双刺激响应型纳米载药系统的构建及性能

采用聚乙二醇单甲醚(mPEG)为亲水段,聚赖氨酸(PzLL)为疏水段,通过二硫键和碳氮双键串联桥连合成了两嵌段共聚物(mPEG-CN-SS-PzLL),其中的二硫键具有还原敏感性,碳氮双键具有pH酸敏感性。通过红外光谱和核磁共振谱等手段测试分析了产物的化学结构。将聚合物通过透析法自组装制备得到双刺激响应型纳米载药粒子。结果表明:该纳米载药粒子的药物包封率较高,达到52%。该载药系统在还原环境或酸性环境下具有良好的体外释药性能。     

刺激响应型聚合物前药

前药(prodrug)是一类经过生物体内转化后才具有药理作用的化合物。与传统纳米药物输送系统相比具有载药率确定、稳定性高、爆释现象小等优点。但是,前药本身也面临着可控性,特异性释药不足而引起效果不佳等问题。因此,能够靶向病灶部位并能够针对病灶部位进行特异性释药的刺激敏感型前药受到广泛研究。本文以国内外学者及本课题组的研究成果为基础,以肿瘤部位特殊的生理环境为背景,综述了近年来pH敏感、温敏、氧化还原敏感、酶敏感等生物刺激响应型抗肿瘤聚合物前药的研究进展。     

基于肿瘤微环境响应的DNA纳米结构递药系统

DNA分子由于其独特的生物相容性和可编程性,在增强药物靶向性和降低药物毒性方面展现了独特的优势和巨大的潜力。随着人们对肿瘤微环境研究的深入和环境响应性的DNA触发器的研制,近些年已报道了许多基于肿瘤微环境响应的DNA纳米结构递药系统,这些DNA纳米结构递药系统结合了纳米运载工具良好的生物分布和药代动力学特性,以及小型药物载体的快速扩散和渗透特性。通过靶向广泛的肿瘤栖息地而不是肿瘤特异性受体,该策略有可能克服肿瘤异质性问题,并可用于设计诊断和治疗多种实体肿瘤的纳米颗粒。在体内能够稳定地转运,在肿瘤组织独特的微环境刺激下释放药物,能有效地控制药物释放部位和释放速度,极大地降低了肿瘤治疗的毒副作用。本文主要从pH响应型、GSH响应型、ATP响应型、酶响应型、抗原响应型五个方面,综述了基于肿瘤微环境响应的DNA纳米结构递药系统的最新研究进展,分类介绍了这些DNA纳米载体的设计策略和响应释放机制,此外,还重点介绍了该领域面临的前景和挑战。     

刺激响应脂质体及其在控制释药中的应用

刺激响应型纳米药物递送系统是一种功能性纳米给药系统.刺激响应脂质体不仅提供定位化学治疗,而且还具有控制释放药物的潜能,因此对于实施控制治疗肿瘤具有重要意义.当脂质体在特殊环境(包括热、光、磁和p H等)刺激下,可通过载体微观结构发生变化释放药物.刺激响应脂质体的优势是可减少或避免药物过早释放,提高靶向部位的释药效率.本文介绍了刺激响应脂质体的结构、特性和功能,分别综述了热、光、磁、p H刺激响应和p H-温度双刺激响应脂质体的特性,并讨论了刺激释药的机制.     

羧甲基壳聚糖/有机累托石纳米复合材料及其药物缓释性能研究

利用简单的溶液插层法制备了羧甲基壳聚糖/有机累托石纳米复合材料,其中累托石(REC)用十六烷基三甲基溴化铵进行改性.用X-射线衍射(XRD)、红外光谱(FTIR)和扫描电镜(SEM)表征了该纳米复合材料的微观结构和形态,实验表明羧甲基壳聚糖插层进入了累托石层间,增大了累托石的层间距,并且累托石均匀地分布在羧甲基壳聚糖基体中.以牛血清蛋白(BSA)为药物模型,研究了纳米复合材料与海藻酸钠形成的微球的药物缓释性能.结果显示,该微球对药物的包封率及缓释性能与纯羧甲基壳聚糖微球相比都有较大改善,包封率从56%提高到86%,药物缓释时间从24 h上升到72 h.并且纳米复合材料/海藻酸钠微球的释药具有pH响应性,在pH为1.2的条件下释药慢,而在pH为7.4时释药快,可用于小肠或结肠定位缓释系统.因此,羧甲基壳聚糖/有机累托石纳米复合材料很有潜力作为药物载体.     

葡萄糖敏感苯硼酸基高分子纳米药物传输体系

近年来,智能葡萄糖敏感自调式药物传递系统备受关注。这种智能药物释放系统能够模拟胰腺分泌胰岛素的生理模式而精准调控药物释放并控制血糖水平,在糖尿病治疗中具有良好的应用前景。其中,苯硼酸(PBA)功能化的葡萄糖敏感高分子纳米载体成为近年来的研究热点之一。该类材料具有体系稳定、可长期储存、可逆的葡萄糖敏感性能等优势。根据响应因素不同,葡萄糖敏感药物传递系统可分为pH响应、温度响应和光响应等类型。本文重点介绍了基于PBA的葡萄糖敏感高分子纳米药物载体的发展过程、性能和应用,并对该领域的发展前景进行了展望。     

丁二酸酐接枝纳米纤维素负载木犀草素及其苷（英文）

将纳米纤维素(NCC)表面接枝丁二酸酐得到丁二酸酐化纳米纤维素(NCSA),再将阳离子表面活性剂十六烷基三甲基溴化铵(CTAB)负载到NCSA,得到一种新的纳米药物载体(CTAB@NCSA).考察了NCSA的物理化学性能,包括扫描、透射电镜,红外光谱,X射线粉末衍射及电位测定;同时研究了NCSA对CTAB的吸附行为.最后以CTAB@NCSA为药物载体,以LUT和LUS为模型药物,通过分子间作用力及疏水作用力得到负载LUT和LUS的纳米复合物微球CTAB@NCSA@LUT和CTAB@NCSA@LUS,并对其体外释药进行了研究.     

阿霉素-姜黄素纳米递药系统制备及体外缓释研究

基于点击反应,高效合成具有pH响应性和高载药率的己烷-1,6-二丙炔酸二酯共交联阿霉素、姜黄素主链型纳米递药系统,并采用紫外光谱、红外光谱、粒度仪、Zata电位、透射电镜进行结构及形貌表征,并考察其在不同pH条件的缓释行为,监测纳米粒降解后的形态学变化。结果表明：所制材料为双药共载均匀球形纳米粒,粒径100～200 nm。通过pH响应化学键实现对药物“智能”化控制释放。纳米粒所载阿霉素的包封率49.7%,载药率59.4%;姜黄素的包封率41.1%,载药率35.7%。缓释曲线显示：随环境pH降低,药物释放率增大,粒径分布变宽,电镜观察形貌从均匀球形变成“树枝状”;而在正常生理条件下药物基本不释放。实验表明该纳米递药系统具有良好的肿瘤微环境pH响应及缓控释性能。     

肿瘤靶向pH响应载药ZnO量子点的制备、表征及对阿霉素的控制释放研究

聚丙烯酸(PAA)接枝聚乙二醇(PEG)和叶酸(FA)形成含有羧基的聚合物PAA-PEG-FA,与氨基修饰的ZnO量子点(ZnO QDs)表面的氨基通过静电作用过,形成具有肿瘤靶向pH响应的ZnO@(PAA-PEGFA)核/壳纳米粒子(量子点为核,聚合物为壳),抗癌药物阿霉素(DOX)通过配位形成肿瘤靶智能释药/显像体系:ZnO@(PAA-PEG-FA)-DOX(量子点的荧光可示踪/显像药物递送过程)。核磁共振(1 H-NMR)和红外光谱测试结果表明,PAA-PEG-FA聚合物和氨基ZnO QDs通过静电引力组合为核/壳纳米粒子;透射电镜(TEM)测得该体系呈规整球形且分布均匀,平均粒径约10nm;体外模拟释放结果表明,载药体系在癌细胞的溶酶体/内涵体(pH 5)内能很好地释放出阿霉素,而在药物输送过程(pH 7.4)中只有很少的阿霉素释放出来。因此,该肿瘤靶向pH响应型ZnO纳米颗粒作为抗癌药物载体具有潜在的应用价值。     

基于cypate光裂解的新型近红外光响应稀土上转换纳米载药系统※

光响应药物释放体系具有非侵入性、远程可控且时空分辨率高等特点, 在杀菌、抗癌等生物医学领域具有重要应用价值. 但目前近红外光响应的光裂解药物递送体系报道较少且光响应效率还有待提高. 本工作将稀土纳米颗粒包覆介孔二氧化硅, 逐步偶联近红外染料cypate、金刚烷胺和β-环糊精来封堵孔口, 利用cypate的自敏光氧化断键作为光响应开关, 成功构建了一种新型近红外光响应稀土上转换纳米载药系统. 该纳米载药系统负载抗生素氧氟沙星表现出极低的药物流失率和较高的808 nm光照释放效率, 并且通过控制光照时间可以满足不同的给药量需求. 体外抗菌实验结果进一步验证了该纳米载药系统的光响应药物释放性能. 此外, 该纳米载药系统在980 nm激光激发下的上转换发光较强且不影响药物释放, 可以实现纳米载药系统的药物定位和生物成像功能. 本研究为发展高效光响应载药体系提供了新的思路.     

基于壳聚糖的纳米药物传递体系

壳聚糖作为天然高分子材料,不仅安全无毒、而且具有良好的生物相容性、可生物降解性等优点,在药物传递领域作为纳米载体倍受关注。壳聚糖基纳米载体材料制备条件简单温和,近年来,其相关研究也颇为新颖。本文以载体形成的驱动力作为切入点,从共价交联、离子相互作用、聚电解质络合物和疏水改性四个方面,总结不同种类壳聚糖基纳米载体的构筑方法,同时介绍该载体对药物传递中载药量、载药率、释放行为以及细胞毒性等方面的影响,在此基础上展望其未来的应用前景。     

Controlled release of 4-hydroperoxycyclophosphamide from the fatty acid dimer-sebacic acid copolymer

Controlled polymeric release of chemotherapeutic agents has shown promise in the management of malignant gliomas. 4-Hydroperoxycyclophosphamide (4HC), loaded on the fatty acid dimer–sebacic acid copolymer (FAD:SA, 1:1), significantly prolonged survival in rats implanted with F98 and 9L gliomas. Here, we studied the in vitro and in vivo release kinetics in phosphate-buffered saline and rat brain of 20% 4HC/FAD:SA (wt:wt), the optimal dose for treatment of rat gliomas. In vitro release under infinite sink conditions was steady over the initial 12 hr to a peak of 20–35% of impregnated drug, consistent with early phase control via surface erosion. Release over the next 3 weeks was minimal, consistent with barrier formation around the polymer by an oily fatty acid dimer degradation product and consequent slowing of release. However, the polymer started to disintegrate by day 4, and there were minimal visible remnants by 3 weeks. Thus, a considerable amount of polymer-carried drug was probably lost in the disintegrating fragments. Also, drug loss is expected from its inherent hydrolytic instability. In vivo release into brain revealed two peak levels of drug at 0–1 hr and 5–20 days. With loaded polymer implanted intraperitoneally or cyclophosphamide injected systemically, peak brain drug levels were measured in 2–8 hr, with substantial decrease by 48 hr without a second peak. Brain levels were substantially higher than blood levels at all time periods. We conclude that FAD:SA (1:1) adequately protects the otherwise labile 4HC, allowing effective and substained drug release in vivo. Furthermore, it should be possible to modify the polymer to adjust the time of peak release for more beneficial therapeutic effects.     

An alternative approach to controlled release of oxprenolol from the implantable delivery system based on biodegradable copolymer and genistein

This paper describes the development of covalent star-shaped poly(L-lactide/?-caprolactone) random copolymer-oxprenolol (OXP) conjugates as a potential approach to controlling drug release from implantable delivery systems. We prepared synthesized materials containing 14–17 mol% OXP, which were conjugated via an ester bond. The conjugates, which were composed of biodegradable copolyester chains, natural genistein as a central core and drug, were characterized by hydrogen nuclear magnetic resonance (¹H-NMR), Fourier transform infrared spectroscopy (FTIR) and viscosity methods. We evaluated the cyto- and genotoxicity of the synthesized copolymeric matrices, followed by the conjugates, with bacterial luminescence, protozoan and Salmonella typhimurium TA1535 assays. Furthermore, we performed in vitro mammalian assays of the obtained products with V79 cells. We found that the in vitro release of OXP from the obtained star-shaped conjugates was dependent on the structure of the synthesized biodegradable matrices.     

A novel route for preparation of multifunctional polymeric nanocarriers for stimuli‐triggered drug release

Fluorescence‐incorporated, crosslinker‐free, pH‐ and thermoresponsive nanocarriers were prepared by the incorporation of drug molecules into the thermoresponsive nanocapsules, which composed of poly(N‐isopropylacrylamide) (PNIPAAm) with carboxylic acid end groups via temperature induced self‐assembling method. Well‐defined, pH‐responsive carboxylic acid group‐ended PNIPAAm homopolymer (HOOC? PNIPAAm? COOH) was synthesized by reversible addition fragmentation chain transfer polymerization with S,S′‐bis(α,α′‐dimethyl‐α″‐acetic acid)trithiocarbonate (CMP) as a chain transfer agent. Rhodamine 6G (R6G), the model drug, was used for three kinds of application: First, the nanostructure fixing; second, the fluorescence‐labeling; and last, the controlled release modeling. The transmission electron microscope images showed the solution type dosing led to the encapsulation of drug molecules into the nanocarriers, while the powder‐type drug‐loading process significantly contributed to the structure preservation of nanocarriers. The controlled release behaviors with various pH values and temperatures were evaluated. These multifunctional nanocarriers have potential to be applied for the biomedical therapy by stimuli‐responsive controlled release. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 561–571     

Antitumor Drug Delivery Modulated by A Polymeric Micelle with an Upper Critical Solution Temperature

Thermally sensitive polymeric nanocarriers were developed to optimize the release profile of encapsulated compounds to improve treatment efficiency. However, when referring to thermally sensitive polymeric nanocarriers, this usually means systems fabricated from lower critical solution temperature (LCST) polymers, which have been intensively studied. To extend the field of thermally sensitive polymeric nanocarriers, we for the first time fabricated a polymeric drug delivery system having an upper critical solution temperature (UCST) of 43 °C based on an amphiphilic polymer poly(AAm‐co‐AN)‐g‐PEG. The resulting polymeric micelles could effectively encapsulate doxorubicin and exhibited thermally sensitive drug release both in vitro and in vivo. A drastically improved anticancer efficiency (IC₅₀ decreased from 4.6 to 1.6 μg mL^?1, tumor inhibition rate increased from 55.6 % to 92.8 %) was observed. These results suggest that UCST‐based drug delivery can be an alternative to thermally sensitive LCST‐based drug delivery systems for an enhanced antitumor efficiency.     

Coencapsulation of Butyl‐Methoxydibenzoylmethane and Octocrylene into Lipid Nanocarriers: UV Performance,Photostability and in vitro Release

The coencapsulation of two UV filters, butyl‐methoxydibenzoylmethane (BMDBM) and octocrylene (OCT), into lipid nanocarriers was explored to develop stable cosmetic formulations with broad‐spectrum photoprotection and slow release properties. Different types of nanocarriers in various concentrations of the two UV filters were tested to find the combination with the best absorption and release properties. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have been the two types of lipid nanocarriers used. The NLCs were based on either medium chain triglycerides (MCT) or squalene (Sq). The following physicochemical properties of the nanocarriers have been evaluated: particle size, morphology, zeta potential (ZP), entrapment efficiency, loading capacity, and thermal behavior. The nanocarriers have been formulated into creams containing low amounts of UV filters (2.5% BMDBM and 1% OCT). The best photoprotection results were obtained with the cream based on NLCs prepared with MCT, having a sun protection factor (SPF) of 17.2 and an erythemal UVA protection factor (EUVA–PF) of 50.8. The photostability of the encapsulated BMDBM filter was confirmed by subjecting the nanocarriers‐based creams to in vitro irradiation. The prolonged UV‐protection efficacy was coupled with a slow in vitro release of the synthetic UV filters, which followed the Higuchi release model.     

In situ forming PLGA implant for 90 days controlled release of leuprolide acetate for treatment of prostate cancer

In prostate cancer, hormone therapy via leuprolide acetate drug (LUP) is used to lower the level of testosterone down to castration level to effectively control the development of prostate cancer. The objective of this study was to evaluate the effective parameters in degradation and controlled release of an injectable in situ formed polymeric implant, loaded with leuprolide acetate, in order to achieve an optimum formulation for sustained drug release for 90 days with minimum burst release. The main problem associating with such implants is their high burst release. Designing an injectable implant with sustained and minimum burst release has thus become an attractive challenge in drug delivery field. Effects of type of poly(lactic‐co‐glycolic acid) 75:25 copolymers (RG752, RG756) and addition of nano‐hydroxyapatite (HA) particles on degradation rates of the implants and release profiles were examined in vitro and in vivo in a rabbit animal model. Results showed that implants containing polymers with higher molecular weights had significantly lower weight loss and molecular weight reduction. Adding nanoparticles of hydroxyapatite into poly(lactic‐co‐glycolic acid) implants caused further reduction in degradation rates, leading to a more sustained drug release in vivo, with reduced burst release. Different conventional kinetic models were applied to drug release and degradation data. The degradation data fit well to the first‐order degradation model. Higuchi model was the best kinetic release model fitted to the experimental in vitro release data. This study led to an optimum formulation (RG756:RG752 3:1 + 5% HA) with sustained leuprolide release and testosterone suppression over a 90‐day period with significant decrease of burst release phase (50%, p < 0.001) compared with the conventional Eligard formulation. The histopathology test showed that the formulated implant had no effects of toxicity or tissue necrosis in organs of the animal model. Copyright © 2017 John Wiley & Sons, Ltd.     

Reduction‐Triggered Transformation of Disulfide‐Containing Micelles at Chemically Tunable Rates

A dilemma exists between the circulation stability and cargo release/mass diffusion at desired sites when designing delivery nanocarriers and in vivo nanoreactors. Reported herein are disulfide‐crosslinked (DCL) micelles exhibiting reduction‐triggered switching of crosslinking modules and synchronized hydrophobic‐to‐hydrophilic transition. Tumor cell targeted DCL micelles undergo cytoplasmic milieu triggered disulfide cleavage and self‐immolative decaging reactions at chemically adjustable rates, generating primary amine moieties. Extensive amidation reactions with neighboring ester moieties then occur because of the high local concentration and suppression of the apparent amine pK_a value within the hydrophobic cores, thus leading to the transformation of crosslinking modules and formation of tracelessly crosslinked (TCL) micelles, with hydrophilic cores, inside live cells. We further integrate this design principle with theranostic nanocarriers for selective intracellular drug transport guided by enhanced magnetic resonance (MR) imaging performance.     

Molecularly imprinted polymer nanocarriers for recognition and sustained release of diclofenac

In this study, a series of imprinted poly(methacrylic acid‐co‐ethylene glycol dimethacrylate) nanocarriers for diclofenac and corresponding nonimprinted polymer nanocarriers have been synthesized in 4 different types of solvents by precipitation polymerization. The products were characterized by Fourier transform infrared, scanning electron microscopy, dynamic light scattering, and Brunauer‐Emmett‐Teller measurement. Results showed that uniformly sized molecularly imprinted polymer (MIP) nanospheres with relatively good porosity could only be obtained in acetonitrile. The effects of solvents on the recognition and release properties of polymer particles were also carefully investigated. The binding experiments indicated that MIPs prepared in acetonitrile displayed much higher binding capacity than other MIPs with a maximum binding capacity of 65.18 mg g⁻¹. The Scatchard analysis showed that synthetic MIPs have special recognition sites for diclofenac, while nonimprinted polymers have not. The Sips model could provide a best fit to the equilibrium data of nanocarriers over whole concentrations. The experimental data of an adsorption kinetic study were well fitted to the pseudo–second‐order kinetic model, indicating the chemisorption mechanism between diclofenac and MIPs in the process of adsorption. The drug release of diclofenac from MIPs could well be described by the Ritger‐Peppas model, suggesting a non‐Fickian diffusion mechanism. In addition, we successfully used MIPs to extract diclofenac at low levels from fetal bovine serum.     

“Smart” carboxymethylchitosan hydrogels crosslinked with poly(N-isopropylacrylamide) and poly(acrylic acid) for controlled drug release

Carboxymethylchitosan (CMC) hydrogels containing thermo-responsive poly(N-isopropylacrylamide) (poly(NIPAAm)) and pH-responsive poly(acrylic acid) (poly(AA)) were prepared via a free radical polymerization in the presence of hexamethylene-1,6-di-(aminocarboxysulfonate) crosslinking agents. A proper ratio of CMC to NIPAAm and AA used in the reaction was investigated such that the thermo- and pH-responsive properties of the hydrogels were obtained. Water swelling of the hydrogels was improved when the solution pH was in basic conditions (pH 10) or the temperature was below its lower critical solution temperature (LCST). Effects of the change in solution temperature and pH on water swelling properties of the hydrogel as well as the releasing rate of an entrapped drug were also investigated. The hydrogels were not toxic and showed antibacterial activity against Straphylococcus aureus (S. aureus). The pH- and thermo-responsive properties of this novel “smart” hydrogel might be efficiently used as dual triggering mechanisms in controlled drug release applications.