蛋白质和多肽类药物的口服给药：尚未实现的希望

实现蛋白质和多肽类药物的口服给药是药物递送长期追求的目标 ,具有很好的发展前景 ,同时也存在许多问题。渗透性、稳定性及在胃肠内的转运时间等是影响该类药物口服吸收的因素 ,但分子大小一般认为是最主要的障碍。本文主要介绍处方组成、包囊技术、大分子复合物和化学修饰四种改善蛋白质和多肽类药物在胃肠道吸收状况的基本方法。对于吸收促进剂和酶抑制剂已进行了多年的研究。此技术着重于通过改变多肽的渗透性和可消化性来改善其在胃肠道的吸收状况 ,这些组分会改变粘膜表面的完整性 ,甚至会产生全身和局部的副作用。最近开发出一种新的…     

介孔碳纳米粒的构建及化疗-光疗联合抗多药耐药肿瘤研究

目的:构建负载化疗药物并具有光热和光动力联合治疗效果的介孔碳纳米粒(MCNs),研究其体外抗多药耐药肿瘤的作用。方法:利用低浓度水热法制备MCNs,通过混酸超声法将MCNs表面羧基化制成MCNs-COOH(MCNC),对其形貌、表面性质等进行表征。利用吸附法构建负载阿霉素(ADR)的ADR/MCNC,通过紫外吸光度计算其载药量,利用透析法考察其释放特性。选用耐ADR人乳腺癌MCF-7/ADR细胞通过共聚焦激光显微镜观察ADR/MCNC的细胞摄取和定位,MTT法考察ADR/MCNC的细胞毒性,用流式细胞术测定NIR光照下细胞内活性氧自由基(ROS)水平。结果:所制备的MCNC的粒径约为90 nm,表面含有羧基,BET比表面积为541.62 m~2/g,孔容为0.34 cm~3/g,孔径分布约为2.5 nm,具有显著光热效应。ADR/MCNC的载药量为47.4%,具有pH/NIR响应性释放特性;NIR光照下能促进ADR的细胞摄取和核内蓄积,能诱导MCF-7/ADR细胞产生ROS,并对细胞有显著的抑制作用。结论:成功制得MCNs,此外ADR/MCNC具有抗多药耐药肿瘤的作用。     

PEG-PLGA包裹的介孔碳纳米给药系统的制备和表征

目的:利用一种简便易行的方法改善介孔碳(MCN)的分散性,并以其为载体构建纳米给药系统,探索其生物应用的效果。方法:利用TEM观察聚乙二醇-聚乳酸-羟基乙酸共聚物(PEG-PLGA)包裹前后MCN的大小和形态变化。稳定性检测用于评估PEG-PLGA包裹的MCN纳米粒(MCNP)的分散性。热效应实验评价MCNP的近红外(NIR)光热转化能力。构建PEG-PLGA包裹的载阿霉素(DOX)的介孔碳给药系统(MCNPD),从Zeta电荷、载药量、释放以及细胞摄取实验对其进行表征。结果:溶液静置24h后,原始MCN几乎完全聚集沉降,而MCNP仍均匀分散;NIR照射后,MCNP表现出很好的热效应;构建的给药系统MCNPD具有较高的载药量,并且呈p H-依赖释放和NIR-触发释放,同时能够很好地摄取进入细胞。结论:PEG-PLGA包裹以提高MCN分散性的方法简单可行,成功构建了一种具有良好分散性的MCN递药载体,利于生物应用。     

PVP和PEG表面修饰对有序介孔碳纳米粒分散性及细胞毒性的影响

目的 通过聚乙烯吡咯烷酮(PVP)和培化磷脂酰乙醇胺(DSPE-mPEG2000)对制备的有序介孔碳纳米粒(MCN)进行表面修饰,以改善材料的疏水性质,并考察其对MCN分散性和细胞毒性的影响。方法 采用低浓度水热法合成MCN,并用PVP和DSPE-mPEG2000对其表面修饰,采用透射电镜(TEM)、扫描电镜(SEM)、氮气吸附脱附仪、粒径仪和红外(IR)等表征其性质。考察了表面修饰对MCN分散性的影响,并用CCK-8法考察材料的细胞毒性,用流式细胞术检测材料对细胞氧化应激的影响。结果 制备的MCN粒径分布均一,平均粒径约90 nm,修饰后的粒径略有增大,Zeta电位稍有升高,分散性明显提高,但修饰前后材料对小鼠成纤维细胞(L929)和宫颈癌细胞(HeLa)的毒性没有显著性差异,在相同浓度下,修饰后的MCN能明显减少细胞氧化应激的产生。结论 MCN具有良好的生物相容性,用PVP和DSPE-mPEG2000修饰后的MCN能明显减少细胞氧化应激的发生。     

智能响应型介孔二氧化硅抗肿瘤纳米递药系统的设计策略与研究应用

恶性肿瘤是危害人类健康的重大疾病,由于其微环境复杂多变,导致大多数抗肿瘤药物不能精准地到达病灶组织并可控释放。智能响应型纳米载体已成为抗肿瘤递药系统研究领域的热点。介孔二氧化硅作为一种优良的纳米材料,具有无毒、稳定、孔容孔径可调及表面易于功能化修饰等优势,凭借其对机体肿瘤微环境或生理变化的感知响应、实现递药系统在病灶组织定位释药或控制释药,使其成为智能响应型递药系统的理想载体。本文基于介孔二氧化硅的智能响应型递药系统的设计策略及研究应用展开综述,以期为抗肿瘤药物纳米制剂的研发提供参考。     

蛋白质和多肽类药物口服给药研究进展

蛋白质和多肽类药物具有良好的选择性和生物活性,已成为治疗众多疾病的首选药物。由于胃肠道内酶的降解作用以及肠道粘膜的低通透性,蛋白质和多肽类药物口服生物利用度极低,其常规给药一直以注射为主。为了使蛋白质和多肽类药物能够广泛应用于临床,研究人员对蛋白质和多肽类药物口服给药系统做了大量研究。目前用于提高蛋白质和多肽类药物口服生物利用度的方法主要有微粒给药系统、内源性细胞转运系统、应用酶抑制剂和黏附给药系统等。文章就这些方法在蛋白质和多肽类药物口服给药中的应用进行了综述。     

基于靶向纳米递药系统用于胰腺癌化疗中的研究现状

胰腺癌是一种恶性程度较高、诊断和治疗均较困难的消化道系统肿瘤。胰腺癌的传统化疗方案靶向性不高,治疗效率低,存在一系列的药物不良反应。近年来纳米靶向递药系统迅猛发展,为胰腺癌的治疗提供了许多的新思路。本文综述了近年来基于靶向纳米递药系统用于胰腺癌化疗的研究进展,从被动靶向、物理化学靶向、主动靶向和化疗药物的联合运载四个方面中的应用进行介绍,以期为胰腺癌的临床治疗提供新的思路和方法。     

基于当归多糖的酶敏肿瘤靶向纳米递药体系的研究

目的构建基于当归多糖(AP)的酶敏肿瘤靶向纳米递药体系:当归多糖-基质金属蛋白酶敏感肽-阿霉素(AP-PP-DOX),研究其理化性质及体外抗肿瘤效果。方法首先将AP用马来酸酐(MA)修饰后得到马来酰化当归多糖(AP-MA),再将APMA和基质金属蛋白酶敏感肽(PP)结合生成当归多糖-基质金属蛋白酶敏感肽(AP-PP),最后将AP-PP和阿霉素(DOX)结合生成当归多糖-基质金属蛋白酶敏感肽-阿霉素(AP-PP-DOX)聚合物。利用FT-IR和1 H-NMR表征各步反应产物;透析法自组装形成纳米粒;粒度分析仪测定纳米粒粒径和电位;TEM观察纳米粒大小及外观形态;紫外分光光度计测定纳米粒载药量;体外模拟释药实验研究纳米粒在MMP-2作用下的酶解释药情况;MTT法研究纳米粒对A549细胞的毒性作用。结果 (1)FT-IR和1 H-NMR表征各步反应产物成功合成;(2)透析法成功制备了AP-PP-DOX纳米粒;(3)测定纳米粒的平均粒径和电位分别是139.00±3.32nm和-28.45±0.22mV;(4)该纳米粒结构圆整,平均粒径为100nm;(5)计算纳米粒载药量为17.00%±1.72%;(6)体外模拟释药结果表明,纳米粒在MMP-2下作用24h累积释药率最高达74.5%;(7)MTT实验表明,当药物质量浓度为9μg·mL-1时,纳米粒对A549细胞的存活率极显著,高于游离DOX(P<0.01),而含有MMP-2的纳米粒对A549细胞存活率极显著,低于不含MMP-2的纳米粒(P<0.01)。结论制备基于AP的酶敏肿瘤靶向纳米递药体系AP-PP-DOX,能够有效实现在MMP-2作用下的酶敏释药及抗肿瘤效果,值得进一步研究。     

氧化介孔碳球纳米粒作为紫杉醇载体的研究

目的制备氧化介孔碳球纳米粒(oMCN),考察其理化性质以及作为抗肿瘤药物紫杉醇递送载体的研究。方法采用低浓度水热法合成介孔碳球纳米粒,观察其形貌特征,测定其介孔性质参数、粒径、Zeta电位、载药量大小,利用透析法研究体外释药行为,用CCK-8法考察体外抗肿瘤活性。结果 oMCN的比表面积为704.63m2/g、孔容积为0.57cm3/g、孔径分布约为3.23nm、平均粒径为140nm、Zeta电位为-36mV、载药量高达45.6%,72h体外累积释药量为57.6%,具有良好的药物负载与缓释性能,对小鼠肺癌LLC细胞具有显著的抑制作用。结论 oMCN作为抗肿瘤药物紫杉醇的载体具有较好的应用前景。     

口服胰岛素毫微球的体外释药及对糖尿病大鼠的降血糖作用

为研制一种生物利用度较高而降血作用时间短的口服INS制剂。制备了胰岛素聚氰基丙烯酸烷基酯毫微球(INS-NP)。其平均粒径为252.4nm,胰岛素的结合率为70.1%±2.3%。INS-NP的体外释药符合双指数函数式,酸性介质中释放更快。Wistar大鼠po不同剂量的INS-NP和胰岛素溶液(INS-SOL),结果显示10u·kg^-1和20u·kg^-1的INS-NP可显著降低血糖,但两个剂量间无显著性差异而INS SOL无降糖作用。用曲线上面积比较poINS-NP和scINS-SOL后的降糖作用,结果前者的相对生物利用度为7.58%。在血糖下降的时间范围内,体外释药的百分率与降糖速率间有一定相关性。     

Silica nanoparticles on the oral delivery of insulin

Introduction: When intravenous or subcutaneous administration of insulin, various side effects or possible risks have been reported. Oral administration of insulin has significant advantages of convenience, painless and mimetic endogenous insulin pathway, and thus it presents patients compliance, protects pancreatic β cells and lessens adverse effects caused by long-term injection. This challenging oral delivery of insulin can be achieved by promising silica nanoparticles (SNs), especially mesoporous silica nanoparticles (MSNs), with controllable morphology and high loading efficiency. This review presents the synthesis and physiological behaviors of SNs such as in vivo and in vitro degradation, absorption, distribution, and excretion, as well as preparations of oral insulin based on SNs. As well, this review will provide insights for innovative oral delivery of SNs and insulin.

Areas covered: Promising SNs and MSNs have gained interests for application in oral drug delivery of insulin.

Expert opinion: After synthesis under proper conditions and methods, promising SNs with controllable structure and suitable stability can be synthesized. By improving permeability and penetration, achieving controlled release and adjusting physiological processes, functionalization on SNs by active groups, molecules, or polymers is necessary for oral delivery of insulin.     

Application of polymeric nanoparticles and micelles in insulin oral delivery

Diabetes mellitus is an endocrine disease in which the pancreas does not produce sufficient insulin or the body cannot effectively use the insulin it produces. Insulin therapy has been the best choice for the clinical management of diabetes mellitus. The current insulin therapy is via subcutaneous injection, which often fails to mimic the glucose homeostasis that occurs in normal individuals. This provokes numerous attempts to develop a safe and effective noninvasive route for insulin delivery. Oral delivery is the most convenient administration route. However, insulin cannot be well absorbed orally because of its rapid enzymatic degradation in the gastrointestinal tract. Therefore, nanoparticulate carriers such as polymeric nanoparticles and micelles are employed for the oral delivery of insulin. These nanocarriers protect insulin from degradation and facilitate insulin uptake via a transcellular and/or paracellular pathway. This review article focuses on the application of nanoparticles and micelles in insulin oral delivery. The recent advances in this topic are also reviewed.     

口服纳米粒递送胰岛素研究进展

药物治疗糖尿病的最新进展当属口服胰岛素,而制备口服胰岛素需要将胰岛素包埋进载体使其避免胃肠降解。可突破肠上皮屏障达到良好降糖效果的口服载体多种多样,其中利用纳米材料制备胰岛素载体(INS-NPs)的研究最热,主要有以下优势:加强药物稳定性,大大提升生物利用率;实现靶向定位释药,降低药物对机体的毒副作用;控制释放药物时量,使药物在体内的作用更加明显等。针对上述优势并结合相关研究结论,本文从生物利用率、降糖时效和控释作用3个方面简述口服纳米粒在糖尿病治疗中的新进展。     

Self-assembly pH-sensitive chitosan/alginate coated polyelectrolyte complexes for oral delivery of insulin

Polyelectrolyte complexes (PEC) provide new opportunities for controlled release system of drugs, and have potentials to address challenges on the way to effective oral insulin delivery. Here, an innovative pH-sensitive PEC for insulin oral administration was developed, which was formed by self-assembly of two oppositely charged nanoparticles (chitosan-coated nanoparticles and alginate-coated nanoparticles) through electrostatic interaction via optimised double emulsion method. The encapsulation efficiency of insulin-loaded alginate-coated and chitosan-coated nanoparticles were 81.5?±?7.4% and 55.2?±?7.0%, respectively, and the particle size of these nanoparticles were in 200–300?nm range. The pH-dependent morphology of PEC was observed by transmission electron microscopy. The PEC exhibited insulin release profile triggered by pH in vitro and was non-cytotoxicity against Caco-2 cell. The insulin-loaded PEC could decrease blood glucose levels effectively and prolong insulin release after oral administration to diabetic rats. The results illustrated that the as-prepared PEC may be employed as a potential oral insulin delivery system.     

蛋白多肽类药物纳米粒口服给药系统的研究进展

目的综述近年来纳米粒作为蛋白质多肽类药物口服传递系统方面的研究现状和进展。方法分析有关文献资料,从纳米粒给药系统的载体材料、口服药效等方面进行了概述。结果纳米粒给药系统可提高蛋白质和多肽类药物的口服吸收效率,提高此类药物的生物利用度。结论纳米粒给药系统在口服传递蛋白质和多肽类药物方面有着广阔的研究和应用前景。     

Facile synthesis of PEI-based crystalline templated mesoporous silica with molecular chirality for improved oral delivery of the poorly water-soluble drug

The aim of this study was to build up a novel chiral mesoporous silica called PEIs@TA-CMS through a facile biomimetic strategy and to explore its potential to serve as a drug carrier for improving the delivery efficiency of poorly water-soluble drug. PEIs@TA-CMS was synthesized by using a chiral crystalline complex associated of tartaric acid and polyethyleneimine (PEIs) as templates, scaffolds and catalysts. The structural features including morphology, size, pore structure and texture properties were systematacially studied. The results showed that PEIs@TA-CMS was monodispersed spherical nanoparticles in a uniformed diameter of 120–130 nm with well-developed pore structure (S_BET: 1009.94 m²/g, pore size <2.21 nm). Then PEIs@TA-CMS was employed as nimodipine (NMP) carrier and compared with the drug carry ability of MCM41. After drug loading, NMP was effectively transformed from the crystalline state to an amorphous state due to the space confinement in mesopores. As expected, PEIs@TA-CMS had superiority in both drug loading and drug release compared to MCM41. It could incorporate NMP with high efficiency, and the dissolution-promoting effect of PEIs@TA-CMS was more obvious because of the unique interconnected curved pore channels. Meanwhile, PEIs@TA-CMS could significantly improve the oral adsorption of NMP to a satisfactory level, which showed approximately 3.26-fold higher in bioavailability, and could effectively prolong the survival time of mice on cerebral anoxia from 10.98 to 17.33 min.     

Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery

Importance of the field: The incorporation of stimuli-responsive properties into nanostructured systems has recently attracted significant attention in the research of intracellular drug/gene delivery. In particular, numerous surface-functionalized, end-capped mesoporous silica nanoparticle (MSN) materials have been designed as efficient stimuli-responsive controlled release systems with the advantageous ‘zero premature release’ property.

Areas covered in this review: Herein, the most recent research progress on the design of biocompatible, capped MSN materials for stimuli-responsive intracellular controlled release of therapeutics and genes is reviewed. A series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different cargoes are summarized. Recent investigations on the biocompatibility of MSN both in vitro and in vivo are also discussed.

What the reader will gain: The reader will gain an understanding of the challenges for the future exploration of biocompatible stimuli-responsive MSN devices.

Take home message: With a better understanding of the unique features of capped MSN and its behaviors in biological environment, these multifunctional materials will find a wide variety of applications in the field of drug/gene delivery.     

The mechanism for increasing the oral bioavailability of poorly water-soluble drugs using uniform mesoporous carbon spheres as a carrier

Abstract

Uniform mesoporous carbon spheres (UMCS) were used as a carrier to improve the bioavailability of the model drug, celecoxib (CEL). Furthermore, we investigated the mechanism responsible for the improved bioavailability of CEL. The association, adhesion and uptake of UMCS by intestinal epithelial cells were studied by transmission electron microscopy (TEM), fluorescence-activated cell sorting (FACS) and laser confocal scanning microscopy (LCSM). UMCS was found to promote cellular uptake of CEL. Drug transport in Caco-2 cell monolayers proved that UMCS can significantly reduce the rate of drug efflux and improve CEL permeability. The dissolution rate of CEL from drug-loaded samples was markedly improved compared with pure crystalline CEL; moreover, oral bioavailability of CEL loaded into UMCS was also markedly improved compared with that of commercially available capsules. UMCS indicates the advantages and potential of this method to achieve improved oral absorption by increasing the dissolution rate, cellular uptake and permeability of the drug.     

胰岛素经口腔给药对正常大鼠的降血糖作用

目的　研究胰岛素溶液 (insulinsolution ,INS SOL)经正常大鼠口腔给药后的降血糖作用。方法　以血糖水平为指标 ,考察各种吸收促进剂经正常大鼠口腔给药后对INS SOL降血糖作用的影响 ,以皮下注射为对照 ,计算不同条件下INS SOL的药理生物利用度 (pharmacologicalbioavailability ,PA)。 结果　不加吸收促进剂的条件下 ,10U·kg-1的INS SOL经口腔给药后的生物利用较低 (PA =6 9% )。十二烷基硫酸钠 (5 % ,PA =14 5 % ) ,苄泽 78(5 % ,PA =2 0 6 % ) ,脱氧胆酸钠 (5 % ,PA =16 5 % )和卵磷脂(10 % ,PA =13 8% )均增加INS SOL的降血糖作用。苄泽78(5 % )可使INS SOL(5U·kg-1)的PA最高达到 33%。结论　在适当的吸收促进剂的作用下INS SOL经口腔给药后具有明显的降血糖效果。