Microfabricated Drug Delivery Systems: Concepts to Improve Clinical Benefit

Important classes of drugs have yet to benefit from advances in drug delivery technology. Strategies to provide reasonable oral bioavailability of peptide and proteins drugs remain elusive, for example. Systemic cancer drugs produce dose-limiting toxicities largely due to their lack of selectivity. Although delivery systems such as immunotoxins and liposomes improve selectivity of a few cancer drugs, current technology is not suitable for the vast majority of such molecules. Systems able to mimic the body's natural feedback mechanisms for secretion of hormones such as insulin represents yet another unmet medical need. Microfabrication techniques may permit the creation of drug delivery systems that possess a combination of structural, mechanical, and perhaps electronic features which may surmount some of these challenges. In this review, drug delivery concepts are presented which capitalize on the strengths of microfabrication. Possible applications include micromachined silicon membranes to create implantable biocapsules for the immunoisolation of pancreatic islet cells—as a possible treatment for diabetes—and sustained release of injectable drugs needed over long time periods. Asymmetrical, drug-loaded microfabricated particles with specific ligands linked to the surface are proposed for improving oral bioavailability of peptide (and perhaps protein) drugs. Similarly designed particles with sizes in the 2–10 m range may be safe to administer intravenously and a clinical strategy is suggested for using such microparticles for treating solid tumors. Although hypothetical now, work is in progress to prove the concepts presented here and to validate the intuitive belief that there is an important place for microfabricated systems in drug delivery.     

Continuous On-Chip Micropumping for Microneedle Enhanced Drug Delivery

Microneedles are promising microfabricated devices for minimally invasive drug delivery applications. Needles can be integrated into a variety of devices. However, any portable drug delivery device with integrated microneedles will need an equally compact means to deliver therapeutics. This work presents microneedles integrated with an on-chip MEMS positive displacement micropump for continuous drug delivery applications. The generation and collapse of thermally generated bubbles with flow rectified by directional check valves are used to achieve net pumping through the device. Visualization methods have observed net flow rates of water out of a microneedle at approximately 2.0 nl/s with a pressure of 3.9 kPa. In addition, continuous pumping was achieved for more than 6 hours with the heaters actuating for over 18 hours (15,000 cycles) without failing.     

Designing Nanoparticle-based Drug Delivery Systems for Precision Medicine

Traditional drugs are facing bottlenecks of lower solubility, absorption, and especially the inefficient organs or cells targeting during the precision medicine era. It is urgently needed to discover and establish new methods or strategies to modify old drugs or create new ones against the above defects. With the support of nanotechnology, the solubility, absorption and targeting of traditional drugs were greatly improved by modifying and fabricating with various types of nanoparticles to some extent, though many shortages remain. In this mini-review we will focus on advances in several most commonly used nanoparticles, from their nature and design, to drug delivery system and clinical application, that they overcome heterogeneous barriers in precision medicine, thereby ultimately improve patient outcome overall.     

BOOK REVIEW: Controlled Drug Delivery: Challenges and Strategies, edited by Kinam Park

PAC98: 8790+y, 0130Kj, 0130Rr     

A Biodegradable and Amphiphilic Linear‐Dendritic Copolymer as a Drug Carrier Platform for Intracellular Drug Delivery

In this work, a biodegradable linear‐dendritic copolymer composed of methoxypolyethylene glycols (mPEG) and a third generation glycolic acid oligomer based dendron is synthesized. The amphiphilic copolymer can self‐assemble into polymeric micelles in aqueous solution with a low critical micelle concentration (CMC). Hydrophobic doxorubicin (DOX) is incorporated into the micellar core via the dialysis method with a high drug loading content of 21.2%. The drug release result implies that the encapsulated drug can be released rapidly at pH 5.0, due to the hydrolysis of the ester bond resulting in quick disassembly of drug‐loaded micelles. Moreover, the results of fluorescence microscopy imaging and flow cytometry measurements demonstrate that the drug carriers can be internalized and DOX released rapidly from them upon endocytosis. Importantly, this drug delivery system exhibits excellent performance to inhibit cancer cell proliferation.

     

A Novel Method for Efficient Drug Delivery

Local delivery of anti-thrombotic and anti-restenotic drugs is desired to achieve high concentrations of agents which may be rapidly degraded systemically or which exhibit very short half-lives in vivo. In this article, the operating characteristics of a novel local drug delivery method are described and its effectiveness demonstrated computationally and experimentally. Computational models used a finite volume method to determine the concentration field. Optical dye density measurements of Evans blue in saline were performed in an in vitro steady flow system. Modeling parameters were kept in the physiologic range. Experimental flow visualization studies demonstrated high concentrations of infusate near the vessel wall. Computational studies predicted high, clinically significant drug concentrations along the wall downstream of the infusion device. When the radial infusion velocity is large (infusion flow rate, Q_inf > 0.5% of the main flow rate, Q), the wall concentration of the infused drug remains high, e.g., levels are greater than 80% of the infusate concentration 5 cm downstream of the infusion device. At lower infusion rates (Q_inf < 0.001Q), the drug concentration at the wall decreases exponentially with axial distance to less than 25% of the infusate concentration 5 cm downstream of the infusion device, although therapeutic drug levels are still readily maintained. The near wall drug concentration is a function of flow conditions, infusion rate, and the drug diffusivity. Good agreement was obtained between computational and experimental concentration measurements. Flow simulation and experimental results indicate that the technique can effectively sustain high local drug concentrations for inhibition of thrombosis and vascular lesion formation.     

Sugar Micro Needles as Transdermic Drug Delivery System

We designed and fabricated an array of sugar micro needles of the length ranging from 150 μ m to 2 mm for transdermic delivery of drugs. Micro needles were molded out of maltose mixed with pharmaceutical material, being expected bio-degradable in the human skin. To test basic tolerance to the healthy human skin, a clinical experiment was carried out for 10 healthy adult volunteers. 500 μ m-needles containing 5 wt% of ascorbate-2-glycoside were inserted into the skin of the forearm and snapped off to be left in the skin. They spontaneously dissolved by hydrolysis to release ascorbate in the epidermis and the dermis. No dermatological problems were observed in terms of the International Contact Dermatitis Research Group criteria. These observations indicate that the present system is a novel approach to achieve transdermic drug delivery.     

A pH‐Sensitive Phospholipid Polymeric Prodrug Based on Branched Polyethylenimine for Intracellular Drug Delivery

A biomimic pH‐sensitive polymeric prodrug based on branched polyethylenimine‐graft‐12‐acryloyloxy dodecyl phosphorylcholine and 6‐maleimidocaproyl‐doxorubicin is rationally designed and successfully synthesized. This polymeric prodrug can spontaneously self‐assemble into spherical nanostructures in aqueous solution. The in vitro drug release results imply that this polymeric prodrug can maintain stable in blood circulation while enhance drug release at endosomal acidic condition. Fluorescence microscopy and flow cytometry results demonstrate that the formed prodrug micelles can be internalized by cancer cells effectively. More importantly, this prodrug exhibits excellent cytotoxicity against Hela cells, indicating the pH‐sensitive polymeric prodrug micelles can potentially work as a promising platform for efficient cancer therapy.

     

曲安耐德缓释膜的制备及其在兔眼穿通伤中的应用研究

以曲安奈德(TA)作为模型药物,壳聚糖和明胶作为基体,制备治疗眼穿通伤用的复合药膜(GICS-TA)。溶剂挥发法制膜,采用红外光谱,X-射线衍射、扫描电镜分析药膜的结构与组成,并植入青紫蓝兔眼脉络膜上腔观察其对眼穿通伤治疗效果。TA与载体有良好的相容性,活性完好。药膜与眼组织生物相容性好,药物可持续释放,通过脉络膜到达视网膜和玻璃体内,抑制眼穿通伤术后创伤性炎症和玻璃体增殖反应,治疗效果优于传统给药方式,可望成为治疗眼穿通伤的新方法。     

Curcumin-Loaded N,O-Carboxymethyl Chitosan Nanoparticles for Cancer Drug Delivery

Abstract

Chitosan (CS) and its carboxymethyl derivatives are smart biopolymers that are non-toxic, biocompatible and biodegradable, and, hence, suitable for various biomedical applications, such as drug delivery, gene therapy and tissue engineering. Curcumin is a major chemotherapeutic agent with antioxidant, anti-inflammatory, anti-proliferative, anticancer and antimicrobial effects. However, the potential of curcumin as a chemotherapeutic agent is limited by its hydrophobicity and poor bioavailability. In this work, we developed a nanoformulation of curcumin in a carboxymethyl chitosan (CMC) derivative, N,O-carboxymethyl chitosan (N,O-CMC). The curcumin-loaded N,O-CMC (curcumin-N,O-CMC) nanoparticles were characterized using DLS, AFM, SEM, FT-IR and XRD. DLS studies revealed nanoparticles with a mean diameter of 150 ± 30 nm. AFM and SEM confirmed that the particles have a spherical morphology within the size range of 150 ± 30 nm. Curcumin was entrapped with in N,O-CMC nanopartcles with an efficiency of 80%. The in vitro drug-release profile was studied at different pH (7.4 and 4.5) at 37°C for different incubation periods with and without lysozyme. Cytotoxicity studies using MTT assay indicated that curcumin-N,O-CMC nanoparticles showed specific toxicity towards cancer cells and non-toxicity to normal cells. Cellular uptake of curcumin-N,O-CMC nanoparticles was analyzed by fluorescence microscopy and was reconfirmed by flow cytometry. Overall, these results indicate that like previously reported curcumin loaded O-CMC nanoparticles, N,O-CMC will also be an efficient nanocarrier for delivering curcumin to cancer cells.     

超声可控释药体系研究进展

超声可控释药体系是一种新兴的靶向给药及基因转运方法。以超声敏感材料作为药物或基因转送的载体,当超声辐照于靶组织或靶器官时, 靶体内载体可定向释放出包裹或附着的基因或药物, 实现对负载药物的定时定量定点释放和提高药物输送效率或基因转染率的目的。文中对超声可控释药体系的作用机制、超声敏感载体材料及生物医学应用等方面进行综述,最后对该领域目前存在的问题和今后的发展方向提出了一些看法。     

热物理在肿瘤治疗及纳米药物靶向输送方面的应用研究

目的 从在体动物模型和细胞水平上研究局部温热促进微纳米颗粒靶向输送并初探其机理。方法利用无菌外科手术将鼠源乳腺癌4T1组织块接种到裸鼠皮脊翼视窗，接种后第4d，7d，8d，10d分别观察肿瘤新生血管的生长情况。利用激光共聚焦荧光显微镜三维实时定性和定量研究微纳米脂质体在正常组织和肿瘤组织间质的渗透和扩散。将脐静脉内皮细胞(HUVEC)接种至模拟肿瘤环境的ECM625胶上，形成类似血管的管状结构，研究温热作用对生长在肿瘤环境下的血管内皮细胞的影响。结果肿瘤新生血管随着时间的变化生长逐渐加快，组织学研究表明肿瘤新生血管在肿瘤内生长受到抑制，在肿瘤边缘的肿瘤新生血管生长非常活跃。微纳米脂质体在正常组织中，在常温和42℃，作用1h基本不渗漏；在肿瘤组织中，42℃，加热1h，微纳米脂质体渗漏显著增加，与常温相比，相对荧光强度提高了4倍左右。42℃，加热1h可促使生长在ECM625胶上的血管内皮细胞变圆，细胞之间连接松散，甚至断裂。结论肿瘤新生血管内皮细胞对热敏感，局部温热作用促使了肿瘤环境下内皮细胞之间连接的破坏，进而促进了微纳米脂质体在肿瘤组织中的渗透。     

Bioadhesive intraoral release systems: design, testing and analysis

The aim of this study was to analyse the adhesion of various polymeric formulations and to measure the in vitro release of a local anaesthetic (febuverine hydrochloride) from a Hydrophobic gel containing 34% (wt/wt) adhesive hydrocolloids. The bioadhesive polymer system was prepared from a polyethylene gel containing various amounts of sodium carfaoxymethylcellulose (NaCMC) as the adhesive, and hydrolysed gelatin as the water sensitive material to ensure rapid swelling. Upon hydration, adhesion studies were performed with a tensile tester equipped with a custom-made cell. The controlled release of the active ingredient was studied with a dissolution cell filled with artificial saliva at 37°C. It was found that the relative adhesive bond strength of the formulations was dependent on the NaCMC content showing a maximum at about 20 wt %. Febuverine hydrochloride release achieved an optimal release rate for formulations with NaCMC in the range of 12–25 wt%.     

抗生素-多孔玻璃陶瓷（A-PGC）药物释放系统（DDS）的研制

目的 研制抗生素多孔玻璃陶瓷(A-PGC)药物释放系统(DDS)为骨髓炎治疗提供一种新方法。方法将两种多孔玻璃陶瓷(PGC)浸于抗生素(含庆大霉素和头孢唑林钠)溶液，真空吸附，制得A-PGC。同法制得抗生素多孔羟基磷灰石陶瓷(A-PHA)作对照。测定其体外、体内释放抗生素的药物浓度及持续时间。结果A-PGC体外释放有效浓度的庆大霉素达42天以上，而APHA为28天。三种陶瓷洗脱液中头孢唑林浓度均低于庆人霉素浓度。A-PGC在兔股骨中维持有效浓度庆大霉素达8周以上且有良好的骨传导作用。结论 A-PGC可望成为治疗骨髓炎的一种新方法。     

Enhancement of Transdermal Drug Delivery by ns Q-swithed Nd ：YAG Laser-induced Pressure Wave

A non-invasive laser enhancing transdermal drug delivery technique has been investigated. The second harmonic wavelength of 532 nm of a Q-Switched Nd：YAG laser with pulse duration of 15 ns was used to irradiate on a black polyethylene sheet covering on the surface of the drug solution, and hence produced pressure waves in the solution. Porcine skin and Rhodamine B were used as skin model and reagent respectively. Fluorescence microscope was employed to examine the mechanisms of drug delivery via the skin samples after laser treatment. The experiment revealed that the penetration depth of Rhodamine B under the illumination of laser increased with the energy density of the laser beam. After 20 laser shots at laser energy density of 70 m J/cm^2, the penetration depth reached 440 μm in 30 minutes, which was about three times as that without laser illumination. One possible explanation was that laser-induced pressure waves formed microchannels in the stratum corneum of the skin tissue. These microchannels provided much more effective paths for infiltration of Rhodamine B through the SC than follicular and intercellular paths. The drug solution diffused into the SC under the concentration gradient through the channels.     

Microneedle Transdermal Drug Delivery Systems for Allergen-Specific Immunotherapy,Skin Disease Treatment,and Vaccine Development

Transdermal drug delivery systems (TDDSs) overcome the hurdle of an intact skin barrier by penetrating the skin to allow molecules through. These systems reduce side effects associated with conventional hypodermic needles. Here, we introduce novel microneedle (MN) TDDSs that enhance drug delivery by creating micron-sized pores across the skin. Many MN TDDSs designed to deliver a diverse array of therapeutics, including allergen-specific immunotherapy, skin disease treatments, and vaccines, are under pre-clinical and clinical trials. Although epicutaneous approaches are emerging as new options for treating food allergy in many clinical trials, MN TDDSs could provide a more efficient and convenient route to deliver macromolecules. Furthermore, MN TDDSs may allow for safe vaccine delivery without permanent scars. MN TDDSs are a major emerging strategy for delivering novel vaccines and treatments for diseases, including skin diseases, allergic diseases, and so on.     

抗生素—多孔玻璃陶瓷(A-PGC)药物释放系统(DDS)的研制

目的研制抗生素多孔玻璃陶瓷(A-PGC)药物释放系统(DDS)为骨髓炎治疗提供一种新方法.方法将两种多孔玻璃陶瓷(PGC)浸于抗生素(含庆大霉素和头孢唑林钠)溶液,真空吸附,制得A-PGC.同法制得抗生素多孔羟基磷灰石陶瓷(A-PHA)作对照.测定其体外、体内释放抗生素的药物浓度及持续时间.结果A-PGC体外释放有效浓度的庆大霉素达42天以上,而A-PHA为28天.三种陶瓷洗脱液中头孢唑林浓度均低于庆大霉素浓度.A-PGC在兔股骨中维持有效浓度庆大霉素达8周以上且有良好的骨传导作用.结论A-PGC可望成为治疗骨髓炎的一种新方法.     

用于药物吸收研究的消化道定点释放药丸系统研究进展

消化道定点释放药丸系统是一种典型的微型机械电子系统,通过外部遥控实现消化道感兴趣区域的定点药物释放,是一种无创的人体药物吸收(human drug absorption,HDA)研究手段.本文对该领域的国际研究成果进行了综述,并对重庆大学最新开发的应用于中药药理学研究的消化道定点释放药丸系统进行了细节介绍.     

Retro-Convection Enhanced Drug Delivery: A Computational Study

Retro-convection enhanced delivery (R-CED) is an emerging drug delivery method to overcome the blood brain barrier (BBB). We have developed a mathematical model to understand the fluid flow and mass transfer in the interstitium of brain tissue in R-CED therapy. The model was used to predict pressure distributions, fluid flow patterns, and drug concentration profiles. Some numerical results were obtained by computer simulations. Three kinds of microdialysis membranes used in R-CED protocols were analyzed in detail. While fluid flow was independent of the choice of membranes, mass transfer processes and drug distributions were found to be highly dependent on the choice of membranes. Sensitivity analysis on a variety of parameters and over a wide range of parameter values was carried out. Although R-CED turned out to be efficacious in generating fluid flows within the brain tissue, it did not favor a large effective treatment volume and needed to be re-examined and re-evaluated experimentally.     

基于非牛顿流体多相流的磁性药物靶向给药捕获效率分析

为研究磁性靶向系统中各参数对捕获效率的影响,根据血液和矩形永磁铁特性,建立描述磁性靶向药物在血液中流动状态的两相卡森-牛顿模型,分析磁性纳米颗粒在血管中受磁力和流体力共同作用的运动轨迹,得到血管三维空间捕获效率的理论公式,并进一步提出药物捕获体积优化模型。使用Matlab仿真比较两相卡森-牛顿模型、单相卡森模型、单相牛顿模型的血液流速、捕获效率,揭示不同模型下磁性药物捕获体积变化规律,探讨磁性药物靶向系统中药物颗粒半径、磁场强度、磁铁与血管距离、血管半径等参数对捕获效率的影响关系。分析表明,非牛顿流体多相流模型可以更好地描述磁性药物靶向系统的特性与规律;而由仿真获知,两相卡森-牛顿模型比单相卡森模型和单相牛顿模型捕获效率均大4%以上,且颗粒的磁性物质半径比为0.75时,捕获的药物体积最大。研究结果可以为磁性靶向系统和药物颗粒设计提供理论依据。