Controlled drug delivery systems based on calixarenes

Recent advances on calixarene-based drug delivery systems in the form of inclusion complexes, amphiphilic self-assembly nanocarriers including micelles, hydrogels, vesicles and liposomes, and supramolecular nanovalves on mesoporous silicas, were reviewed and discussed.     

Targeted delivery of proteins by nanosized carriers

Proteic drug administration poses some additional issues as compared with conventional drugs because of protein high molecular weight and short half‐life in plasma. It is well known that protein delivery canbe significantly improved by using targeted nanocarriers. Among the diverse investigated systems, this overview focuses onliposomes and nanoparticles. Indeed, because of their subcellular size, nanocarriers can cross the fenestration of the vascular epithelium and penetrate tissues. Moreover, nanosystems can be confined at the location of choice by conjugation to molecules that strongly bind the target cells. In spite of the significant progress made in the design and engineering of liposomes and nanoparticles tailored to the targeted delivery of proteins, these nanocarriers seldom succeed in delivering proteins directly inside the cell cytosol. Accordingly, some attention is also paid to virosomes and fusion proteins. These systems have a few advantages over conventional nanocarriers, particularly the ability to cross the cell membrane. They also share the main drawback of being highly immunogenic. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1–11, 2008     

Application of thermal analysis to the study of lipidic prodrug incorporation into nanocarriers

Anti HIV molecules as numerous drugs cannot efficiently penetrate into the brain. Prodrug synthesis and encapsulation into pegylated nanocarriers have been proposed as an approach for brain delivery. Pegylated polymeric nanoparticles and liposomes were chosen to incorporate glycerolipidic prodrugs of didanosine. Differential scanning calorimetry experiments were performed on mixtures of prodrugs and lipids or polymer in order to study their interaction. The optimal incorporation ratios were determined for each prodrug and compared for both types of nanocarriers. All these results would be used to prepare optimised formulations of didanosine prodrugs loaded into pegylated nanocarriers for brain drug delivery.     

Nano Carrier Drug Delivery Systems for the Treatment of Neuropsychiatric Disorders: Advantages and Limitations

Neuropsychiatric diseases are one of the main causes of disability, affecting millions of people. Various drugs are used for its treatment, although no effective therapy has been found yet. The blood brain barrier (BBB) significantly complicates drugs delivery to the target cells in the brain tissues. One of the problem-solving methods is the usage of nanocontainer systems. In this review we summarized the data about nanoparticles drug delivery systems and their application for the treatment of neuropsychiatric disorders. Firstly, we described and characterized types of nanocarriers: inorganic nanoparticles, polymeric and lipid nanocarriers, their advantages and disadvantages. We discussed ways to interact with nerve tissue and methods of BBB penetration. We provided a summary of nanotechnology-based pharmacotherapy of schizophrenia, bipolar disorder, depression, anxiety disorder and Alzheimer’s disease, where development of nanocontainer drugs derives the most active. We described various experimental drugs for the treatment of Alzheimer’s disease that include vector nanocontainers targeted on β-amyloid or tau-protein. Integrally, nanoparticles can substantially improve the drug delivery as its implication can increase BBB permeability, the pharmacodynamics and bioavailability of applied drugs. Thus, nanotechnology is anticipated to overcome the limitations of existing pharmacotherapy of psychiatric disorders and to effectively combine various treatment modalities in that direction.     

Endogenous nucleotide as drug carrier: base-paired guanosine-5′-monophosphate:pemetrexed vesicles with enhanced anticancer capability

Endogenous substance such as nucleotide as a drug carrier has been proposed as a novel drug delivery system.The nucleotide guanosine-5’-monophosphate(GMP) is used to transport an anticancer drug pemetrexed disodium heptahydrate(PMX) via specific base pairing.The endogenous nature of GMP helps to avoid biocompatibility issues that are generally accompanied with nanocarriers including cytotoxicity,immunogenicity and blood compatibility.Furthermore,the low-molecular weight of the GMP nucleotide carrier significantly boosts the drug loading capacity compared to traditional liposomes and high-molecular weight carriers.Hydrogen-bonding interaction between the carrier and drug realizes the controlled release of loaded drug,and also facilitates large scale manufacture since no additional chemical synthesis is required.More importantly,in vivo experiments reveal that the base-paired GMP:PMX nanovesicles improve the target specificity and pharmacokinetic properties of PMX,and exhibit remarkably enhanced anticancer abilities compared to standalone PMX without any carriers.We envision that this strategy could be extended to other endogenous substances and drugs bearing functional groups capable of specific interaction,and promote the construction of drug delivery systems with inherent biocompatibility,enhanced drug delivery efficacy,and a simplified preparation method.     

Size-controlled long-circulating PICsome as a ruler to measure critical cut-off disposition size into normal and tumor tissues

Selective disposition of nanocarriers into target tissue is an essential issue in drug delivery. Critical size of nanocarriers (～150 nm) discriminating the permeability into normal and tumor tissues was determined by the use of size-tunable, polyion complex hollow vesicles (PICsome) as a ruler.     

Resealed erythrocytes: Towards a novel approach for anticancer therapy

Cancer is one of the deadliest diseases in the history of mankind, accounting for almost 10 million deaths per year. Even though significant advances in chemotherapy have been made however many challenges need the attention of scientists for providing a safe and economic treatment. As a result, oncological science is focusing on developing innovative and effective pharmacotherapy such as targeted therapy, immunotherapy, gene therapy, laser therapy, RNA interference therapy, nanoparticles, and biocarrier therapeutics that can mitigate serious side effects induced by traditional treatments. Targeted drug delivery is one approach in which the drug is concentrated selectively at a particular tissue and is able to deliver cytotoxic drugs safely and effectively by making use of various carriers such as lipidic nanocarriers, metallic nanoparticles, liposomes, niosomes, and cellular carriers. Resealed erythrocytes have emerged as one of the most effective biocarriers studied recently because of their easy preparation and drug loading, biodegradability, and possess long circulation half-life. This article gives an insight on the source and isolation of erythrocytes, merits and demerits of using erythrocytes as a carrier, methods of drug encapsulation and release kinetics, and storage methods of red blood cells with special attention on using resealed erythrocytes as carriers for anti-tumor drugs.     

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。     

Release of small molecules from aggregates consisting of an amphiphilic oligonucleotide functionalized by a photochromic azobenzene unit

Stimuli-responsive nanocarriers offer favorable properties for the target-specific delivery of drugs. Herein, we employed photoirradiation as an external stimulus for the construction of a molecular system that encapsulated small molecules, which were released upon photoirradiation. These nanocarriers consisted of DNA amphiphiles (ODAz 1), in which an oligodeoxynucleotide and an alkyl chain were employed as the hydrophilic and hydrophobic parts, respectively, and these two parts were linked by a photochromic azobenzene unit. In aqueous solutions, ODAz 1 formed nanosized aggregates that encapsulated hydrophobic molecules in their hydrophobic core. Photoirradiation induced isomerization of the azobenzene unit led to changes in aggregate size and the immediate release of the molecules. The aggregate smoothly penetrated the cell membrane, and the photochemical release and delivery of small molecules into living cells were achieved. Thus, ODAz 1 aggregates represent promising photosensitive nanocarriers that may be applicable to drug delivery and targeting.     

DNA纳米结构在药物转运载体和智能载药中的应用进展

纳米材料具有荷载效率高、靶向性能好、半衰期较长等优点, 非常适于作为药物转运载体, 可有效提高药物的水溶性、稳定性和疾病治疗效果.目前, 开发具有良好生物相容性、可控靶向释放能力和精确载药位点的理想药物转运载体, 仍是该领域存在的挑战性问题和当前研究的重点.自组装DNA纳米结构是一类具有精确结构、功能多样的纳米生物材料, 具有良好的生物相容性和稳定性、较高的膜渗透性和可控靶向释放能力等优点, 是理想的药物转运载体和智能载药材料.本文总结了DNA纳米结构的发展历程、DNA纳米结构作为药物转运载体的研究现状、动态DNA纳米结构在智能载药中的应用进展, 并对其发展前景进行了展望.     

基于透明质酸的刺激响应纳米给药系统的研究进展

透明质酸(Hyaluronic acid, HA)是一种天然多糖,具有良好的生物相容性和生物降解性,利用 HA 构建的纳米载体自身就具有肿瘤靶向功能,可以作为抗癌药物载体将药物传递到肿瘤细胞内从而实现精准到达病患处。近年来透明质酸在应用于肿瘤靶向给药系统中的关注越来越多,成为了靶向治疗肿瘤的一大研究热点。基于透明质酸的基本特性和肿瘤靶向的生理学基础,在不同的刺激响应下,透明质酸型纳米给药系统能将药物集中释放于肿瘤的微环境内,更好地杀死肿瘤细胞,同时避免其他正常的组织受到药物损害。本文主要综述了透明质酸型纳米药物输送系统在各种刺激响应下释放药物的最新研究进展。     

Modeling of highly efficient drug delivery system induced by self-assembly of nanocarriers: A density functional study

Owing to the importance of drug delivery in cancer or other diseases’ therapy, the targeted drug delivery (TDD) system has been attracting enormous interest. Herein, we model the TDD system and design a novel rod-like nanocarrier by using the coarse grained model-based density functional theory, which combines a modified fundamental measure theory for the excluded-volume effects, Wertheim’s first-order thermodynamics perturbation theory for the chain connectivity and the mean field approximation for van der Waals attraction. For comparison, the monomer nanocarrier TDD system and the no nanocarrier one are also investigated. The results indicate that the drug delivery capacity of rod-like nanocarriers is about 62 times that of the no nanocarrier one, and about 6 times that of the monomer nanocarriers. The reason is that the rod-like nanocarriers would self-assemble into the smectic phase perpendicular to the membrane surface. It is the self-assembly of the rod-like nanocarriers that yields the driving force for the targeted delivery of drugs inside the cell membrane. By contrast, the conventional monomer nanocarrier drug delivery system lacks the driving force to deliver the drugs into the cell membrane. In short, the novel rod-like nanocarrier TDD system may improve the drug delivery efficiency. Although the model in this work is simple, it is expected that the system may provide a new perspective for cancer targeted therapy.     

Dual drug delivery system with flexible and controllable drug ratios for synergistic chemotherapy

Determination of whether multidrug nanocarriers can deliver and release loaded drugs at a predefined synergistic ratio to target cancer cells is crucial. Although there are many successful applications for delivery of multiple drugs, most current carriers are unable to achieve coordinated loading and release, leading to a drug release ratio that disagrees with the predefined loading ratio.In this work, a simple dual-drug delivery system with a flexible and controllable drug release ratio was constructed to deliver two anticancer drugs, doxorubicin(DOX) and curcumin(CUR). The drug ratio of DOX and CUR can be easily tuned for an enhanced synergistic effect, and the drugs can be released at predesigned ratios due to synchronous drug activation and nanoparticle collapse. Drug release at predefined ratios for synergistic anticancer therapy was demonstrated via in vitro and in vivo experiments. Therefore, the dual drug delivery system developed here provides a simple and efficient strategy for combination chemotherapy.     

A General Approach to Enzyme-Responsive Liposomes

Liposomes are effective nanocarriers due to their ability to deliver encapsulated drugs to diseased cells. Nevertheless, liposome delivery would be improved by enhancing the ability to control the release of contents at the target site. While various stimuli have been explored for triggering liposome release, enzymes provide excellent targets due to their common overexpression in diseased cells. We present a general approach to enzyme-responsive liposomes exploiting targets that are commonly aberrant in disease, including esterases, phosphatases, and β-galactosidases. Responsive lipids correlating with each enzyme family were designed and synthesized bearing an enzyme substrate moiety attached via a self-immolating linker to a non-bilayer lipid scaffold, such that enzymatic hydrolysis triggers lipid decomposition to disrupt membrane integrity and release contents. Liposome dye leakage assays demonstrated that each enzyme-responsive liposome yielded significant content release upon enzymatic treatment compared to minimal release in controls. Results also showed that fine-tuning liposome composition was critical for controlling release. DLS analysis showed particle size increases in the cases of esterase- and β-galactosidase-responsive lipids, supporting alterations to membrane properties. These results showcase an effective modular strategy that can be tailored to target different enzymes, providing a promising new avenue for advancing liposomal drug delivery.     

Recent advances in surface-active ionic liquid-assisted self-assembly systems for drug delivery

Surface-active ionic liquids (SAILs) are receiving growing interest as environmentally friendly designer surfactants for various applications, including drug formulation and delivery. The use of SAILs in the pharmaceutical industry has the potential to address the challenges associated with conventional surfactants. The tunable formation of complementary ion pairs from a diverse range of ions enables the task-specific optimization of SAILs. SAILs comprising second and third-generation cations and anions have been used to design biocompatible self-assembled systems including micelles, microemulsions, vesicles, liposomes, and nanoparticles for drug delivery carriers. Compared with conventional surfactant-based carriers, SAIL-based systems offer better pharmacokinetic and pharmacodynamic properties. This mini-review highlights recent findings on the formation of ionic liquid-based self-assembled systems and their potential applications in drug delivery.     

Sterically Stabilized Vesicles

After significant developments in liquid crystal and polymer research, scientists became interested in lyotropic systems containing polymers. These studies investigated, for instance, phase behavior and stability characteristics of suspensions of colloidal particles containing water-soluble or surface-adsorbed polymers or block copolymers. The most frequently studied were micelles, latex prticles, and lipid vesicles (liposomes). Liposomes aggregate and fuse in the presence of hydrophilic polymers but their properties were difficult to explain when block copolymers were adsorbed or surfactants with larger polymeric polar heads were inserted into the liposome membrane, because such systems are inherently ill defined. Liposomes containing diacyl surfactants with covalently linked, longer polymer chains display many new properties with very important consequences for both basic and applied research. They stimulate fundamental studies on phase behavior and polymer conformation, scaling laws, colloidal and surface properties, and cell function: applications deal predominantly with liposomes as drug delivery systems. While in basic research theory is currently more advanced than experiment, in medical applications theoretical understanding lags behind experimental achievements. It was discovered only relatively late that liposomes with an appropriate polymer coating are significantly more stable in a biological milieu, a necessary condition for their utility as drug carriers. In particular in medical applications, this practice has rejuvenated the field of anticancer therapy and targeted drug deliviery. All these advances were made possible by an effective and synergistic overlap of many different disciplines.     

Lipid carrier systems for targeted drug and gene delivery

For effective chemotherapy, it is necessary to deliver therapeutic agents selectively to their target sites, since most drugs are associated with both beneficial effects and side effects. The use of lipid dispersion carrier systems, such as lipid emulsions and liposomes, as carriers of lipophilic drugs has attracted particular interest. A drug delivery system can be defined as a methodology for manipulating drug distribution in the body. Since drug distribution depends on the carrier, administration route, particle size of the carrier, lipid composition of the carrier, electric charge of the carrier and ligand density of the targeting carrier, these factors must be optimized. Recently, the lipid carrier system has also been applied to gene delivery systems for gene therapy. However, in both drug and gene medicine cases, a lack of cell-selectivity limits the wide application of this kind of drug and/or gene therapy. Therefore, lipid carrier systems for targeted drug and gene delivery must be developed for the rational therapy. In this review, we shall focus on the progress of research into lipid carrier systems for drug and gene delivery following systemic or local injection.     

Preparation and characterization of complexes of liposomes with gold nanoparticles

Gold nanoparticles (Au NPs), which are extremely useful materials for imaging and photothermal therapy, typically require a drug delivery system to transport them to the affected tissue and into the cells. Since liposomes are approved as drug carriers, complexes of liposomes with Au NPs were considered ideal solutions to deliver Au NPs to the target site in vivo. In this study, we prepared complexes of various liposomes with Au NPs via physical absorption and characterized them. The time dependency of the surface plasmon resonance of this complex, which is a unique property of Au NPs, shows that the liposomes promote the formation of stable dispersions of Au NPs under isotonic conditions, even though intact Au NPs aggregate immediately. From a release assay of calcein from liposomes and transmission electron microscopy analysis, the Au NPs were complexed with liposomes without membrane disruption. These complexes could be formed by using cationic liposomes and polyethylene glycol-modified liposomes, as well as by using phosphatidylcholine liposomes, which are useful for drug and gene delivery. We proposed this kind of complex as a nanomedicine with diagnostic and therapeutic ability.     

高分子包囊药物释放体系

用高分子作为载体的高分子微包囊和纳米级包囊药物制剂不仅能控制药物以一定的速度释放，而且可对生物体的生理指标变化作出反馈，因而可以成为靶向药物释放体系。通过用高分子包囊还可以延长蛋白质和多肽类药物的生理活性，提高药物稳定性，使之成为长效药物，并使一些难以口服的药物能够制成口服制剂。文章在介绍有关高分子药物释放体系的一些基本原理，以及与之相关的药学、药理学、物理化学和高分子材料科学方面知识的基础上，较全面地综述了高分子包囊药物的制备技术和应用。阐述了高分子包囊的粒径、表面积、孔度、药物性能和药含量，以及高分子包囊材料的性能对药物释放行为的影响。对药物传送机理亦进行了扼要的介绍。     

Zwitterionic polymers: Addressing the barriers for drug delivery

Nanocarriers play an important role in drug delivery for disease treatment. However, nanocarriers face a series of physiological barriers after administration such as blood clearance, nonspecific tissue/cell localization, poor cellular uptake, and endosome trapping. These physiological barriers seriously reduce the accumulation of drugs in target action site, which results in poor therapeutic efficiency. Although polyethylene glycol (PEG) can increase the blood circulation time of nanocarriers, its application is limited due to the “PEG dilemma”. Zwitterionic polymers have been emerging as an appealing alternative to PEG owing to their excellent performance in resisting nonspecific protein adsorption. Importantly, the diverse structures bring functional versatility to zwitterionic polymers beyond nonfouling. This review focuses on the structures and characters of zwitterionic polymers, and will discuss and summarize the application of zwitterionic polymers for drug delivery. We will highlight the strategies of zwitterionic polymers to address the physiological barriers during drug delivery. Finally, we will give some suggestions that can be utilized for the development of zwitterionic polymers for drug delivery. This review will also provide an outlook for this field. Our aim is to provide a comprehensive and systemic review on the application of zwitterionic polymers for drug delivery and promote the development of zwitterionic polymers.