Drug Discovery Today

Recent advances in intra-articular drug delivery systems for osteoarthritis therapy ()
Publication date: Available online 21 May 2018 Source:Drug Discovery Today Author(s): Pierre Maudens, Olivier Jordan, Eric Allémann Osteoarthritis (OA) is the most common degenerative disease of the joint. Despite many reports and numerous clinical trials, OA is not entirely understood, and there is no effective treatment available for this disease. To satisfy this unmet medical need, drug delivery systems (DDSs) containing disease-modifying OA drugs (DMOADs) for intra-articular (IA) administration are required to improve the health of OA patients. DDSs should provide controlled and/or sustained drug release, enabling long-term treatment with a reduced number of injections. This paper reviews the role and interaction among different tissues involved in OA and summarizes recent clinical trials and research on DDSs, focusing on small-molecule delivery. To achieve an ideal treatment, various key criteria have been identified to design and develop an IA DDS matching the clinical needs. Optimized intra-articularly administered drug delivery systems associated with potent disease-modifying osteoarthritis drugs that can stop and/or reverse osteoarthritis evolution represent a promising approach for effective therapy.
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Nanogels as potential drug nanocarriers for CNS drug delivery ()
Publication date: Available online 20 May 2018 Source:Drug Discovery Today Author(s): Arti Vashist, Ajeet Kaushik, Atul Vashist, Jyoti Bala, Roozbeh Nikkhah-Moshaie, Vidya Sagar, Madhavan Nair Hydrogel-based drug delivery systems (DDSs) have versatile applications such, as tissue engineering, scaffolds, drug delivery, and regenerative medicines. The drawback of higher size and poor stability in such DDSs are being addressed by developing nano-sized hydrogel particles, known as nanogels, to achieve the desired biocompatibility and encapsulation efficiency for better efficacy than conventional bulk hydrogels. In this review, we describe advances in the development of nanogels and their promotion as nanocarriers to deliver therapeutic agents to the central nervous system (CNS). We also discuss the challenges, possible solutions, and future prospects for the use of nanogel-based DDSs for CNS therapies.
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Current approaches to the discovery of novel inhaled medicines ()
Publication date: Available online 20 May 2018 Source:Drug Discovery Today Author(s): Peter Strong, Kazuhiro Ito, John Murray, Garth Rapeport Inhaled administration is underutilised because the drug discovery process is viewed as challenging, risky, and expensive. However, unmet medical need continues to grow, and significant opportunities exist to discover novel inhaled medicines delivering the required lung concentrations while minimising systemic exposure. This profile could be achieved by a combination of properties, including lung retention and low oral bioavailability. Property-based rules exist for orally administered compounds, but there has been limited progress defining in silico predictors to guide the discovery of novel inhaled drugs. Recently, the use of informative cell- and tissue-based screens has greatly facilitated the identification of compounds with optimal characteristics for inhaled delivery. Here, we address opportunities for novel inhaled drugs, and the key challenges and uncertainties hampering progress. Identifying novel inhaled therapies could address significant unmet need in respiratory diseases. Such undertakings are regarded as particularly challenging and risky; therefore, here we discuss potential approaches to overcoming these challenges.
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Structural basis for selective inhibition of antibacterial target MraY, a membrane-bound enzyme involved in peptidoglycan synthesis ()
Publication date: Available online 18 May 2018 Source:Drug Discovery Today Author(s): Jenny Hering, Elin Dunevall, Margareta Ek, Gisela Brändén The rapid growth of antibiotic-resistant bacterial infections is of major concern for human health. Therefore, it is of great importance to characterize novel targets for the development of antibacterial drugs. One promising protein target is MraY (UDP-N-acetylmuramyl-pentapeptide: undecaprenyl phosphate N-acetylmuramyl-pentapeptide-1-phosphate transferase or MurNAc-1-P-transferase), which is essential for bacterial cell wall synthesis. Here, we summarize recent breakthroughs in structural studies of bacterial MraYs and the closely related human GPT (UDP-N-acetylglucosamine: dolichyl phosphate N-acetylglucosamine-1-phosphate transferase or GlcNAc-1-P-transferase). We present a detailed comparison of interaction modes with the natural product inhibitors tunicamycin and muraymycin D2. Finally, we speculate on possible routes to design an antibacterial agent in the form of a potent and selective inhibitor against MraY. We describe recent breakthroughs in structural studies of the antibacterial target MraY and related human GPT, speculating on how these structures can guide the design of selective antibacterial drugs.
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Renal Pre-Competitive Consortium (RPC2): discovering therapeutic targets together ()
Publication date: Available online 18 May 2018 Source:Drug Discovery Today Author(s): Mark Tomilo, Heather Ascani, Barbara Mirel, Maria Chiara Magnone, Carol Moreno Quinn, Anil Karihaloo, Kevin Duffin, Uptal D. Patel, Matthias Kretzler Despite significant effort, patients with kidney disease have not seen their outcomes improved significantly over the past two decades. This has motivated clinicians and researchers to consider alternative methods to identifying risk factors, disease progression markers, and effective therapies. Genome-scale data sets from patients with renal disease can be used to establish a platform to improve understanding of the molecular basis of disease; however, such studies require expertise and resources. To overcome these challenges, we formed an academic–industry consortium to share molecular target identification efforts and expertise across academia and the pharmaceutical industry. The Renal Pre-Competitive Consortium (RPC2) aims to accelerate novel drug development for kidney diseases through a systems biology approach. Here, we describe the rationale, philosophy, establishment, and initial results of this strategy. Establishment of the first pre-competitive consortium toward therapies for chronic kidney diseases.
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Bioorthogonal chemistry in bioluminescence imaging ()
Publication date: Available online 18 May 2018 Source:Drug Discovery Today Author(s): Aurélien Godinat, Arkadiy A. Bazhin, Elena A. Goun Bioorthogonal chemistry has developed significant over the past few decades, to the particular benefit of molecular imaging. Bioluminescence imaging (BLI) along with other imaging modalities have significantly benefitted from this chemistry. Here, we review bioorthogonal reactions that have been used to signific antly broaden the application range of BLI. The current review summarizes recent progress in the development of assays based on bioorthogonal reactions for bioluminescent imaging of various biological processes in cells and in animals.
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Corticosteroids and perinatal hypoxic-ischemic brain injury ()
Publication date: Available online 17 May 2018 Source:Drug Discovery Today Author(s): Katherine R. Concepcion, Lubo Zhang Perinatal hypoxic-ischemic (HI) brain injury is the major cause of neonatal mortality and severe long-term neurological morbidity. Yet, the effective therapeutic interventions currently available are extremely limited. Corticosteroids act on both mineralocorticoid (MR) and glucocorticoid (GR) receptors and modulate inflammation and apoptosis in the brain. Neuroinflammatory response to acute cerebral HI is a major contributor to the pathophysiology of perinatal brain injury. Here, we give an overview of current knowledge of corticosteroid-mediated modulations of inflammation and apoptosis in the neonatal brain, focusing on key regulatory cells of the innate and adaptive immune response. In addition, we provide new insights into targets of MR and GR in potential therapeutic strategies that could be beneficial for the treatment of infants with HI brain injury. Glucocorticoids modulate inflammation and apoptosis in the neonatal brain, providing potential therapeutic strategies that could be beneficial for the treatment of infants with HI brain injury.
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Targeting HIF-2α as therapy for advanced cancers ()
Publication date: Available online 16 May 2018 Source:Drug Discovery Today Author(s): Thanabal Murugesan, Gurukumari Rajajeyabalachandran, Swetha Kumar, Shruthi Nagaraju, Sooriya Kumar Jegatheesan Hypoxia-inducible factors (HIF-1α, -2α -3α, and -β) are key factors that control hypoxia-induced carcinogenic pathways. HIF-1α is predominantly involved in the early stages of cancer, whereas HIF-2α is actively involved in the later stages; in addition, chronic (prolonged) rather than acute (short) hypoxia is a feature of metastasis and chemoresistance that occur during the later stages of cancer. Oncometabolites, onco-miRNAs, glucose deprivation, pseudohypoxia, cytokine/chemokine secretion, and some unique upstream proteins are involved in the signaling switch from HIF-1α to HIF-2α; thus, understanding this signaling switch is critical for the treatment of advanced cancer. In this review, we highlight data relating to HIF-2α rather than HIF-1α signaling in cancer pathways and discuss prospective drugs that target this important factor.
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Prolyl hydroxylase 2: a promising target to inhibit hypoxia-induced cellular metabolism in cancer cells ()
Publication date: Available online 14 May 2018 Source:Drug Discovery Today Author(s): Lakhveer Singh, Sara Aldosary, Abdulaziz S. Saeedan, Mohd. Nazam Ansari, Gaurav Kaithwas Hypoxia-inducible factor-1α (HIF-1α) shifts the metabolism of glucose from highly efficient oxidative phosphorylation to less efficient glycolysis. Pyruvic acid thus accumulated is oxidized to lactic acid which is pumped out in the tumor microenvironment. Protons generated from the pentose phosphate pathway (PPP) and upon hydrolysis of ATP further enhance the acidity in the tumor microenvironment. The resultant pH in the tumor microenvironment activates an endoplasmic reticulum protein: sterol regulatory element binding protein-1c (SREBP-1c), which once activated enhances proliferation of the tumor cell. Prolyl hydroxylase 2 (PHD2) is a negative regulator of HIF-1α and causes degradation of HIF-1α in the presence of oxygen. Chemical activation of PHD2 can downregulate HIF-1α and thus restore all its effects. The present review is an attempt to describe PHD2 as the target to combat cancer hypoxia and consequential cellular and metabolic alterations.
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Translation of innovative chemistry into screening libraries: an exemplar partnership from the European Lead Factory ()
Publication date: Available online 9 May 2018 Source:Drug Discovery Today Author(s): Remy Morgentin, Mark Dow, Anthony Aimon, George Karageorgis, Tuomo Kalliokoski, Didier Roche, Stephen Marsden, Adam Nelson The identification of high-quality starting points for drug discovery is an enduring challenge in medicinal chemistry. Yet, the chemical space explored in discovery programmes tends be limited by the narrow toolkit of robust methods that are exploited in discovery workflows. The European Lead Factory (ELF) was established in 2013 to boost early-stage drug discovery within Europe. In this Feature, we describe an exemplar partnership that has led to the addition of 21119 distinctive screening compounds to the ELF Joint European Compound Library. The partnership could serve as a blueprint for the translation of innovative academic chemistry into discovery programmes.
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Targeting cancer metabolism to develop human lactate dehydrogenase (hLDH)5 inhibitors ()
Publication date: Available online 8 May 2018 Source:Drug Discovery Today Author(s): Shao-Lin Zhang, Yun He, Kin Yip Tam Cancer cells feature a switch in glucose metabolism from oxidative phosphorylation to cytoplasm-based glycolysis. This altered cellular metabolic pathway meets the survival and proliferation needs for tumor progression. Targeting the metabolic remodeling could offer opportunities for developing effective anticancer therapeutics. Human lactate dehydrogenase (hLDH)5 plays a crucial part in the promotion of glycolysis and is overexpressed in various human tumors, and thus could be a potential anticancer drug target. Here, we briefly discuss the roles of hLDH5 and its connections with cancer metabolism. Then, we review the reported small molecules in light of their binding modes to hLDH5. Finally, possible directions for future development of hLDH5 inhibitors are proposed. We hope that this review will provoke interest in developing hLDH5 inhibitors. Graphical abstract image
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Machine learning in chemoinformatics and drug discovery ()
Publication date: Available online 8 May 2018 Source:Drug Discovery Today Author(s): Yu-Chen Lo, Stefano E. Rensi, Wen Torng, Russ B. Altman Chemoinformatics is an established discipline focusing on extracting, processing and extrapolating meaningful data from chemical structures. With the rapid explosion of chemical ‘big’ data from HTS and combinatorial synthesis, machine learning has become an indispensable tool for drug designers to mine chemical information from large compound databases to design drugs with important biological properties. To process the chemical data, we first reviewed multiple processing layers in the chemoinformatics pipeline followed by the introduction of commonly used machine learning models in drug discovery and QSAR analysis. Here, we present basic principles and recent case studies to demonstrate the utility of machine learning techniques in chemoinformatics analyses; and we discuss limitations and future directions to guide further development in this evolving field.
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2017 in review: FDA approvals of new molecular entities ()
Publication date: Available online 8 May 2018 Source:Drug Discovery Today Author(s): Michael S. Kinch, Rebekah H. Griesenauer An overview of drugs approved by the FDA in 2017 reflected a reversion to the mean after a low number of NME approvals in 2016. This reversal was largely driven by the largest number of biologics-based NMEs recorded to date, which offset an average number of small-molecule approvals. Oncology indications continued to dominate followed by novel treatments for infectious, immunologic and neurologic diseases. From a mechanistic standpoint, the industry has continued a trend of target diversification, reflecting advances in scientific understanding of disease processes. Finally, 2017 continued a period of relatively few mergers and acquisitions, which broke a more-than-a-decade-long decline in the number of organizations contributing to research and development.
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Is the adenosine A2B ‘biased’ receptor a valuable target for the treatment of pulmonary arterial hypertension? ()
Publication date: Available online 7 May 2018 Source:Drug Discovery Today Author(s): Mafalda Bessa-Gonçalves, Bruno Bragança, Eduardo Martins-Dias, Paulo Correia-de-Sá, Ana Patrícia Fontes-Sousa Pulmonary arterial hypertension (PAH) is a maladaptive disorder characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Adenosine released by injured tissues, such as the lung and heart, influences tissue remodeling through the activation of adenosine receptors. Evidence regarding activation of the low-affinity A2BAR by adenosine points towards pivotal roles of this receptor in processes associated with both acute and chronic lung diseases. Conflicting results exist concerning the beneficial or detrimental roles of the A2B ‘biased’ receptor in right ventricular failure secondary to PAH. In this review, we discuss the pros and cons of manipulating A2BARs as a putative therapeutic target in PAH.
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Dual-therapy strategy for modification of adiponectin receptor signaling in aging-associated chronic diseases ()
Publication date: Available online 7 May 2018 Source:Drug Discovery Today Author(s): Masaaki Waragai, Gilbert Ho, Yoshiki Takamatsu, Yuka Shimizu, Hiromu Sugino, Shuei Sugama, Takato Takenouchi, Eliezer Masliah, Makoto Hashimoto Given the paradigm of anti-insulin resistance in therapies for metabolic syndrome, there has been considerable interest in adiponectin (APN), an adipocyte-derived sensitizer of insulin receptor signaling. In contrast to hypoadiponectinemia in metabolic syndrome, evidence suggests that Alzheimer’s disease (AD) and other diseases, including chronic heart failure (CHF) and chronic kidney disease (CKD), are characterized by hyperadiponectinemia as well as the APN/obesity paradoxes, indicating that a decrease in APN might also be beneficial for these diseases. Thus, distinct from metabolic syndrome, it is anticipated that APN receptor antagonists rather than agonists might be effective in therapy for some chronic diseases.
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The extent and effects of patient involvement in pictogram design for written drug information: a short systematic review ()
Publication date: Available online 7 May 2018 Source:Drug Discovery Today Author(s): Mara M. van Beusekom, Anne H. Kerkhoven, Mark J.W. Bos, Henk-Jan Guchelaar, Jos M. van den Broek This short review provides insight into the extent and effectiveness of patient involvement in the design and evaluation of pictograms to support patient drug information. Pubmed, CINAHL, Cochrane Library, Embase, PsycINFO, Academic Search Premier and Web of Science were searched systematically; the 73 included articles were evaluated with the MMAT. We see that, usually, non-patient end-users are involved in the design of pharmaceutical pictograms – patients are more commonly involved in the final evaluation of pictogram success. Repeated involvement of (non-)patients aids the design of effective pharmaceutical pictograms, although there is limited evidence for such effects on patient perception of drug information or health behaviour.
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Real-world evidence approach to traditional herbal medicinal products ()
Publication date: Available online 7 May 2018 Source:Drug Discovery Today Author(s): Xinyu Weng
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Bioinspired bone therapies using naringin: applications and advances ()
Publication date: Available online 7 May 2018 Source:Drug Discovery Today Author(s): Pedro Lavrador, Vitor M. Gaspar, João F. Mano The use of natural compounds for treating chronic bone diseases holds remarkable potential. Among these therapeutics, naringin, a flavanone glycoside, represents one of the most promising candidates owing to its multifaceted effect on bone tissues. This review provides an up-to-date overview on naringin applications in the treatment of bone disorders, such as osteoporosis and osteoarthritis, and further highlights its potential for stem cell pro-osteogenic differentiation therapies. A critical perspective on naringin clinical translation is also provided. The topic is discussed in light of recently developed biomaterial-based approaches that potentiate its bioavailability and bioactivity. Overall, the reported pro-osteogenic, antiresorptive and antiadipogenic properties establish this flavanone as an exciting candidate for application in bone tissue engineering and regenerative medicine.
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When fragments link: a bibliometric perspective on the development of fragment-based drug discovery ()
Publication date: Available online 5 May 2018 Source:Drug Discovery Today Author(s): Angelo K.S. Romasanta, Peter van der Sijde, Iina Hellsten, Roderick E. Hubbard, Gyorgy M. Keseru, Jacqueline van Muijlwijk-Koezen, Iwan J.P. de Esch Fragment-based drug discovery (FBDD) is a highly interdisciplinary field, rich in ideas integrated from pharmaceutical sciences, chemistry, biology, and physics, among others. To enrich our understanding of the development of the field, we used bibliometric techniques to analyze 3642 publications in FBDD, complementing accounts by key practitioners. Mapping its core papers, we found the transfer of knowledge from academia to industry. Co-authorship analysis showed that university–industry collaboration has grown over time. Moreover, we show how ideas from other scientific disciplines have been integrated into the FBDD paradigm. Keyword analysis showed that the field is organized into four interconnected practices: library design, fragment screening, computational methods, and optimization. This study highlights the importance of interactions among various individuals and institutions from diverse disciplines in newly emerging scientific fields. We study the organizational aspects of the development of fragment-based drug discovery (FBDD), using tools from bibliometrics.
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Applying the 3Rs to neuroscience research involving nonhuman primates ()
Publication date: Available online 4 May 2018 Source:Drug Discovery Today Author(s): Roger N. Lemon This Feature focuses on UK neuroscience research using nonhuman primates (NHPs), and the application of the 3Rs, in the light of the recent EU SCHEER report and subsequent article by Prescott et al. (2017). The challenge of understanding the human brain and its disorders means that NHP research is still very much needed, although it is essential that this research is complemented by studies using other approaches, such as human volunteers and patients, and other alternatives to NHP use. Analysis of recent publications shows that these complementary approaches are already being actively exploited by NHP researchers in the UK. Application of the 3Rs has been led by the UK National Centre for the 3Rs (NC3Rs), with active participation of UK NHP researchers, who are constantly refining research methodology. However, not all refinements work, and those that do succeed need to be fully validated before they can be introduced more widely into current practice. More generally, the 3Rs have helped to ameliorate harm experienced by NHPs in procedures, although there is still more to do. Accumulating evidence from recent UK Home Office statistics suggests that most monkeys used in scientific procedures experience a moderate rather than a severe level of harm.
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Cochlear hair cell regeneration: an emerging opportunity to cure noise-induced sensorineural hearing loss ()
Publication date: Available online 4 May 2018 Source:Drug Discovery Today Author(s): Ibrahima Youm, Wei Li In mammals, cochlear hair cells have a pivotal role in transducing mechanical energy into electrical signals. Cochlear hair cells are sensitive to acoustic trauma, drug insults, aging, and environmental or genetic influences that can cause permanent hearing loss. Currently, many researchers have focused on noise-induced sensorineural hearing loss (SNHL). Noise-induced SNHL is primarily caused by damage to hair cells of the cochlear sensory epithelium. Here, we summarize recent progress in restoring the sensory epithelium after SNHL resulting from noise exposure. The prevalent strategy to regenerate cochlear hair cells is through transdifferentiation of the supporting cells via the inhibition of the NOTCH 1 pathway.
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Protein–peptide docking: opportunities and challenges ()
Publication date: Available online 4 May 2018 Source:Drug Discovery Today Author(s): Maciej Ciemny, Mateusz Kurcinski, Karol Kamel, Andrzej Kolinski, Nawsad Alam, Ora Schueler-Furman, Sebastian Kmiecik Peptides have recently attracted much attention as promising drug candidates. Rational design of peptide-derived therapeutics usually requires structural characterization of the underlying protein–peptide interaction. Given that experimental characterization can be difficult, reliable computational tools are needed. In recent years, a variety of approaches have been developed for ‘protein–peptide docking’, that is, predicting the structure of the protein–peptide complex, starting from the protein structure and the peptide sequence, including variable degrees of information about the peptide binding site and/or conformation. In this review, we provide an overview of protein–peptide docking methods and outline their capabilities, limitations, and applications in structure-based drug design. Key challenges are also briefly discussed, such as modeling of large-scale conformational changes upon binding, scoring of predicted models, and optimal inclusion of varied types of experimental data and theoretical predictions into an integrative modeling process.
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Contents page 1 ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5
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Contents page 2 ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5
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Novel nanotherapeutic strategies: fabrication approaches, application and clinical challenges ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Vivek Agrahari, Vibhuti Agrahari
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Circulatory-cell-mediated nanotherapeutic approaches in disease targeting ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Thierry Burnouf, Pierre-Alain Burnouf, Yu-Wen Wu, Er-Yuan Chuang, Long-Sheng Lu, Hadi Goubran Circulating blood cells, and cell-derived microvesicles, are emerging as pragmatic delivery systems that can smartly complement the already existing nanotherapeutic platforms evaluated to treat or diagnose diseases. The valuable distinctive features of circulatory cells over synthetic nanocarriers encompass their biological origin which confers immune transparence, known biodegradability, high drug loading, relatively long half-life and a targeting capacity associated with their physiological surface functionality. Absence of nuclei in red blood cells and platelets provides further rationale for their use as cargo vehicles for nucleotoxic agents. Ongoing developments in cell-based and cell-inspired nanotherapies can move drug delivery into reachable frontiers and exhibit high potentiality for translatability into clinical use.
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Strategies for the enhanced intracellular delivery of nanomaterials ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Cláudia Azevedo, Maria Helena Macedo, Bruno Sarmento The intracellular delivery of nanomaterials and drugs has been attracting increasing research interest, mainly because of their important effects and functions in several organelles. Targeting specific organelles can help treat or decrease the symptoms of diabetes, cancer, infectious, and autoimmune diseases. Tuning biological and chemical properties enables the creation of functionalized nanomaterials with enhanced intracellular uptake, ability to escape premature lysosome degradation, and to reach a specific target. Here, we provide an update of recent advances in the intracellular delivery mechanisms that could help drugs reach their target more efficiently. This review provides an update of recent advances in intracellular delivery and reports mechanisms that could help drugs reach their target efficiently, resulting in smarter drugs that reach their target still with the original bioavailability.
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Recent advances in galactose-engineered nanocarriers for the site-specific delivery of siRNA and anticancer drugs ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Ashay Jain, Atul Jain, Prahlad Parajuli, Vijay Mishra, Gargi Ghoshal, Bhupinder Singh, Uma Shankar Shivhare, Om Prakash Katare, Prashant Kesharwani Galactosylated nanocarriers have recently emerged as viable and versatile tools to deliver drugs at an optimal rate specifically to their target tissues or cells, thus maximizing their therapeutic benefits while circumventing off-target effects. The abundance of lectin receptors on cell surfaces makes the galactosylated carriers suitable for the targeted delivery of bioactives. Additionally, tethering of galactose (GAL) to various carriers, including micelles, liposomes, and nanoparticles (NPs), might also be appropriate for drug delivery. Here, we review recent advances in the development of galactosylated nanocarriers for active tumor targeting. We also provide a brief overview of the targeting mechanisms and cell receptor theory involved in the ligand–receptor-mediated delivery of drug carriers. Galactose-functionalized nanocarriers open new avenues for the design of highly effective multifunctional, targeted drug delivery systems.
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Facilitating the translation of nanomedicines to a clinical product: challenges and opportunities ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Vibhuti Agrahari, Vivek Agrahari There are numerous hurdles hindering the clinical translation of nanomedicines. The major challenges are: reproducible manufacturing and scale-up, availability of appropriate characterization methods, instability under in vivo environments, safety issues, poor understanding of the disease heterogeneity and patient preselection strategies, regulatory barriers and inadequate understanding of the biophysical and chemical interactions of nanoformulations. Thus, a better understanding of key physicochemical attributes and their characterization methods, in vivo behavior and the in-vitro–in-vivo characterization cascade of stability, safety and efficacy testing is needed to accelerate nanomedicine translation. Technologies such as quality-by-design, process analytical techniques and microfluidics could significantly accelerate the translation of nanomedicines. However, these approaches require further learning and an adequate regulatory background. Overall, to achieve an efficient clinical translation, collaboration among academia, industry and regulatory bodies is required to ensure safe and effective nanomedicine products. This review discusses the challenges and opportunities to facilitate the translation of nanomedicines to a commercial product. Understanding of fundamental, characterization, clinical and regulatory aspects of nanomedicines is vital to enhance their translational potential. Hence, challenges and opportunities related to the commercialization of nanomedicines are discussed.
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Design strategies for physical-stimuli-responsive programmable nanotherapeutics ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Fitsum Feleke Sahle, Muhammad Gulfam, Tao L. Lowe Nanomaterials that respond to externally applied physical stimuli such as temperature, light, ultrasound, magnetic field and electric field have shown great potential for controlled and targeted delivery of therapeutic agents. However, the body of literature on programming these stimuli-responsive nanomaterials to attain the desired level of pharmacologic responses is still fragmented and has not been systematically reviewed. The purpose of this review is to summarize and synthesize the literature on various design strategies for simple and sophisticated programmable physical-stimuli-responsive nanotherapeutics. Here, we present a systematic approach to design different programmable physical-stimuli-responsive nanotherapeutics intended for controlled and targeted delivery of various therapeutic agents.
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Personalized nanomedicine for CNS diseases ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Ajeet Kaushik, Rahul Dev Jayant, Vinay Bhardwaj, Madhavan Nair Central nervous system (CNS) diseases are rapidly increasing globally. Currently used therapeutic agents to treat CNS diseases exhibit significant efficacy. However, the inability of these drugs to cross the blood–brain barrier (BBB) and invasiveness of the technologies to achieve localized drug delivery in disease-specific parts of the brain have thwarted pain-free and complete treatment of CNS diseases. Therefore, the safe, non-invasive, and targeted delivery of drugs to the brain using nanoparticles (NPs) is currently receiving considerable research attention. Here, we highlight advances in state-of-the-art personalized nanomedicine for the treatment of CNS diseases (with a focus on dementia), the related challenges, possible solutions, and prospects for nano-enabled personalized medicine.
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Carbon nanomaterials in oncology: an expanding horizon ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Neelesh K. Mehra, Amit K. Jain, Manoj Nahar Carbon nanomaterials have been attracting attention in oncology for the development of safe and effective cancer nanomedicines in increasing improved patient compliance for generally recognized as safe (GRAS) prominence. Toxicity, safety and efficacy of carbon nanomaterials are the major concerns in cancer theranostics. Various parameters such as particle size and shape or surface morphology, surface charge, composition, oxidation and nonoxidative-stress-related mechanisms are prone to toxicity of the carbon nanomaterials. Currently, few cancer-related products have been available on the market, although some are underway in preclinical and clinical phases. Thus, our main aim is to provide comprehensive details on the carbon nanomaterials in oncology from the past two decades for patient compliance and safety.
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Microarray patches: potentially useful delivery systems for long-acting nanosuspensions ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Ryan F. Donnelly, Eneko Larrañeta Long-acting drug nanosuspension formulations are coming to the fore as controlled release strategies for several medical conditions and as a preventative measure against HIV infection. However, such delivery systems must, by necessity, be given by hypodermic injection, typically into muscle. This poses problems for patients who are needle-phobic, given that injections have to be administered on a weekly or monthly basis. Needle-stick injuries, inappropriate reuse of needles, and poor disposal practices are major challenges in developing countries. Dissolving microneedles (MNs) are capable of delivering high drug doses, if suitably designed and formulated, and are also capable of delivering nanoparticles (NPs) into viable skin. Given that such microneedles are minimally invasive and self-disabling, the potential for major enhancement in patient care and compliance exists. In this review, we explore the key considerations in the development of these combination drug delivery systems.
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Nanomedicine safety in preclinical and clinical development: focus on idiosyncratic injection/infusion reactions ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Seyed Moein Moghimi Injection/infusion reactions to nanopharmaceuticals (and particulate drug carriers) are idiosyncratic and well documented. The molecular basis of nanoparticle-mediated injection reactions is debatable, with two hypotheses as front-runners. The first is complement-activation-related ‘pseudoallergy’, where a causal role for nanoparticle-mediated complement activation in injection/infusion reactions is considered. However, the second hypothesis (the rapid phagocytic response hypothesis) states a transitional link from robust clearance of nanoparticles (NPs) from the blood by strategically placed responsive macrophages to adverse hemodynamic and cardiopulmonary reactions, regardless of complement activation. Here, I critically examine and discuss these hypotheses. Current experimentally derived evidence appears to be more in support of the rapid phagocytic response hypothesis than of the ‘pseudoallergy’ hypothesis.
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Applications of stimuli-responsive nanoscale drug delivery systems in translational research ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Mengjie Gu, Xin Wang, Tan Boon Toh, Edward Kai-Hua Chow Nanoscale drug delivery systems or nanocarriers have shown tremendous promise in the target-specific delivery of therapeutics as well as diagnostic agents. Additional properties can be introduced into nanocarriers to enhance the bioavailability and targeting efficiency of the transported drugs at diseased sites. Such nanocarriers are usually incorporated with stimuli-responsive components that can be triggered by specific stimuli (e.g., temperature, pH, or enzymes) and further induced by certain biological responses, such as enzyme hydrolysis and molecular conformational changes, leading to the controlled release of the transported molecules at targeted sites. In this review, we discuss various stimuli-responsive nanoscale delivery systems and summarize the current perspectives as well as challenges facing the successful translation of these innovative stimuli-responsive nanocarriers from the bench to the bedside.
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Macromolecule nanotherapeutics: approaches and challenges ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Puneet Tyagi, Jose Luis Santos With the advent of technology, newer forms of drugs, such as proteins, DNA, and RNA, have entered mainstream product development. However, systemic delivery of macromolecules is limited by rapid blood clearance, poor stability in vivo, and inadequate uptake by cells. Nanoparticle (NP)-based delivery systems have emerged as suitable carriers for overcoming such pharmacokinetic limitations of macromolecule delivery. Nanocarriers, such as liposomes, provide protection for sensitive drug materials and also enhance the circulation half-life of therapeutics. Nanocarriers have also been shown to promote cellular uptake and the release of intact macromolecules in the cell. Besides liposomes, other nanocarriers, such as gold and iron oxide NPs, are also now being tested in clinical trials. Graphical abstract image
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Light-triggerable formulations for the intracellular controlled release of biomolecules ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Miguel M. Lino, Lino Ferreira New therapies based on the use of biomolecules [e.g., proteins, peptides, and non-coding (nc)RNAs] have emerged during the past few years. Given their instability, adverse effects, and limited ability to cross cell membranes, delivery systems are required to fully reveal their biological potential. Sophisticated nanoformulations responsive to light offer an excellent opportunity for the controlled release of these biomolecules, enabling the control of timing, duration, location, and dosage. In this review, we discuss the design principles for the delivery of biomolecules, in particular proteins and RNA-based therapeutics, by light-triggerable formulations. We further discuss the opportunities offered by these formulations in terms of endosomal escape, as well as their limitations.
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Stem cells as vehicles and targets of nanoparticles ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Sonia Pinho, Maria H. Macedo, Catarina Rebelo, Bruno Sarmento, Lino Ferreira Modulation of endogenous adult stem cell niches represents a promising strategy for regeneration of tissues and to correct cell abnormalities, including cancer. Recent advances show the possibility to target endogenous stem cells or their progenies by using nanoparticles conjugated with specific biomolecules. In addition, the targeting of the stem cell niche can be accomplished by using stem cells loaded with nanoparticles. This review examines principles for the targeting of endogenous stem cells as well as factors for the modulation of stem cells.
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An update on the role of nanovehicles in nose-to-brain drug delivery ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Yunhai Feng, Haisheng He, Fengqian Li, Yi Lu, Jianping Qi, Wei Wu A quantitative analysis has cast doubt over the limited advantages provided by particles for nose-to-brain (NTB) drug delivery. Thus, it is imperative to identify the role of nanovehicles in NTB drug delivery. If nanocarriers are used merely as an option to improve various properties of the drugs or the formulations, it is difficult for them to outperform conventional formulations, such as solutions or gels. However, nanovehicles bring about special features, such as maintenance of the solubilized state of drugs, sustained or delayed release, and enhanced penetration because of surface modifications, all of which lead to enhanced NTB delivery efficiency.
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Thymoquinone-based nanotechnology for cancer therapy: promises and challenges ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Farah Ballout, Zeina Habli, Omar Nasser Rahal, Maamoun Fatfat, Hala Gali-Muhtasib Thymoquinone (TQ), the active ingredient of black seed, is a promising anticancer molecule that inhibits cancer cell growth and progression in vitro and in vivo. Despite the promising anticancer activities of TQ, its translation to the clinic is limited by its poor bioavailability and hydrophobicity. As such, we and others encapsulated TQ in nanoparticles to improve its delivery and limit undesirable cytotoxicity. These TQ-nanoparticle formulations showed improved anticancer and anti-inflammatory activities when compared with free TQ. Here, we provide an overview of the various TQ-nanoparticle formulations, highlight their superior efficacy and discuss up-to-date solutions to further enhance TQ bioavailability and anticancer activity, thus improving potential for clinical translation.
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Nanomedicine as a potential approach to empower the new strategies for the treatment of preeclampsia ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Lucie Valero, Khair Alhareth, Sophie Gil, Edouard Lecarpentier, Vassilis Tsatsaris, Nathalie Mignet, Thierry Fournier, Karine Andrieux Preeclampsia is a serious pregnancy disorder characterized by the onset of high blood pressure and proteinuria. Although the understanding of the disease is increasing, it remains without treatment, other than the delivery of the baby and the placenta. This review sets out to discuss some new developments and strategies in the treatment of preeclampsia. We briefly review the current knowledge on the preeclamptic pathophysiology. We then examine the recent trends in preeclampsia treatment and, in particular, the tracks of potential therapeutic targets. Finally, we focus on the possibilities nanocarriers could offer in the management of preeclampsia. Indeed, nanocarriers could help to prevent transplacental passage and promote placental-specific drug delivery, thereby enhancing efficacy and improving safety. Tendencies are then drawn from the available studies on the optimal characteristics of a nanocarrier to deliver drugs to the placenta.
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Navigating albumin-based nanoparticles through various drug delivery routes ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Yeong L. Tan, Han K. Ho As a natural polymer, albumin is well-received for being nontoxic, nonimmunogenic, biodegradable and biocompatible. Together with its targeting potential on specific cells, albumin-based nanoparticles appear as an effective carrier for various therapeutics. In recent years, there has been an increasing number of studies investigating the use of albumin-based nanoparticles across different administration routes. Although each route and target tissue presents a distinct anatomical and physiological profile that demands specific consideration, pharmaceuticals could still be delivered effectively via albumin-based nanoparticles. Therefore, this review discusses the features that warrant such applications across various delivery routes and explores their possibilities in other administration routes. The challenges associated with its use will also be elaborated to provide a holistic consideration to realise their clinical potentials.
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Recent advances in near-infrared light-responsive nanocarriers for cancer therapy ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Ankit Saneja, Robin Kumar, Divya Arora, Sandeep Kumar, Amulya K. Panda, Sundeep Jaglan In recent years, research has focused on the development of smart nanocarriers that can respond to specific stimuli. Among the various stimuli-responsive platforms for cancer therapy, near-infrared (NIR) light (700–1000nm)-responsive nanocarriers have gained considerable interest because of their deeper tissue penetration capacity, precisely controlled drug release, and minimal damage towards normal tissues. In this review, we outline various therapeutic applications of NIR-responsive nanocarriers in drug delivery, photothermal therapy (PTT), photodynamic therapy (PDT), and bioimaging. We also highlight recent trends towards NIR-responsive combinatorial therapy and multistimuli-responsive nanocarriers for improving therapeutic outcomes.
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Advances in glycosylation-mediated cancer-targeted drug delivery ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Lulu Cai, Zhipeng Gu, Jian Zhong, Di Wen, Guojun Chen, Lin He, Jun Wu, Zhen Gu Targeted drug delivery for cancer therapy is expected to enhance therapeutic efficacy with minimized side effects, where the ligand-receptor recognition serves as a common targeting approach. Various ligands have been reported and carbohydrates, one of the crucial structures of tumor cell membranes, have been demonstrated effective for cell-selective binding. Hence, glycosylation-mediated cancer-targeted drug nanocarriers have received increasing attention in recent years. This review surveys a variety of glycosylated drug delivery systems as well as their applications for cancer therapy. Their challenges, opportunities, and future perspectives are also discussed in the end.
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Advances and applications of block-copolymer-based nanoformulations ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Vibhuti Agrahari, Vivek Agrahari Advances in polymer synthetic approaches have significantly enhanced the ability to rationally design the block copolymers with tailor-made functionality and variable molecular weight. Hence, block copolymers have been extensively applied in the formulation of nanostructure materials. Owing to their amphiphilic characteristics, block copolymers can generate different nanostructures, providing easy adjustability of their size, stability and surface chemistry. In this review, block copolymer classification, synthesis, characterization, stimuli-responsive behavior and nanostructure applications are summarized. Although block copolymers hold great potential for improving the therapeutic efficacy of drugs, a comprehensive delivery potential of these systems has not been fully exploited. Thus, an outlook on future developments on block-copolymer-based assemblies are further discussed. The new developments in block copolymers are expected to contribute significantly to the field of polymeric nanomedicine.
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Nanodiamond applications in skin preparations ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Roshanak Namdar, Shohreh Nafisi The biocompatibility and nontoxicity of nanodiamonds (NDs) in combination with their excellent physical performance have rendered them attractive candidates for biomedical applications. NDs have great potential in drug nanoformulations because of their small size compared with other carbon nanomaterials. They are nontoxic with excellent adsorption properties and can be formulated into skin care products. Even though NDs have shown encouraging potential in skin preparations, only a few studies have reviewed their application in topical drug delivery systems. Therefore, here we focus on the application of NDs in skin care preparations, skin cancer medication, and wound healing. We also highlight the development of topical drug delivery by NDs and their cytotoxicity.
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Cancer theranostic applications of lipid-based nanoparticles ()
Publication date: May 2018 Source:Drug Discovery Today, Volume 23, Issue 5 Author(s): Wei-Lun Tang, Wei-Hsin Tang, Shyh-Dar Li A variety of nanoplatforms have been developed and applied for cancer therapy, imaging, or the combination thereof. These nanoplatforms, combined with therapeutic and imaging functionalities, display great potential to enhance medical care. In particular, lipid-based nanoparticles (LNPs) are among the most-studied platforms that have resulted in many encouraging advances in theranostics. LNPs are biodegradable and biocompatible, and their formulation can be tailored for various applications. Here, we provide an overview of recent developments of four representative LNP platforms for theranostics: stealth liposomes, triggered-release liposomes, porphysomes, and lipid-coated calcium phosphate NPs (LCPs). We discuss their potential, limitations, and potential applications for cancer care and highlight perspectives and future directions for the nanotheranostics field.
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Role of lncRNAs in ovarian cancer: defining new biomarkers for therapeutic purposes ()
Publication date: Available online 23 April 2018 Source:Drug Discovery Today Author(s): Manish K. Tripathi, Kyle Doxtater, Fatemeh Keramatnia, Chidi Zacheaus, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan Long noncoding RNAs (lncRNAs) are a class of noncoding RNA, involved in regulation of diverse physiological and pathological processes. Ovarian cancer is the leading cause of death among all gynecological malignancies in the world and its underlying mechanism is still unclear. LncRNAs exhibit multiple biological functions in various stages of ovarian cancer development. We will discuss and summarize the new and important lncRNAs and their involvement in disease, which might represent promising therapeutic targets. Therapeutic intervention based on silencing or functional inhibition of target lncRNAs will be beneficial for ovarian cancer patients.
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Cyclodextrins as excipients in tablet formulations ()
Publication date: Available online 22 April 2018 Source:Drug Discovery Today Author(s): Jaime Conceição, Oluwatomide Adeoye, Helena Maria Cabral-Marques, José Manuel Sousa Lobo This paper aims to provide a critical review of cyclodextrins as excipients in tablet formulations, highlighting: (i) the principal pharmaceutical applications of cyclodextrins; (ii) the most relevant technological aspects in pharmaceutical formulation development; and (iii) the actual regulatory status of cyclodextrins. Moreover, several illustrative examples are presented. Cyclodextrins can be used as complexing excipients in tablet formulations for low-dose drugs. By contrast, for medium-dose drugs and/or when the complexation efficiency is low, the methods to enhance the complexation efficiency play a key part in reducing the cyclodextrin quantity. In addition, these compounds are used as fillers, disintegrants, binders and multifunctional direct compression excipients of the tablets.
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The remarkable therapeutic potential of response-based dose individualisation in drug trials and patient care ()
Publication date: Available online 12 April 2018 Source:Drug Discovery Today Author(s): Chao Chen The FDA reported that most drugs are effective in only 25–62% of patients. Although many drugs require dose individualisation in clinical practice, dose-finding trials usually aim to identify an optimal dose for the patient population. Such a dose would be suboptimal for many patients. Simulations show that individualised dose titration, balancing efficacy against toxicity, can remarkably increase the response rate — doubling it in some situations. Dose titration in a clinical trial can efficiently establish the realistic expectations for the drug’s true utility in a trial setting that reflects clinical practice, as well as generate important knowledge to guide patient care through informative drug labels. This design answers key questions truly relevant to patient care that other designs cannot — will a patient benefit from a given therapy, to what extent and at what dose? Therefore, response-based dose titration should be considered for dose-finding trials, where appropriate, for drugs that will eventually be used this way in the clinic.
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