h后,细胞存活率均在89%以上,表明载体具有良好的生物相容性;体外抗肿瘤活性实验结果表明,相比于其余载药制剂组,DOX@HMSN-PEOz-RGD组细胞的生长明显得到抑制,RGD修饰显著促进了DOX的细胞摄取。本研究所构建的纳米载体能够特异性靶向递送DOX,具有一定的应用前景。     

靶向光敏剂NaYF4:Yb,Tm@ NaGdF4:Yb@TiO2@PEI-PAA-FA的制备和性能

采用水解法用TiO_2包覆上转换纳米粒子Na YF4:Yb,Tm@NaGdF4:Yb,然后修饰聚乙烯亚胺(PEI)和聚丙烯酸(PAA)并偶联叶酸(FA),制备了叶酸受体靶向纳米光敏剂(NaYF4∶Yb,Tm@NaGdF4∶Yb@TiO_2@PEIPAA-FA)。借助XRD和TEM表征NaYF4∶Yb,Tm@NaGdF4∶Yb@TiO_2的物相和形貌,FTIR和Zeta电位证实有机成分的成功修饰,并测试了产物的上转换发光光谱。结果表明:在980 nm近红外光(NIR)下,纳米光敏剂存在下的1,3-二苯基异苯并呋喃溶液吸收光谱的降低证明了单线态氧的产生。此外,纳米光敏剂可以载带阿霉素(DOX),最大载药率为50.8%,包封率为84.7%。载药后的纳米光敏剂中DOX释放对介质具有pH响应性,在NIR照射的酸性介质(pH=5.0)中12 h的累积缓释率为38.1%,远高于中性介质(pH=7.4)的10.4%。     

壳聚糖改性蒙脱石作为药物控释载体的研究

采用壳聚糖(CS)对钠基蒙脱石(MMT)进行改性制备有机蒙脱石(CS-MMT),对改性后的蒙脱石进行红外光谱(FT-IR)和X射线衍射(XRD)等分析表征.以5-氟尿嘧啶(5-FU)为药物模型制备出壳聚糖改性蒙脱石载药复合物(5-FU/CS-MMT),并以钠基蒙脱石载药复合物(5-FU/MMT)作为对照,探究载药复合物在模拟人工胃液、人工小肠液和人工结肠液中的药物释放情况.结果 表明,当CS的用量是MMT的1.0倍阳离子交换容量时,形成的有机蒙脱石的层间距增大,且对5-FU的载药量达到393 mg/g,而同等情况下,MMT的载药量为239 mg/g.体外释放试验的结果表明,5-FU/CS-MMT中5-FU的体外释放能力主要受释放介质pH值的影响,当pH值为7.4时,5-FU的累积释放率最大,在pH值为1.5时的结果最小.     

pH敏感释药型聚氨酯-阿霉素的合成及性能研究

以聚乙二醇、六亚甲基二异氰酸酯、2,2-二羟甲基丙酸为原料,采用预聚法合成了含羧基的聚氨酯(PU-COOH);PU-COOH经水合肼改性后,再与阿霉素(DOX)反应,制备了侧链键合药物的pH敏感释药型聚氨酯前药(PU-hyd-DOX)。采用核磁共振氢谱(1H-NMR)、凝胶渗透色谱(GPC)和紫外可见分光光谱(UV-vis)等手段对产物的结构进行了表征,前药中DOX的键合质量分数可达17.6%。在37℃不同pH缓冲溶液中的体外释药实验结果表明,PU-hyd-DOX具有良好的pH敏感释药性能,且在pH=7.4的缓冲溶液中对DOX无暴释。CCK-8细胞实验测试结果表明,PU-COOH对人乳腺癌细胞(MCF-7)基本无毒性,但PU-hyd-DOX对MCF-7细胞表现出良好的生长抑制作用。     

配位交联的DOX纳米颗粒的制备与质量评价

目的：以单宁酸(TA)和三氯化铁(FeCl₃)为载体材料,盐酸阿霉素(DOX)为主药,通过配位交联法制备纳米颗粒,并进行质量评价。方法：超声条件下将TA、FeCl₃、DOX依次混合制备纳米颗粒;使用粒径仪测量粒径和PDI值,并在透射电子显微镜(TEM)下观察纳米颗粒的形貌;考察纳米颗粒的稳定性及其体外药物释放行为;通过MTT法研究其在肿瘤细胞4T1上的毒性。结果：成功制备了以TA、FeCl₃为载体的DOX纳米颗粒(TA-Fe-DOX)。该纳米颗粒呈类球形,粒径为190nm;在一周内保持稳定;体外释放实验证明纳米颗粒在酸性环境的释药速率高于中性环境,具有明显的pH敏感性释药特征;细胞毒性实验结果表明TA-Fe空白载体没有明显毒性,而制备的TAFe-DOX纳米颗粒相对于游离药物DOX具有较高的抗肿瘤作用。结论：制备的TA-Fe-DOX纳米颗粒具有良好的pH敏感释药特性,能够提高肿瘤靶向性,为肿瘤治疗提供新的思路。     

疏水修饰磁性壳聚糖载药纳米粒子的制备与表征

利用O-羧甲基壳聚糖(O-CMC)的表面多种官能团(如-NH_2,-OH,-COOH等)与胆酸(CA)进行化学修饰得到两亲性共聚物,再以反溶剂法将Fe_3O_4和阿霉素(DOX)包埋在两亲性共聚物疏水的核中,制备两亲性的磁性壳聚糖载药纳米粒子,并对磁性载药纳米粒子的形貌、粒径大小、磁性、药物控释等进行了研究。结果表明:磁性壳聚糖纳米粒子有较高的药物包埋效率(92.3%),与自由阿霉素相比,磁性复合物具有明显的缓释作用和pH响应性;同时,有较好的超顺磁性。这些说明制备的疏水修饰磁性壳聚糖载药纳米粒子具有双重响应性,有望作为药物输送载体对肿瘤进行实时跟踪、诊断和治疗。     

二硫化钼纳米花球负载阿霉素对癌细胞的光热-化疗协同治疗作用

以钼酸钠、硫脲、柠檬酸及PEG-400为原料,通过水热法制备纳米MoS₂,考察了材料的光热转换性能及其对阿霉素（DOX）的负载及控释性能,并探讨了该载药体系对癌细胞的光热-化疗协同治疗作用。结果表明,通过该水热反应体系制备的尺寸约500 nm花球状MoS₂纳米材料具有良好的光热转换性能,对DOX的负载率可以达到136.8%,且其释药行为具有pH响应性,pH=5.8时DOX的累积释放量达到70.29%,约为pH=7.4条件下的7倍,表明该材料在药物负载/控释方面具有一定应用价值。此外,负载DOX后的MoS₂-DOX的纳米复合物在近红外光照射下对肝癌细胞HuH-7的抑制率高达92.09%,抑制效果明显高于单一的光热治疗和化疗。     

共轭亚油酸钠修饰TiO2纳米片稳定双水相Pickering乳液

采用水热法制备超薄TiO₂纳米片(TiO₂ NSs),以共轭亚油酸钠(SCL)在TiO₂ NSs表面吸附并引发SCL自交联制备共轭亚油酸钠修饰的TiO₂纳米片SCL@TiO₂ NSs,用紫外、红外、热重等手段证实SCL双层吸附在TiO₂ NSs表面上。以SCL@TiO₂ NSs稳定聚乙二醇20000(PEG 20000)-葡聚糖500000(DEX 500000)双水相Pickering乳液,结果表明,以0.5%(质量分数)的SCL@TiO₂ NSs即可稳定乳液,当控制乳化剂浓度不变时,改变两相比例可以使乳液发生相反转。该双水相Pickering乳液具有pH响应性。     

纳米硼粉的改性及其对硼/硝化棉纳米纤维的影响

为了改善硼粉在含能材料中的分散性,用3-氨丙基三乙氧基硅烷(KH-550)对纳米硼粉进行改性,并用静电纺丝法制备了硼/硝化棉(B/NC)和改性B/NC纳米纤维;用扫描电镜(SEM)、透射电镜(TEM)和能谱仪(EDS)对样品进行了表征,用TG-DSC联合热分析仪对硼粉及改性前后的硼/硝化棉纳米纤维的热性能进行了分析。结果表明,改性对硼粉的粒径影响不大,改性后的硼粉在硝化棉纳米纤维中分散更均匀,纤维粗细相对均匀,改性前后硼/硝化棉纳米纤维的平均直径均为350nm左右;TG曲线表明,随着改性硼粉在NC中分散性的改善,B/NC纳米纤维和改性B/NC纳米纤维中的硼质量增加比原硼粉多46.53%和74.3%;与硼粉放热峰峰温相比,B/NC纳米纤维和改性B/NC纳米纤维中硼的放热峰峰温分别降低37.4℃和71.9℃。     

还原响应性含硒纳米胶束的制备及其载药性能研究

以亲水性单甲氧基聚乙二醇(mPEG)与一端修饰有疏水性十六烷醇的3,3′-二硒代二丙酸(DSeDPA)通过酯化反应合成了两亲性聚合物mPEG-Se-Se-C_(16),以此为载体制备了负载抗癌药物阿霉素(DOX)的载药胶束,通过Raman光谱、FTIR和~1HNMR对中间体和聚合物结构进行表征。TEM、DLS和CMC分析发现胶束呈规则的圆球状,纳米载药胶束粒径为(198±5)nm(PDI=0.239),聚合物的临界胶束浓度为0.079 mg·mL~(-1)。载药胶束的包封率为51.92%,载药率为9.01%。药物释放和细胞毒性研究表明,基于二硒键的纳米载药胶束有显著的GSH敏感性,能将DOX快速、完全地释放出来,对肿瘤细胞具有精确的选择性和特异性,对正常细胞无明显毒性。     

Hollow superparamagnetic iron oxide nanoshells as a hydrophobic anticancer drug carrier: intracelluar pH-dependent drug release and enhanced cytotoxicity

With curcumin and doxorubicin (DOX) base as model drugs, intracellular delivery of hydrophobic anticancer drugs by hollow structured superparamagnetic iron oxide (SPIO) nanoshells (hydrodynamic diameter: 191.9 ± 2.6 nm) was studied in glioblastoma U-87 MG cells. SPIO nanoshell-based encapsulation provided a stable aqueous dispersion of the curcumin. After the SPIO nanoshells were internalized by U-87 MG cells, they localized at the acidic compartments of endosomes and lysosomes. In endosome/lysosome-mimicking buffers with a pH of 4.5-5.5, pH-dependent drug release was observed from curcumin or DOX loaded SPIO nanoshells (curcumin/SPIO or DOX/SPIO). Compared with the free drug, the intracellular curcumin content delivered via curcumin/SPIO was 30 fold higher. Increased intracellular drug content for DOX base delivered via DOX/SPIO was also confirmed, along with a fast intracellular DOX release that was attributed to its protonation in the acidic environment. DOX/SPIO enhanced caspase-3 activity by twofold compared with free DOX base. The concentration that induced 50% cytotoxic effect (CC(50)) was 0.05 ± 0.03 μg ml(-1) for DOX/SPIO, while it was 0.13 ± 0.02 μg ml(-1) for free DOX base. These results suggested SPIO nanoshells might be a promising intracellular carrier for hydrophobic anticancer drugs.     

Imaging‐Guided pHe and Glutathione Dual Responsive Polypeptide Nanogel for Smart Drug Delivery

A negatively charged polypeptide nanogel, near‐infrared (NIR) cyanine dye (Cy5.5) conjugated and 2,3‐dimethylmaleic anhydride (DMA) modified poly‐l ‐lysine‐co‐l ‐cystine (CDPLC), is synthesized and is used as an imaging‐guided sequential drug delivery system. The CDPLC nanogel can respond to two general stimulations in sequence: extracellular tumor acidic microenvironment pHe (6.8–6.5) and intracellular high concentration glutathione (GSH). Under pHe, the DMA shell of the nanogel is removed and a charge reversal takes place, resulting in positively charged nanogel which can be internalized by cancer cells easily. Once internalized into tumor cells, the increased intracellular GSH concentration further promotes DOX release from the nanogel and DOX is enriched to the nucleus. Cy5.5 is conjugated to the nanogel as an NIR fluorescent probe, making it possible for imaging‐guided drug delivery, which is confirmed by the MTT and confocal laser scanning microscopy via in vitro experiments. The as‐prepared nanogel is a potential theranostic for cancer therapy.     

Green fabrication of porous chitosan/graphene oxide composite xerogels for drug delivery

Porous chitosan (CS)/graphene oxide (GO) composite xerogels were prepared through a simple and “green” freeze‐drying method. Scanning electron microscopy, Fourier transform infrared spectrometry, powder X‐ray diffraction, and compressive strength measurements were performed to characterize the microstructures and mechanical properties of as‐prepared composite xerogels. The results show that the incorporation of GO resulted in an observable change in the porous structure and an obvious increase in the compressive strength. The abilities of the composite xerogels to absorb and slowly release an anticancer drug, doxorubicin hydrochloride (DOX), in particular, the influence of different GO contents, were investigated systematically. The porous CS/GO composite xerogels exhibited efficient DOX‐delivery ability, and both the adsorption and slow‐release abilities increased obviously with increasing GO content. Additionally, the best adsorption concentration of DOX was 0.2 mg/mL, and the cumulative release percentage of DOX from the xerogels at pH4 much higher than that at pH 7.4. Therefore, such porous CS/GO composite xerogels could be promising materials as postoperation implanting stents for the design of new anticancer drug‐release carriers. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2014 , 131, 40006.     

血小板膜伪装介孔聚多巴胺纳米药物传递系统的制备及应用

以三甲基苯为模板剂,采用一锅法制备了具有介孔结构的聚多巴胺纳米粒子(MPDA).通过静电吸附负载盐酸阿霉素(DOX),通过血小板膜(PLTM)仿生伪装得到PLTM-DOX@MPDA纳米粒子.采用TEM、纳米粒度分析仪、BET和UV-Vis对纳米粒子的性质、形貌和粒径进行表征.结果表明,MPDA表面具有清晰的介孔结构,经PLTM包裹后的PLTM-DOX@MPDA平均粒径约为184 nm.MPDA孔径主要分布于45 nm左右,孔容为0.6232 cm3/g,比表面积高达61.181 m2/g,该介孔结构支持MPDA作为高效的药物传递系统.体外释药、体外细胞摄取和体外细胞毒性实验结果表明,PLTM-DOX@MPDA具有pH响应性控制药物释放,可以实现药物缓释,可以避免巨噬细胞吞噬并且主动靶向癌细胞,可显著提高DOX对人乳腺癌细胞(MDA-MB-231)细胞的杀伤作用.     

Design and characterization of pH stimuli-responsive nanofiber drug delivery system: The promising targeted carriers for tumor therapy

New carrier platforms have been designed for an electrospun pyridinium calixarene nanofiber for controlled drug delivery. First, 5,11,17,23-tetra-tert-butyl-25,27-bis(3-aminomethyl-pyridineamido)-26,28-dihydroxycalix[4]arene (3-AMP) scaffold was produced by electrospinning. AMP scaffold was modified by human serum albumin (HSA), folic acid (FA), and glutathione (GSH). Doxorubicin (DOX) was loaded to surfaces of the AMP, AMP-HSA, AMP-HSA-FA, and AMP-HSA-GSH nanofibers by using DOX solution in different buffers with, 2.2, 4.0, 6.0, and 7.4 pH. The release studies DOX from four different nanofibers was also done in a various amount microenviroments by changing pH values. The loading and release amount of DOX was estimated from the calibration curve drawn at 480 and 560 nm of excitation and emission wavelengths by using a fluorescence spectrophotometer. The loading studies were confirmed by Fourier transforms infrared, atomic force microscopy, transmission electron microscopy, scanning electron microscope, and energy-dispersive X-ray (EDX) analysis.     

Polyurethane/doxorubicin nanoparticles based on electrostatic interactions as pH‐sensitive drug delivery carriers

In order to obtain a pH‐sensitive delivery carrier for doxorubicin (DOX), DOX‐loaded polyurethane (PU·DOX) nanoparticles were readily prepared in water by electrostatic interactions between amphiphilic polyurethane with carboxyl pendent groups (PU‐COOH) and doxorubicin hydrochloride (DOX·HCl). The structures of the products obtained were characterized by Fourier transform infrared spectroscopy, ¹H NMR spectroscopy, gel permeation chromatography, UV–visible spectroscopy, dynamic light scattering and transmission electron microscopy. The average hydrodynamic size of the PU·DOX nanoparticles was around 182 nm with negative surface charge (?1.1 mV) and a spherical or rodlike shape. PU·DOX nanoparticles had a higher drug‐loading content of 14.1 wt%. The in vitro drug release properties of PU·DOX nanoparticles were investigated at pH 4.0, 5.0 and 7.4, respectively. PU·DOX nanoparticles exhibited a good pH‐sensitive drug release property, but there was almost no release of DOX from PU·DOX nanoparticles at pH 7.4. The in vitro cellular uptake assay and the Cell Counting Kit‐8 assay demonstrated that PU·DOX nanoparticles had a higher level of cellular internalization and higher inhibitory effects on the proliferation of human breast cancer (MCF‐7) cells than pure DOX. The enhancement of the inhibition effects resulted from increasing apoptosis‐inducing effects on MCF‐7 cells, which was related to the enhancement of Bax expression and the reduction of Bcl‐2 expression confirmed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay, real‐time polymerase chain reaction (PCR) assay and western blot assay. © 2018 Society of Chemical Industry     

PEG and PEG-peptide based doxorubicin delivery systems containing hydrazone bond

mPEG and mPEG-peptide based drug delivery systems were prepared by conjugating doxorubicin (DOX) to these carrier molecules via hydrazone bond. The peptide, AT1, with a sequence of CG₃H₆G₃E served as mPEG and doxorubicin attachment site. Histidines were incorporated to the sequence to improve pH responsiveness of the carrier molecule. Hydrodynamic diameters (mean sizes) of mPEG-based drug delivery system (mPEG-HYD-DOX) were measured as 9?±?0.5 and 7?±?0.5 nm at pH 7.4 and pH 5.0, respectively. Mean size of the aggregates of the peptide containing drug delivery system, mPEG-AT1-DOX, was determined as 12?±?2 nm at neutral pH. At pH 5.0, on the other hand, mPEG-AT1-DOX exhibited a size distribution between 20 and 100 nm centered at about 40 nm. Comparison of % DOX release values of the drug delivery systems obtained at pH 7.4 and pH 5.0 indicated that mPEG-AT1-DOX has enhanced pH sensitivity. DOX equivalent absolute IC₅₀ values were obtained as 0.96?±?0.51, 21.9?±?5.9, and 5.55?±?0.75 μg/mL for free DOX, mPEG-HYD-DOX, and mPEG-AT1-DOX, respectively. Considering more pronounced pH sensitivity and cytotoxicity of mPEG-AT1-DOX, the use of both pH responsive functional groups and acid cleavable chemical bond between the carrier molecule and drug can be a promising approach in the design of drug delivery systems for cancer therapy.     

Synthesis and physicochemical characterization of amphiphilic block copolymers bearing acid-sensitive orthoester linkage as the drug carrier

Amphiphilic block copolymers bearing an acid-sensitive orthoester linkage, composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(γ-benzyl L-glutamate) (PBLG), were prepared as the carrier capable of selectively releasing the hydrophobic drug at the mildly acidic condition. Diblock copolymers with various lengths of PBLG were synthesized via ring opening polymerization of benzyl glutamate NCA in the presence of the acid-labile PEG as a macroinitiator. Owing to their amphiphilicities, the copolymers formed spherical micelles in aqueous conditions, and their particle sizes (22-106 nm in diameter) were dependent on the block length of PBLG. These nanoparticles were stable in the physiological buffer (pH 7.4), whereas they were readily decomposed under the acidic condition. In particular, the block copolymer with a smaller hydrophobic portion was rapidly disassembled under the acidic condition. Doxorubicin (DOX), chosen as the model anti-cancer drug, was effectively encapsulated into the hydrophobic core of the micelles using the solvent casting method. The loading efficiency depended on the hydrophobic block length of the copolymer; i.e., the longer hydrophobic block allowed for loading of larger amounts of the drug. In vitro release studies demonstrated that DOX was slowly released from the pH-sensitive micelles in the physiological buffer (pH 7.4), whereas the release rate of DOX significantly increased under the acidic condition (pH 5.0). From the in vitro cytotoxicity test, it was found that DOX-loaded pH-sensitive micelles showed higher toxicity to SCC7 cancer cells than DOX-loaded micelles without the orthoester linker. These results suggest that the amphiphilic block copolymer bearing the orthoester linkage is useful for pH-triggered delivery of the hydrophobic drug.     

A versatile strategy to construct surface functionalized pH/redox dual stimuli-responsive nanogels for targeted drug delivery

Developing facile, green, and efficient synthetic methodology for preparing surface-functionalized nanogels has attracted tremendous attention in the field of polymer chemistry and biomaterials engineering. Herein, a series of “clickable” P(MAA-PMA) nanogels with reactive alkyne groups were conveniently prepared by “one-pot” reflux-precipitation polymerization (RPP), their particle sizes and zeta potentials are solid content-dependent. Using P(MAA-PMA)-1 nanogels as the model, the physicochemical properties including particle size, surface potential, morphology, solution stability, and pH/redox responsiveness were characterized in detail. Moreover, the pH/redox dual-responsive drug release feature/kinetics and parameters were analyzed using Korsmeyer–Peppas model and Gallagher–Corrigan model. Then the surface of nanogels was facilely modified with various thiol-containing functional ligands via thiol-yne photo click reaction. As targeted drug carriers, doxorubicin (DOX)-loaded folic acid (FA)-functionalized nanogels (FA@Nanogels/DOX) demonstrated higher tumor cell proliferation inhibition effect in B16F10 cancer cells than that in CHO-K1 normal cells, while the non-FA-functionalized counterparts (Nanogels/DOX) do not show similar effect. This work provides a versatile “one-pot RPP-photo Click functionalization” strategy to construct surface-functionalized pH/redox dual responsive nanogels for efficient and targeted drug delivery.     

Poly(β,L-malic acid)/Doxorubicin ionic complex: A pH-dependent delivery system

Poly(β,L-malic acid) (PMLA) was made to interact with the cationic anticancer drug Doxorubicin (DOX) in aqueous solution to form ionic complexes with different compositions and an efficiency near to 100%. The PMLA/DOX complexes were characterized by spectroscopy, thermal analysis, and scanning electron microscopy. According to their composition, the PMLA/DOX complexes spontaneously self-assembled into spherical micro or nanoparticles with negative surface charge. Hydrolytic degradation of PMLA/DOX complexes took place by cleavage of the main chain ester bond and simultaneous release of the drug. In vitro drug release studies revealed that DOX delivery from the complexes was favored by acidic pH and high ionic strength.