Exosomes and Other Extracellular Vesicles with High Therapeutic Potential: Their Applications in Oncology,Neurology, and Dermatology

Until thirty years ago, it was believed that extracellular vesicles (EVs) were used to remove unnecessary compounds from the cell. Today, we know about their enormous potential in diagnosing and treating various diseases. EVs are essential mediators of intercellular communication, enabling the functional transfer of bioactive molecules from one cell to another. Compared to laboratory-created drug nanocarriers, they are stable in physiological conditions. Furthermore, they are less immunogenic and cytotoxic compared to polymerized vectors. Finally, EVs can transfer cargo to particular cells due to their membrane proteins and lipids, which can implement them to specific receptors in the target cells. Recently, new strategies to produce ad hoc exosomes have been devised. Cells delivering exosomes have been genetically engineered to overexpress particular macromolecules, or transformed to release exosomes with appropriate targeting molecules. In this way, we can say tailor-made therapeutic EVs are created. Nevertheless, there are significant difficulties to solve during the application of EVs as drug-delivery agents in the clinic. This review explores the diversity of EVs and the potential therapeutic options for exosomes as natural drug-delivery vehicles in oncology, neurology, and dermatology. It also reflects future challenges in clinical translation.     

Pillararene-Based Supramolecular Vesicles for Stimuli-Responsive Drug Delivery

Supramolecular vesicles (SMVs) self-assembled from the supra-amphiphiles, consisting of two scaffolds linked together through noncovalent interactions, can realize stimuli-responsive controlled release of encapsulated drugs for enhanced therapeutic efficacy and minimized side effect of drugs. Pillararenes (PAs), an emerging kind of macrocyclic hosts in 2008, are easy to modify with a variety of functionalities. SMVs from PAs and specific guests mainly based on the host–guest interactions have attracted increasing attention because of their drug delivery and controlled drug release. A great progress in the construction and stimuli-responsive drug delivery of the PA-based SMVs has been made since the first work was reported in 2012. This review summarizes the major achievements of the PA-based SMVs for stimuli-responsive drug delivery over the past 5 years, including the microstructures of SMVs, multiple stimuli-responsive SMVs, prodrug SMVs from prodrug PAs and guests, bola-type SMVs, multifunctional SMVs, glucose-responsive SMVs for insulin delivery, novel SMVs from responsive PAs, thermo-responsive SMVs, and ternary SMVs, for chemotherapy, photothermal therapy, photodynamic therapy, and other biological applications. The future challenges and research directions of PA-based SMVs are also outlined from the points of views of the fundamental research, biological applications, and clinical applications of PA-based SMVs.     

基于环糊精的靶向药物传递系统

癌症等恶性增殖疾病的靶向治疗有赖于靶向药物传递系统（targeted drug delivery system,TDDS）的开发。环糊精具有低毒、易修饰等优良性质,并可通过与药物分子形成包合物而提高药物的溶解性、稳定性、安全性和生物利用度等,因而具有成为优秀药物载体的潜力。环糊精不仅可以以其本身或修饰环糊精的形式充当载体,还可通过聚轮烷、阳离子聚合物或纳米粒等形式构建有效的药物载体。肿瘤或人体某些病变部位的细胞表面存在过度表达的生物受体如叶酸受体、去唾液酸糖蛋白受体、透明质酸受体、转铁蛋白受体和整合素受体等,可以与其相应的配体产生特异性识别。用适当的化学方法将配体分子如叶酸、单糖或寡糖、透明质酸、转铁蛋白及RGD肽等键接在基于环糊精的载体上,可形成具有靶向性质的药物载体,进而与药物分子一起构筑靶向药物传递系统。这种药物传递系统不仅针对于化学治疗药物,在核酸传递中也得到了丰富的应用。本文综述了基于环糊精的靶向药物传递系统的靶向机理及最新研究进展,并对其发展前景作了展望。     

Advances in Exosomes‐Based Drug Delivery Systems

Exosomes, a subgroup of extracellular vesicles, are important mediators of long‐distance intercellular communication and are involved in a diverse range of biological processes such as the transport of lipids, proteins, and nucleic acids. Researchers, seeing the problems caused by the toxic effects and clearance of synthetic nanoparticles, consider exosomes as an interesting alternative to such nanoparticles in the specific and controlled transport of drugs. In recent years, there have been remarkable advances in the use of exosomes in cancer therapeutics or for treating neurological diseases, among other applications. The objective of this work is to analyze studies focused on exosomes used in drug delivery system, present and future applications in this field of research are discussed based on the results obtained.     

Advanced Drug Delivery Micro- and Nanosystems for Cardiovascular Diseases

Advanced drug delivery micro- and nanosystems have been widely explored due to their appealing specificity/selectivity, biodegradability, biocompatibility, and low toxicity. They can be applied for the targeted delivery of pharmaceuticals, with the benefits of good biocompatibility/stability, non-immunogenicity, large surface area, high drug loading capacity, and low leakage of drugs. Cardiovascular diseases, as one of the primary mortalities cause worldwide with significant impacts on the quality of patients’ life, comprise a variety of heart and circulatory system pathologies, such as peripheral vascular diseases, myocardial infarction, heart failure, and coronary artery diseases. Designing novel micro- and nanosystems with suitable targeting properties and smart release behaviors can help circumvent crucial challenges of the tolerability, low stability, high toxicity, and possible side- and off-target effects of conventional drug delivery routes. To overcome different challenging issues, namely physiological barriers, low efficiency of drugs, and possible adverse side effects, various biomaterials-mediated drug delivery systems have been formulated with reduced toxicity, improved pharmacokinetics, high bioavailability, sustained release behavior, and enhanced therapeutic efficacy for targeted therapy of cardiovascular diseases. Despite the existing drug delivery systems encompassing a variety of biomaterials for treating cardiovascular diseases, the number of formulations currently approved for clinical use is limited due to the regulatory and experimental obstacles. Herein, the most recent advancements in drug delivery micro- and nanosystems designed from different biomaterials for the treatment of cardiovascular diseases are deliberated, with a focus on the important challenges and future perspectives.     

主客体超分子囊泡及其药物载运性能研究

伴随着新型主体分子的不断出现,主客体超分子囊泡的研究受到越来越多的关注。环糊精、杯芳烃、葫芦脲和柱芳烃等主体分子均可以和特定结构的客体分子通过主客体识别作用构筑超分子双亲分子,得到的超分子双亲分子可以进一步自组装为主客体超分子囊泡。主客体超分子囊泡是一类具有敏感响应性的囊泡体系,具有制备简单、生物相容性好和易于控制组装等优点。该囊泡体系对外界刺激具有良好的响应性,从而可以实现药物分子的可控运输和释放,使其成为一种性能独特的药物载运系统。本文结合近年来主体分子的发展,首先介绍了环糊精、杯芳烃、葫芦脲和柱芳烃等主客体超分子囊泡的研究进展,然后对该类超分子囊泡的载药途径进行了总结。该囊泡体系不仅可以在囊泡膜层和空腔中载药,还可以在主体分子的空腔中载药。同时,对载药主客体超分子囊泡的不同刺激响应性进行了归纳概括。最后结合该体系现阶段的研究状况,对该类超分子囊泡的发展前景进行了展望。     

Theragnostic Applications of Mammal and Plant-Derived Extracellular Vesicles: Latest Findings,Current Technologies,and Prospects

The way cells communicate is not fully understood. However, it is well-known that extracellular vesicles (EVs) are involved. Researchers initially thought that EVs were used by cells to remove cellular waste. It is now clear that EVs function as signaling molecules released by cells to communicate with one another, carrying a cargo representing the mother cell. Furthermore, these EVs can be found in all biological fluids, making them the perfect non-invasive diagnostic tool, as their cargo causes functional changes in the cells upon receiving, unlike synthetic drug carriers. EVs last longer in circulation and instigate minor immune responses, making them the perfect drug carrier. This review sheds light on the latest development in EVs isolation, characterization and, application as therapeutic cargo, novel drug loading techniques, and diagnostic tools. We also address the advancement in plant-derived EVs, their characteristics, and applications; since plant-derived EVs only recently gained focus, we listed the latest findings. Although there is much more to learn about, EV is a wide field of research; what scientists have discovered so far is fascinating. This paper is suitable for those new to the field seeking to understand EVs and those already familiar with it but wanting to review the latest findings.     

Nano-Drug Delivery Systems Based on Different Targeting Mechanisms in the Targeted Therapy of Colorectal Cancer

Colorectal cancer (CRC) is a usual digestive tract malignancy and the third main cause of cancer death around the world, with a high occurrence rate and mortality rate. Conventional therapies for CRC have certain side effects and restrictions. However, the exciting thing is that with the rapid development of nanotechnology, nanoparticles have gradually become more valuable drug delivery systems than traditional therapies because of their capacity to control drug release and target CRC. This also promotes the application of nano-drug targeted delivery systems in the therapy of CRC. Moreover, to make nanoparticles have a better colon targeting effect, many approaches have been used, including nanoparticles targeting CRC and in response to environmental signals. In this review, we focus on various targeting mechanisms of CRC-targeted nanoparticles and their latest research progress in the last three years, hoping to give researchers some inspiration on the design of CRC-targeted nanoparticles.     

基于生物矿化的纳米载药体系

基于生物矿化的纳米载药体系具有制备简单、良好的生物相容性和控制药物释放的能力、易被修饰且具备多功能性和靶向性等优点,在临床中拥有巨大的应用前景。本文系统阐述了基于生物矿化的纳米载体的构建原理和分类,重点介绍了它们的靶向性策略和刺激响应释放策略,并展望了其在临床治疗中的应用。     

基于生物矿化的纳米载药体系

基于生物矿化的纳米载药体系具有制备简单、良好的生物相容性和控制药物释放的能力、易被修饰且具备多功能性和靶向性等优点,在临床中拥有巨大的应用前景。本文系统阐述了基于生物矿化的纳米载体的构建原理和分类,重点介绍了它们的靶向性策略和刺激响应释放策略,并展望了其在临床治疗中的应用。     

Drug Delivery Systems Based on Porous Chitosan/Polyacrylic acid Microspheres

Porous microspheres have been prepared by suspension free radical polymerization of acrylic acid (AA) in the presence of chitosan (CHI). The microspheres were characterized by FTIR and environmental SEM. The PAA content of the microspheres was estimated to be in the range 45–50 wt.‐%. The swelling degree of these particles is almost constant in the range 2 < pH < 5, but it increases considerably as the pH is raised from 5 to 10. The release profiles of microspheres loaded with meclofenamic acid (MF) were determined at pH 2, 7.4, and 10. The in vitro release of MF at different pHs was modulated by the solubility of the drug. These microcapsules are biodegradable and presented good biocompatibility and biodegradability during in vivo experiments.

ESEM microphotograph of the porous PAA/CHI microspheres.     

pH-Sensitive Glycyrrhizin Based Vesicles for Nifedipine Delivery

Glycyrrhizic acid, or glycyrrhizin (GA), a major active component of licorice root, has been widely used in traditional Chinese and Japanese medicine since ancient times. However, only in the last decades has a novel and unusual property of the GA been discovered to form water-soluble, supramolecular complexes with a variety of lipophilic drugs. These complexes show significant advantages over other known delivery systems, in particular, due to strong pH sensitivity, the properties of GA self-associates. In the present study, a supramolecular complex formation of the hypotensive and antiarrhythmic drug nifedipine with GA has been studied at different pH values, corresponding to the different degrees of GA dissociation, including a fully dissociated state of GA. Both NMR experiments and molecular dynamics simulations demonstrate the existence of the nifedipine complex with GA at all dissociation states of GA. However, optical absorption experiments show the decrease of complex stability and solubility at pH > 6 when the GA molecule is fully deprotonated. It means the higher release rate of the drug in a neutral and basic environment compared with acid media. These results could form the basis of follow-up studies of GA self-associates as pH-controlled drug delivery systems.     

抗肿瘤药物输送系统

大多数小分子抗肿瘤药物均存在水溶性差、给药量大、体内半衰期短等问题,它们经口服或静脉注射给药后,只能通过自由扩散方式进入细胞,往往缺乏选择性,同时,对肿瘤细胞和正常细胞产生细胞毒性,具有较强的毒副作用,甚至对患者造成二次伤害。因此,它们在临床应用上受到很大限制。通过选择适宜的载体材料构筑抗肿瘤药物输送系统（如胶束、凝胶、纳米粒子等）,不仅可以延长小分子抗肿瘤药物的半衰期、降低其毒副作用,而且还可提高其溶解性和生物利用度,因而受到广大科研人员及制药企业的广泛重视。到目前为止,抗肿瘤药物输送系统的发展历史已有60多年,大致可分为传统型、智能型和靶向型三个不同的发展阶段。本文将从这三个不同发展阶段来综述抗肿瘤药物输送系统及其最新的研究进展,并对其未来的发展进行展望。     

Soft Contact Lenses as Drug Delivery Systems: A Review

This review describes the role of contact lenses as an innovative drug delivery system in treating eye diseases. Current ophthalmic drug delivery systems are inadequate, particularly eye drops, which allow about 95% of the active substance to be lost through tear drainage. According to the literature, many interdisciplinary studies have been carried out on the ability of contact lenses to increase the penetration of topical therapeutic agents. Contact lenses limit drug loss by releasing the medicine into two layers of tears on either side of the contact lens, eventually extending the time of contact with the ocular surface. Thanks to weighted soft contact lenses, a continuous release of the drug over an extended period is possible. This article reviewed the various techniques to deliver medications through contact lenses, examining their advantages and disadvantages. In addition, the potential of drug delivery systems based on contact lenses has been extensively studied.     

铂类抗癌药物的多功能纳米递送体系

以顺铂为代表的小分子铂类抗癌药物是临床应用的一线化疗药物,但其严重的毒副作用和难以克服的耐药性限制了铂类药物的临床应用和研发。运用纳米药物递送技术可以实现药物的靶向递送和可控释放,来提高药物的生物利用度,降低药物的毒副作用以及耐药性,为癌症的治疗带来新的希望。此外,丰富多样的纳米递送体系易于实现药物与具有生物学活性试剂的共运输,从而为各种治疗策略以及诊疗策略的联用提供可能,为最终实现癌症的精准治疗展现广阔前景。本文从靶向递药、药物可控释放、联合治疗、诊疗一体化四个方面对铂类抗癌药物的多功能纳米递送体系在癌症治疗中的最新研究进展进行综述,同时通过列举最新研究成果,展示了新材料、新技术以及新颖设计思想在铂基纳米递送体系中的应用。     

光控释药型药物递送系统的研究进展

释药可控的药物递送系统能够在特定刺激条件下,在时间和空间上精确实现在病灶处释放包载的药物分子,具有药物利用率高、毒副作用低等诸多优点,为各种重大疾病,如肿瘤的精准治疗提供了新思路.在众多的可控释药递送系统中,利用特定光照控制药物释放的光控释药型药物递送系统展现出广阔的应用潜力,受到研究者的广泛关注.近年来,基于不同光响应机理的光控释药型药物递送系统被设计开发用于药物的精确可控释放,本文介绍了四种光敏感基团的不同光响应机理,对基于不同光响应机理的光控释药型药物递送系统的研究进展进行了综述,指出现有光控释药型药物递送系统存在的问题及对未来的研究方向进行了展望.     

Nanomaterials for Ocular Drug Delivery

Efficient drug delivery to the eye remains a challenging task for pharmaceutical scientists. Due to the various anatomical barriers and the clearance mechanisms prevailing in the eye, conventional drug delivery systems, such as eye drop solutions, suffer from low bioavailability. More invasive methods, such as intravitreal injections and implants, cause adverse effects in the eye. Recently, an increasing number of scientists have turned to nanomaterial‐based drug delivery systems to address the challenges faced by conventional methods. This paper highlights recent applications of various nanomaterials, such as polymeric micelles, hydrogels, liposomes, niosomes, dendrimers, and cyclodextrins as ocular drug delivery systems to enhance the bioavailability of ocular therapeutic agents.

     

Supersaturation-Based Drug Delivery Systems: Strategy for Bioavailability Enhancement of Poorly Water-Soluble Drugs

At present, the majority of APIs synthesized today remain challenging tasks for formulation development. Many technologies are being utilized or explored for enhancing solubility, such as chemical modification, novel drug delivery systems (microemulsions, nanoparticles, liposomes, etc.), salt formation, and many more. One promising avenue attaining attention presently is supersaturated drug delivery systems. When exposed to gastrointestinal fluids, drug concentration exceeds equilibrium solubility and a supersaturation state is maintained long enough to be absorbed, enhancing bioavailability. In this review, the latest developments in supersaturated drug delivery systems are addressed in depth.     

The Role of Extracellular Vesicles in the Pathogenesis,Diagnosis, and Treatment of Osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease that affects the entire joint and has been a tremendous burden on the health care system worldwide. Although cell therapy has made significant progress in the treatment of OA and cartilage regeneration, there are still a series of problems. Recently, more and more evidence shows that extracellular vesicles (EVs) play an important role in the progression and treatment of OA. Here, we discuss that EVs from different cell sources not only participate in OA progression, but can also be used as effective tools for the diagnosis and treatment of OA. In addition, cell pretreatment strategies and EV tissue engineering play an increasingly prominent role in the field of OA treatment. This article will systematically review the latest developments in these areas. As stated above, it may provide new insights for improving OA and cartilage regeneration.