Therapeutic potential of controlled drug delivery systems in neurodegenerative diseases

Several compounds that exhibit a therapeutic effect in experimental models of neurodegenerative diseases have been identified over recent years. Safe and effective drug delivery to the central nervous system is still one of the main obstacles in translating these experimental strategies into clinical therapies. Different approaches have been developed to enable drug delivery in close proximity to the desired site of action. In this review, we describe biodegradable polymeric systems as drug carriers in models of neurodegenerative diseases. Biomaterials described for intracerebral drug delivery are well tolerated by the host tissue and do not exhibit cytotoxic, immunologic, carcinogenic or teratogenic effects even after chronic exposure. Behavioral improvement and normalization of brain morphology have been observed following treatment using such biomaterials in animal models of Parkinson's, Alzheimer's and Huntington's diseases. Application of these devices for neuroactive drugs is still restricted due to the relatively small volume of tissue exposed to active compound. Further development of polymeric drug delivery systems will require that larger volumes of brain tissue are targeted, with a controlled and sustained drug release that is carefully controlled so it does not cause damage to the surrounding tissue.     

Matrix metalloproteinase inhibitors: a review on bioanalytical methods, pharmacokinetics and metabolism

Enzymes are major drug targets in drug discovery and development processes in the pharmaceutical and biotechnology industry. A recent survey found that nearly half of all the marketed small-molecule drugs are inhibitors of enzymes. Matrix metalloproteinases (MMPs) are a family of 28 enzymes capable of degrading the constituents of the extracellular matrix (ECM) and the basement-membrane. MMPs play an essential role in several normal physiological processes including growth, wound healing and tissue repair. Over-expression and activation of MMPs has been linked to a range of diseases which include osteoarthritis, tumor metastasis, angiogenesis and cardiovascular diseases. The development of MMP inhibitors as therapeutic agents has kept an important place in drug discovery. Therefore, there is also an increasing need for robust analytical methods for evaluation of inhibitory potency and for the analysis of MMP inhibitors and their metabolites which can even play a more significant role than the parent drug. Modern analytical techniques and hyphenated instrumentations such as liquid chromatography-mass spectrometry with a function of structure elucidation can provide a profound insight into the research of MMP inhibitors and also serve as a complementary method to zymographic techniques for the analysis of biological samples. This review mainly summarizes bioanalytical methods, pharmacokinetics and related metabolites of MMP inhibitors over the last 12 years.     

Targeting polymer therapeutics to bone

An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides a unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems.     

Cell-mediated drug delivery

INTRODUCTION: Drug targeting to sites of tissue injury, tumor or infection with limited toxicity is the goal for successful pharmaceutics. Immunocytes (including mononuclear phagocytes (dendritic cells, monocytes and macrophages), neutrophils and lymphocytes) are highly mobile; they can migrate across impermeable barriers and release their drug cargo at sites of infection or tissue injury. Thus, immune cells can be exploited as Trojan horses for drug delivery. AREAS COVERED: This paper reviews how immunocytes laden with drugs can cross the blood-brain or blood-tumor barriers to facilitate treatments for infectious diseases, injury, cancer, or inflammatory diseases. The promises and perils of cell-mediated drug delivery are reviewed, with examples of how immunocytes can be harnessed to improve therapeutic end points. EXPERT OPINION: Using cells as delivery vehicles enables targeted drug transport and prolonged circulation times, along with reductions in cell and tissue toxicities. Such systems for drug carriage and targeted release represent a new disease-combating strategy being applied to a spectrum of human disorders. The design of nanocarriers for cell-mediated drug delivery may differ from those used for conventional drug delivery systems; nevertheless, engaging different defense mechanisms in drug delivery may open new perspectives for the active delivery of drugs.     

斑马鱼模型在中枢神经系统疾病中的研究进展

中枢神经系统（Central Nervous System,CNS）疾病严重损伤人的身心健康,在全球范围内造成巨大的疾病负担,且患病人数逐年呈增长趋势。由于CNS疾病的复杂性、多因素性及多基因调控性,导致相关疾病的发病机制尚不明确,市场上也严重缺乏针对该类疾病的有效药物。因此,探索CNS疾病的病理机制对药物的开发十分重要,急需一种模式生物来构建CNS疾病模型。斑马鱼（Danio rerio）作为一种重要的模式生物,不仅具有与人类高度保守的大脑组织区域,且具有丰富的社会学行为,成为研究CNS疾病和药物研发的重要工具。本文综述了近年来斑马鱼在CNS疾病研究中的相关研究进展,同时也介绍了一些小分子化合物在斑马鱼疾病模型中的研究应用,为今后CNS疾病的研究和相关药物的研发提供了基础。     

Growth factor delivery for oral and periodontal tissue engineering

The treatment of oral and periodontal diseases and associated anomalies accounts for a significant proportion of the healthcare burden, with the manifestations of these conditions being functionally and psychologically debilitating. Growth factors are critical to the development, maturation, maintenance and repair of craniofacial tissues, as they establish an extracellular environment that is conducive to cell and tissue growth. Tissue-engineering principles aim to exploit these properties in the development of biomimetic materials that can provide an appropriate microenvironment for tissue development. These materials have been constructed into devices that can be used as vehicles for delivery of cells, growth factors and DNA. In this review, different mechanisms of drug delivery are addressed in the context of novel approaches to reconstruct and engineer oral- and tooth-supporting structures, namely the periodontium and alveolar bone.     

眼部给药系统的研究进展

目的介绍眼部给药系统的研究进展。方法查阅总结近年来眼部给药系统的最新研究成果,展望其发展前景。结果胶粒给药系统使不同阶段眼部疾病的治疗成为可能;靶向给药使得药物能够透过各种屏障到达眼部病变部位;原位凝胶显著延长了药物在眼部的滞留时间;可降解植入剂避免了释药后的二次手术;眼部电离子渗透技术大大降低了眼部治疗的创伤。结论随着临床医学、药物制剂学、高分子材料学的发展及新技术的应用,眼部给药系统在眼部疾病治疗中的应用更加广泛,具有很好的发展前景。     

Two Faces of Inflammation: An Immunopharmacological View

Inflammation is a protective response intended to eliminate pathogens and other offending agents which have potential to cause cell injury, as well as malignant and necrotic cells. However, if the inflammatory response is dysregulated or inappropriately focused, it has considerable potential to cause harm and can lead to development of inflammatory diseases such as allergic and autoimmune diseases. Despite the recent success in cytokine‐targeted therapies, for example by the use of specific biological drugs, there are still considerable unmet needs in the treatment of inflammatory diseases. Further, recent discoveries in many diseases in addition to the classical inflammatory diseases have revealed inflammation to be a major factor participating in the underlying pathophysiological processes, either through activation of inflammatory cells or through triggering of inflammatory signalling mechanisms in the tissue cells. Examples of such diseases and conditions are many cardiovascular, metabolic and degenerative diseases, as well as cancer, obesity and pain. This brings the immunopharmacological approach into a new perspective in the drug development in very wide therapeutic areas. Immunopharmacology investigates mechanisms of inflammation and potential molecules and targets to treat inflammatory diseases. The current issue of Basic and Clinical Pharmacology and Toxicology focuses on some of the novel inflammatory mechanisms with potential in anti‐inflammatory drug development, including kinase pathways, TRP ion channels, eicosanoid system, obesity‐related adipokines, autoantibodies against citrullinated proteins, eosinophils, platelets and pathways connecting nervous and immune systems. The MiniReviews are based on lectures given at the symposium “Novel Drugs and Drug Targets to Treat Inflammation” in Ylläs, Finland, in March 2013.     

非结核分枝杆菌病的治疗研究进展

非结核分枝杆菌病系由结核分枝杆菌复合群和麻风分枝杆菌以外的分枝杆菌(Non-tuberculous mycobacteria,NTM) 引起的疾病。NTM除引起肺部病变外,尚可引起其他部位病变,常见的是淋巴结炎、皮肤软组织感染和骨骼系统病变,对严重的细胞免疫抑制者还可引起血源性播散。由于多数传统抗结核药物对大多数NTM很少或没有活性,所以NTM病治疗困难,预后不佳。近十余年来对NTM病的研究已取得很大进展,药物研究亦在迅速进展中。在原有抗结核药物的基础上,又出现了一些抗结核新药,其中一些对NTM病有效。尤其近年研究的疏水衍生物,显示了更大的抗NTM活性。     

Application of porcine gastrointestinal organoid units as a potential in vitro tool for drug discovery and development

The gastrointestinal tract (GI) is a crucial part of the body for growth and development and its dysregulation can lead to several diseases with detrimental effects. Most of these diseases lack effective treatment, occurring as a result of inappropriate models to develop safe and potent therapies. Organoids are three‐dimensional self‐organizing and self‐renewing structures that are composed of a cluster of different cells in vitro that resemble their organ of origin in architecture and function. Over recent years, organoids have been increasingly used to study developmental biology, disease progression, i.e., cancer, tissue engineering and regenerative medicine and other biological processes. Owing to their complex nature and ability to retain the morphological and molecular patterns of their tissue‐of‐origin, they have great potential as alternative tools/models for drug screening, development and biomarker discovery. Using a species with similar genetic homology to humans as a source of organoids, such as the porcine model may offer huge translational relevance. This review focuses on the culture and establishment of porcine organoid units and their potential use and application as in vitro models to further the science of drug discovery, by overcoming current limitations of established two‐ and three‐dimensional models. It also highlights the translational application of using porcine organoids as a model of different disease contexts.     

Cell-mediated drug delivery

Introduction: Drug targeting to sites of tissue injury, tumor or infection with limited toxicity is the goal for successful pharmaceutics. Immunocytes (including mononuclear phagocytes (dendritic cells, monocytes and macrophages), neutrophils and lymphocytes) are highly mobile; they can migrate across impermeable barriers and release their drug cargo at sites of infection or tissue injury. Thus, immune cells can be exploited as Trojan horses for drug delivery.

Areas covered: This paper reviews how immunocytes laden with drugs can cross the blood–brain or blood–tumor barriers to facilitate treatments for infectious diseases, injury, cancer, or inflammatory diseases. The promises and perils of cell-mediated drug delivery are reviewed, with examples of how immunocytes can be harnessed to improve therapeutic end points.

Expert opinion: Using cells as delivery vehicles enables targeted drug transport and prolonged circulation times, along with reductions in cell and tissue toxicities. Such systems for drug carriage and targeted release represent a new disease-combating strategy being applied to a spectrum of human disorders. The design of nanocarriers for cell-mediated drug delivery may differ from those used for conventional drug delivery systems; nevertheless, engaging different defense mechanisms in drug delivery may open new perspectives for the active delivery of drugs.     

Quantitative Systems Pharmacology for Rare Disease Drug Development

Though hundreds of drugs have been approved by the US Food and Drug Administration (FDA) for treating various rare diseases, most rare diseases still lack FDA-approved therapeutics. To identify the opportunities for developing therapies for these diseases, the challenges of demonstrating the efficacy and safety of a drug for treating a rare disease are highlighted herein. Quantitative systems pharmacology (QSP) has increasingly been used to inform drug development; our analysis of QSP submissions received by FDA showed that there were 121 submissions as of 2022, for informing rare disease drug development across development phases and therapeutic areas. Examples of published models for inborn errors of metabolism, non-malignant hematological disorders, and hematological malignancies were briefly reviewed to shed light on use of QSP in drug discovery and development for rare diseases. Advances in biomedical research and computational technologies can potentially enable QSP simulation of the natural history of a rare disease in the context of its clinical presentation and genetic heterogeneity. With this function, QSP may be used to conduct in-silico trials to overcome some of the challenges in rare disease drug development. QSP may play an increasingly important role in facilitating development of safe and effective drugs for treating rare diseases with unmet medical needs.     

肺泡巨噬细胞摄取微粒作用影响因素的研究进展

摘 要近几年来肺部给药传递系统已成为人们研究的新焦点,但将微粒转运到肺组织后微粒与肺泡巨噬细胞间的作用却很少被人关注。根据不同的疾病通过调控微粒与肺泡巨噬细胞的摄取作用能够提高药物的治疗作用。文章参考大量的文献,综述了一些常见疾病与巨噬细胞间的关系并总结了肺部给药传递系统中肺泡巨噬细胞对微粒摄取作用的影响因素,为肺部给药制剂的发展与临床应用奠定基础。     

Emerging techniques for the discovery and validation of therapeutic targets for skeletal diseases

Advances in genomics and proteomics have revolutionised the drug discovery process and target validation. Identification of novel therapeutic targets for chronic skeletal diseases is an extremely challenging process based on the difficulty of obtaining high-quality human diseased versus normal tissue samples. The quality of tissue and genomic information obtained from the sample is critical to identifying disease-related genes. Using a genomics-based approach, novel genes or genes with similar homology to existing genes can be identified from cDNA libraries generated from normal versus diseased tissue. High-quality cDNA libraries are prepared from uncontaminated homogeneous cell populations harvested from tissue sections of interest. Localised gene expression analysis and confirmation are obtained through in situ hybridisation or immunohistochemical studies. Cells overexpressing the recombinant protein are subsequently designed for primary cell-based high-throughput assays that are capable of screening large compound banks for potential hits. Afterwards, secondary functional assays are used to test promising compounds. The same overexpressing cells are used in the secondary assay to test protein activity and functionality as well as screen for small-molecule agonists or antagonists. Once a hit is generated, a structure-activity relationship of the compound is optimised for better oral bioavailability and pharmacokinetics allowing the compound to progress into development. Parallel efforts from proteomics, as well as genetics/transgenics, bioinformatics and combinatorial chemistry, and improvements in high-throughput automation technologies, allow the drug discovery process to meet the demands of the medicinal market. This review discusses and illustrates how different approaches are incorporated into the discovery and validation of novel targets and, consequently, the development of potentially therapeutic agents in the areas of osteoporosis and osteoarthritis. While current treatments exist in the form of hormone replacement therapy, antiresorptive and anabolic agents for osteoporosis, there are no disease-modifying therapies for the treatment of the most common human joint disease, osteoarthritis. A massive market potential for improved options with better safety and efficacy still remains. Therefore, the application of genomics and proteomics for both diseases should provide much needed novel therapeutic approaches to treating these major world health problems.     

Drug delivery strategies for cathepsin inhibitors in joint diseases

Cathepsins play important roles in the development of joint and bone diseases such as osteoporosis, rheumatoid arthritis (RA) and osteoarthritis (OA). Cathepsin inhibitors are presently in development and clinical testing for use as novel disease-modifying drugs for the improved treatment of osteoporosis. They may also be applicable for the treatment of joint diseases. However, some barriers still hamper their clinical applications in these indications. Based on pathophysiological features of RA and OA, the authors discuss six potential drug delivery strategies for the effective delivery of cathepsin inhibitors or other antiarthritic drugs to the arthritic joint tissue. Successful application of these strategies may significantly contribute to a more effective and safe treatment of RA and OA.     

How multi-organ microdevices can help foster drug development

Multi-organ microdevices can mimic tissue–tissue interactions that occur as a result of metabolite travel from one tissue to other tissues in vitro. These systems are capable of simulating human metabolism, including the conversion of a pro-drug to its effective metabolite as well as its subsequent therapeutic actions and toxic side effects. Since tissue–tissue interactions in the human body can play a significant role in determining the success of new pharmaceuticals, the development and use of multi-organ microdevices present an opportunity to improve the drug development process. The devices have the potential to predict potential toxic side effects with higher accuracy before a drug enters the expensive phase of clinical trials as well as to estimate efficacy and dose response. Multi-organ microdevices also have the potential to aid in the development of new therapeutic strategies by providing a platform for testing in the context of human metabolism (as opposed to animal models). Further, when operated with human biopsy samples, the devices could be a gateway for the development of individualized medicine. Here we review studies in which multi-organ microdevices have been developed and used in a ways that demonstrate how the devices' capabilities can present unique opportunities for the study of drug action. We will also discuss challenges that are inherent in the development of multi-organ microdevices. Among these are how to design the devices, and how to create devices that mimic the human metabolism with high authenticity. Since single organ devices are testing platforms for tissues that can later be combined with other tissues within multi-organ devices, we will also mention single organ devices where appropriate in the discussion.     

Drug delivery strategies for cathepsin inhibitors in joint diseases

Cathepsins play important roles in the development of joint and bone diseases such as osteoporosis, rheumatoid arthritis (RA) and osteoarthritis (OA). Cathepsin inhibitors are presently in development and clinical testing for use as novel disease-modifying drugs for the improved treatment of osteoporosis. They may also be applicable for the treatment of joint diseases. However, some barriers still hamper their clinical applications in these indications. Based on pathophysiological features of RA and OA, the authors discuss six potential drug delivery strategies for the effective delivery of cathepsin inhibitors or other antiarthritic drugs to the arthritic joint tissue. Successful application of these strategies may significantly contribute to a more effective and safe treatment of RA and OA.     

Role of angiopoietin-2 in inflammatory autoimmune diseases: A comprehensive review

Angiogenesis is defined as the growth of new capillaries sprouting from pre-existing vasculature. Pathological angiogenesis signals can lead to dysregulated development of new vessels. Inflammation is accompanied by pathological angiogenesis. During an inflammatory process, newly formed blood vessels provide oxygen and nutrients to the inflamed tissue, facilitating the transport of inflammatory cells. Therefore, angiogenesis is closely related to pathogenesis of inflammatory autoimmune diseases. As a member of the angiopoietin family, Angiopoietin-2 (Ang-2) plays an irreplaceable role in angiogenesis. This review will narrate the expression of Ang-2 and its role in inflammatory autoimmune diseases. Collecting this information may improve the acquaintance of Ang-2 and provide a theoretical foundation for clinical trials and drug development in the future.     

New drug targets in inflammation: efforts to expand the anti-inflammatory armoury

Inflammation is a beneficial host response to challenge by foreign bodies or to tissue injury. When this normal physiological process (which is designed to restore normal tissue structure and function), becomes dysregulated, it can become harmful and destructive leading to inflammatory diseases that are a major burden on humanity. Despite some notable successes, there are still major unmet medical needs in the treatment of inflammatory diseases and the development of new anti-inflammatory drugs features prominently in the research portfolios of most pharmaceutical and biotech companies. New insights into inflammatory processes and new anti-inflammatory drug targets were the subjects of a Focus Topic organized for the Life Sciences 2007 meeting in Glasgow (July 2007). The speakers from this meeting were invited to generate reviews on the basis of their presentations and these reviews contribute to this themed issue and are summarized in this short article.     

Delivery strategies for sustained drug release in the lungs

Drug delivery to the lungs by inhalation offers a targeted drug therapy for respiratory diseases. However, the therapeutic efficacy of inhaled drugs is limited by their rapid clearance in the lungs. Carriers providing sustained drug release in the lungs can improve therapeutic outcomes of inhaled medicines because they can retain the drug load within the lungs and progressively release the drug locally at therapeutic levels. This review presents the different formulation strategies developed to control drug release in the lungs including microparticles and the wide array of nanomedicines. Large and porous microparticles offer excellent aerodynamic properties. Their large geometric size reduces their uptake by alveolar macrophages, making them a suitable carrier for sustained drug release in the lungs. Similarly, nanocarriers present significant potential for prolonged drug release in the lungs because they largely escape uptake by lung-surface macrophages and can remain in the pulmonary tissue for weeks. They can be embedded in large and porous microparticles in order to facilitate their delivery to the lungs. Conjugation of drugs to polymers as polyethylene glycol can be particularly beneficial to sustain the release of proteins in the lungs as it allows high protein loading. Drug conjugates can be readily delivered to respiratory airways by any current nebulizer device. Nonetheless, liposomes represent the formulation most advanced in clinical development. Liposomes can be prepared with lipids endogenous to the lungs and are particularly safe. Their composition can be adjusted to modulate drug release and they can encapsulate both hydrophilic and lipophilic compounds with high drug loading.