Human-specific approaches to brain research for the 21 st century: a South American perspective Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-13 Marcia Triunfol, Stevens Rehen, Marina Simian, Troy Seidle
The 21 st century paradigm in toxicology, which emphasizes mechanistic understanding and species-relevant modeling of human biology and pathophysiology, is gaining traction in the wider biosciences through a global workshop series organized by the BioMed21 Collaboration. The second of this series, entitled Emerging Technology Toward Pathway-Based Human Brain Research, was held in Brazil in 2017, bringing together leading South American and international scientists, research funders and other stakeholders. The aims were to foster strategic scientific dialogue and identify actionable consensus recommendations as a first step toward a roadmap for 21 st century, human-specific health research and funding in the region.
Retinal pigment epithelial cells as a therapeutic tool and target against retinopathies Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-13 Barbara Pavan, Alessandro Dalpiaz
Retinal pigment epithelium (RPE) is a cell monolayer essential for photoreceptor function and forming the blood–retinal barrier. RPE and retinal neurons share the same origin and a polarized cytoarchitecture. Several factors determine the phagocytosis and permeability of RPE, influencing photoreceptor renewal and drug delivery, efficacy and toxicity. Adult human RPE expresses neuronal markers in vitro, indicating a potential transdifferentiation. Degeneration of the RPE leads to death of photoreceptors and retinal neurons, resulting in the vision loss of retinopathy. Here, we suggest tools for cell engineering to discover new ways for activating the endogenous regeneration of barrier functions and/or of the retinal precursors in RPE cells.
Pragmatic clinical trials: ethical imperatives and opportunities Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-12 Shona Kalkman, Ghislaine J.M.W. van Thiel, Diederick E. Grobbee, Johannes J.M. van Delden
Pragmatic clinical trials generate robust real-world evidence that holds great potential to better inform decision making regarding new medicines. For clinicians, patients and regulators, this evidence would preferably be available sooner rather than later. This means that, ideally, market authorization of any given medicine is accompanied by evidence obtained from a pragmatic trial. Given the operational and regulatory complexities of pragmatic trials in general, stakeholders tend to be hesitant to employ more pragmatism at the time of market approval. One prominent hurdle for the conduct of pragmatic trials is the concern that pragmatic design features conflict with ethical standards for clinical trials. To encourage timely yet responsible generation of real-world evidence through clinical trials, it is important to delineate exactly which areas, from a societal point of view, demand early pragmatic evaluations. We also urge stakeholders to recognize how the current system of trial ethics oversight already accommodates for more-pragmatic approaches, and how new ideas about their permissibility have progressed in the bioethics literature.
Drugp-Induced Rhabdomyolysis Atlas (DIRA) for idiosyncratic adverse drug reaction management Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-11 Zhining Wen, Yu Liang, Yingyi Hao, Brian Delavan, Ruili Huang, Mike Mikailov, Weida Tong, Menglong Li, Zhichao Liu
Drug-induced rhabdomyolysis (DIR) is an idiosyncratic and fatal adverse drug reaction (ADR) characterized in severe muscle injuries accompanied by multiple-organ failure. Limited knowledge regarding the pathophysiology of rhabdomyolysis is the main obstacle to developing early biomarkers and prevention strategies. Given the lack of a centralized data resource to curate, organize, and standardize widespread DIR information, here we present a Drug-Induced Rhabdomyolysis Atlas (DIRA) that provides DIR-related information, including: a classification scheme for DIR based on drug labeling information; postmarketing surveillance data of DIR; and DIR drug property information. To elucidate the utility of DIRA, we used precision dosing, concomitant use of DIR drugs, and predictive modeling development to exemplify strategies for idiosyncratic ADR (IADR) management.
Why are there no drugs indicated for sciatica, the most common chronic neuropathic syndrome of all? Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-09 John D. Markman, Ralf Baron, Jennifer S. Gewandter
Here, we examine the stark contrast between the successes and failures of the clinical development of analgesics for different types of chronic low back pain (CLBP) syndrome over the past three decades. Multiple drugs with differing mechanisms of action have been developed for nonspecific axial-predominant low back syndromes and yet not a single therapy is indicated for any neuropathic low back pain syndrome (e.g., sciatica). Clinician findings have informed the entry criteria for neuropathic low back pain clinical trials, whereas entry criteria of axial CLBP trials have prioritized only patient reports of pain. This key difference could account for the lack of success in developing therapies for neuropathic low back pain in an era marked by successful development of analgesics for other types of CLBP as well as many chronic pain syndromes associated with nerve injury, such as post-herpetic neuralgia (PHN).
Interrogating the microbiome: experimental and computational considerations in support of study reproducibility Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-08 Carine Poussin, Nicolas Sierro, Stéphanie Boué, James Battey, Elena Scotti, Vincenzo Belcastro, Manuel C Peitsch, Nikolai V. Ivanov, Julia Hoeng
Therapeutic application of antibody fragments in autoimmune diseases: current state and prospects Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-08 João C Fernandes
Over the past decades, conventional antibodies have been dissected through different strategies into smaller antigen-binding fragments. Therapeutic solutions built on such fragments can offer several advantages, including the capacity to access challenging epitopes, reduced immunogenicity, lower production costs, and higher stability. Although the development of antibody fragments for cancer therapy has received more attention than any other potential therapeutic application, the development of pharmacological tools based on these molecules for the treatment of autoimmune diseases (AIDs) has been growing at a fast pace. Here, I provide an in-depth characterization of the various formats for the treatment of autoimmune diseases in development across the industry, including antigen-binding fragments (Fab), single-chain variable fragments (scFv), and single variable-domain fragments, as well as multimeric antibody fragments and antibody–drug conjugates.
The fruit fly Drosophila melanogaster as an innovative preclinical ADME model for solute carrier membrane transporters, with consequences for pharmacology and drug therapy Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-08 Yiwen Wang, Bernard Moussian, Elke Schaeffeler, Matthias Schwab, Anne T. Nies
Solute carrier membrane transporters (SLCs) control cell exposure to small-molecule drugs, thereby contributing to drug efficacy and failure and/or adverse effects. Moreover, SLCs are genetically linked to various diseases. Hence, in-depth knowledge of SLC function is fundamental for a better understanding of disease pathophysiology and the drug development process. Given that the model organism Drosophila melanogaster (fruit fly) expresses SLCs, such as for the excretion of endogenous and toxic compounds by the hindgut and Malpighian tubules, equivalent to human intestine and kidney, this system appears to be a promising preclinical model to use to study human SLCs. Here, we systematically compare current knowledge of SLCs in Drosophila and humans and describe the Drosophila model as an innovative tool for drug development.
Translational strategy: humanized mini-organs Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-05 Duong T. Nguyen, Magnus Althage, Maria Chiara Magnone, Sepideh Heydarkhan-Hagvall
Mini-organs engineered from decellularized organs repopulated with human stem cells can transform preclinical model strategies in target validation and biomarker discovery. Recellularized organs are whole humanized organs with preserved native architecture, conformity of the organ, composition of extracellular matrix and vascular matrix structures. With mini-organ models further understanding of developmental biology and assessment of potential therapeutic targets can be elucidated utilizing human induced pluripotent stem cells. As a next step, co-cultured mini-organ models could simulate pharmacokinetics and pharmacodynamics in physiological and pathological conditions. By overcoming key challenges, the development of humanized mini-organs as integrated biotechnology can address the translational gaps between in vitro, ex vivo and in vivo systems for an elevated human target validation model.
Supermolecular drug challenge to overcome drug resistance in cancer cells Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-04 Yasuhiko Onishi, Yuki Eshita, Rui-Cheng Ji, Takashi Kobayashi, Masayasu Onishi, Masaaki Mizuno, Jun Yoshida, Naoji Kubota
Computational prediction of chemical reactions: current status and outlook Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-03 Ola Engkvist, Per-Ola Norrby, Nidhal Selmi, Yu-hong Lam, Zhengwei Peng, Edward C. Sherer, Willi Amberg, Thomas Erhard, Lynette A. Smyth
Over the past few decades, various computational methods have become increasingly important for discovering and developing novel drugs. Computational prediction of chemical reactions is a key part of an efficient drug discovery process. In this review, we discuss important parts of this field, with a focus on utilizing reaction data to build predictive models, the existing programs for synthesis prediction, and usage of quantum mechanics and molecular mechanics (QM/MM) to explore chemical reactions. We also outline potential future developments with an emphasis on pre-competitive collaboration opportunities.
Quantitative metrics for drug–target ligandability Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-06 Sinisa Vukovic, David J. Huggins
Ligandability is a prerequisite for druggability and is a much easier concept to understand, model and predict because it does not depend on the complex pharmacodynamic and pharmacokinetic mechanisms in the human body. In this review, we consider a metric for quantifying ligandability from experimental data. We discuss ligandability in terms of the balance between effort and reward. The metric is evaluated for a standard set of well-studied drug targets – some traditionally considered to be ligandable and some regarded as difficult. We suggest that this metric should be used to systematically improve computational predictions of ligandability, which can then be applied to novel drug targets to predict their tractability.
Prediction of brain:blood unbound concentration ratios in CNS drug discovery employing in silico and in vitro model systems Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-13 Houfu Liu, Kelly Dong, Wandong Zhang, Scott G. Summerfield, Georg C. Terstappen
Recent years have seen a paradigm shift away from optimizing the brain:blood concentration ratio toward the more relevant brain:blood unbound concentration ratio (Kp,uu,br) in CNS drug discovery. Here, we review the recent developments in the in silico and in vitro model systems to predict the Kp,uu,br of discovery compounds with special emphasis on the in-vitro–in-vivo correlation. We also discuss clinical ‘translation’ of rodent Kp,uu,br and highlight the future directions for improvement in brain penetration prediction. Important in this regard are in silico Kp,uu,br models built on larger datasets of high quality, calibration and deeper understanding of experimental in vitro transporter systems, and better understanding of blood–brain barrier transporters and their in vivo relevance aside from P-gp and BCRP.
Redundancy in two major compound databases Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-17 Dimitar Yonchev, Dilyana Dimova, Dagmar Stumpfe, Martin Vogt, Jürgen Bajorath
Public repositories of compounds and activity data are of prime importance for pharmaceutical research in academic and industrial settings. Major databases have evolved over the years. Their growth is accompanied by an increasing tendency toward data sharing. This is a positive development but not without potential problems. Using ChEMBL and PubChem as examples, we show that crosstalk between databases also leads to substantial data redundancy that might not be obvious. Redundancy is an important issue because it biases data analysis and knowledge extraction and leads to inflated views of available compounds, assays and activity data. Going forward it will be important to further refine data exchange and deposition criteria and make redundancy as transparent as possible.
N-acylethanolamine hydrolyzing acid amidase inhibition: tools and potential therapeutic opportunities Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-19 Pauline Bottemanne, Giulio G. Muccioli, Mireille Alhouayek
N-acylethanolamines (NAEs) (e.g., N-palmitoylethanolamine, N-arachidonoylethanolamine, N-oleoylethanolamine) are bioactive lipids involved in many physiological processes including pain, inflammation, anxiety, cognition and food intake. Two enzymes are responsible for the hydrolysis of NAEs and therefore regulate their endogenous levels and effects: fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA). As discussed here, extensive biochemical characterization of NAAA was carried out over the years that contributed to a better understanding of NAAA enzymology. An increasing number of studies describe the synthesis and pharmacological characterization of NAAA inhibitors. Recent medicinal chemistry efforts have led to the development of potent and stable inhibitors that enable studying the effects of NAAA inhibition in preclinical disease models, notably in the context of pain and inflammation.
Computational modeling approaches to quantitative structure–binding kinetics relationships in drug discovery Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-21 Pier G. De Benedetti, Francesca Fanelli
Simple comparative correlation analyses and quantitative structure–kinetics relationship (QSKR) models highlight the interplay of kinetic rates and binding affinity as an essential feature in drug design and discovery. The choice of the molecular series, and their structural variations, used in QSKR modeling is fundamental to understanding the mechanistic implications of ligand and/or drug–target binding and/or unbinding processes. Here, we discuss the implications of linear correlations between kinetic rates and binding affinity constants and the relevance of the computational approaches to QSKR modeling.
EU decision-making for marketing authorization of advanced therapy medicinal products: a case study Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-21 Sofieke de Wilde, Delphi G.M. Coppens, Jarno Hoekman, Marie L. de Bruin, Hubert G.M. Leufkens, Henk-Jan Guchelaar, Pauline Meij
A comparative analysis of assessment procedures for authorization of all European Union (EU) applications for advanced therapy medicinal products (ATMPs) shows that negative opinions were associated with a lack of clinical efficacy and identified severe safety risks. Unmet medical need was often considered in positive opinions and outweighed scientific uncertainties. Numerous quality issues illustrate the difficulties in this domain for ATMP development. Altogether, it suggests that setting appropriate standards for ATMP authorization in Europe, similar to elsewhere, is a learning experience. The experimental characteristics of authorized ATMPs urge regulators, industry, and clinical practice to pay accurate attention to post-marketing risk management to limit patient risk. Methodologies for ATMP development and regulatory evaluations need to be continuously evaluated for the field to flourish.
Strategic R&D transactions in personalized drug development Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-21 Tomohiro Makino, Yeongjoo Lim, Kota Kodama
Although external collaboration capability influences the development of personalized medicine, key transactions in the pharmaceutical industry have not been addressed. To explore specific trends in interorganizational transactions and key players, we longitudinally surveyed strategic transactions, comparing them with other advanced medical developments, such as antibody therapy, as controls. We found that the financing deals of start-ups have surged over the past decade, accelerating intellectual property (IP) creation. Our correlation and regression analyses identified determinants of financing deals among alliance deals, acquisition deals, patents, research and development (R&D) licenses, market licenses, and scientific papers. They showed that patents positively correlated with transactions, and that the number of R&D licenses significantly predicted financing deals. This indicates, for the first time, that start-ups and investors lead progress in personalized medicine.
Can hi-jacking hypoxia inhibit extracellular vesicles in cancer? Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-22 Michelle C. Lowry, Lorraine O’Driscoll
Increasing evidence indicates that extracellular vesicles (EVs) are key players in undesirable cell–cell communication in cancer. However, the release of EVs is not unique to cancer cells; normal cells release EVs to perform physiological roles. Thus, selective inhibition of EV release from cancer cells is desirable. Hypoxia contributes to tumour development and aggressiveness. EV quantities and thus undesirable communications are substantially increased in hypoxia. Targeting hypoxia could selectively inhibit EV release from tumour cells without disturbing physiologically relevant EVs. The unfavourable association between hypoxia and EV release is evident in multiple tumour types; therefore, targeting hypoxia could have a broad therapeutic benefit.
Extension of quality-by-design concept to the early development phase of pharmaceutical R&D processes Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-27 Ildikó Csóka, Edina Pallagi, Tamás L. Paál
Here, we propose the extension of the quality-by-design (QbD) concept to also fit the early development phases of pharmaceuticals by adding elements that are currently widely applied, but not yet included in the QbD model in a structured way. These are the introduction of a ‘zero’ preformulation phase (i.e., selection of drug substance, possible dosage forms and administration routes based on the evaluated therapeutic need); building in stakeholders’ (industry, patient, and regulatory) requirements into the quality target product profile (QTTP); and the use of modern quality management tools during the composition and process design phase [collecting critical quality attributes (CQAs) and selection of CPPs) for (still laboratory-scale) design space (DS) development. Moreover, during industrial scale-up, CQAs (as well as critical process parameters; CPPs) can be changed; however, we recommend that the existing QbD elements are reconsidered and updated after this phase.
Update on the main use of biomaterials and techniques associated with tissue engineering Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-30 Daniela Steffens, Daikelly I. Braghirolli, Natasha Maurmann, Patricia Pranke
Regenerative medicine involves the study of cells, signaling cues and biomatrices to restore normal function of tissues and organs. To develop the matrices for use in tissue engineering there are three main groups of biomaterials: (i) naturally derived materials; (ii) synthetic polymers; and (iii) decellularized organ or tissue scaffolds. These biomaterials, in various forms such as hydrogels, nanofibers and 3D scaffolds, among others, have been employed for different tissue regeneration purposes, with several techniques involved in their production, including rapid prototyping, tissue decellularization and electrospinning. In this review, the main topics of hydrogels, 3D printing and electrospun scaffolds, other biomaterials and decellularization and recellularization will be discussed.
Advances in treatment formulations for acute myeloid leukemia Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-02 Thomas Briot, Emilie Roger, Sylvain Thépot, Frederic Lagarce
Acute myeloid leukemia (AML) is the most common cause of leukemia-related mortality. The combination of cytarabine and anthracycline has been the gold standard of treatment over the past 40 years, but the distribution of the drugs in the body leads to severe adverse effects. Poor prognosis of older patients with AML is the consequence not only of comorbidities, but also of chemoresistance resulting from frequent secondary AML. Numerous strategies using nanotechnologies are in development to improve drug targeting, pharmacokinetics, administration route, chemoresistance, and adverse effects generally observed. Among the four new drugs approved for AML by the US Food and Drug Administration (FDA) in 2017, Vyxeos® is a novel liposomal formulation of historical AML drugs. Here, we review current AML treatments and discuss how the development of new formulations will change the therapeutic armamentarium.
Recommendations toward a human pathway-based approach to disease research Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-02 Lindsay J. Marshall, Christopher P. Austin, Warren Casey, Suzanne C. Fitzpatrick, Catherine Willett
Failures in the current paradigm for drug development have resulted in soaring research and development costs and reduced numbers of new drug approvals. Over 90% of new drug programs fail, the majority terminated at the level of Phase 2/3 clinical trials, largely because of efficacy failures or unexplained toxicity. A recent workshop brought together members from research institutions, regulatory agencies, industry, academia, and nongovernmental organizations to discuss how existing programs could be better applied to understanding human biology and improving drug discovery. Recommendations include increased emphasis on human relevance, better access and curation of data, and improved interdisciplinary and international collaboration.
Deubiquitinating enzymes in cancer stem cells: functions and targeted inhibition for cancer therapy Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-01 Kamini Kaushal, Ainsley Mike Antao, Kye-Seong Kim, Suresh Ramakrishna
The ability of cancers to evade conventional treatments, such as chemotherapy and radiation therapy, has been attributed to a subpopulation of cancer stem cells (CSCs). CSCs are regulated by mechanisms similar to those that regulate normal stem cells (NSCs), including processes involving ubiquitination and deubiquitination enzymes (DUBs) that regulate the expression of various factors, such as Notch, Wnt, Sonic Hedgehog (Shh), and Hippo. In this review, we discuss the roles of various DUBs involved in the regulation of core stem cell transcription factors and CSC-related proteins that are implicated in the modulation of cellular processes and carcinogenesis. In addition, we discuss the various DUB inhibitors that have been designed to target processes relevant to cancer and CSC maintenance.
Why breast cancer signatures are no better than random signatures Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-01 Wilson Wen Bin Goh, Limsoon Wong
Random signature superiority (RSS) occurs when random gene signatures outperform published and/or known signatures. Unlike reproducibility and generalizability issues, RSS is relatively underexplored. Yet, understanding it is imperative for better analytical outcome. In breast cancer, RSS correlates strongly with enrichment for proliferation genes and signature size. Removal of proliferation genes from random signatures reduces the predictive power of random signatures. Almost all genes are correlated to a certain extent with the proliferation signature, making complete elimination of its confounding effects impossible. RSS goes beyond breast cancer, because it also exists in other diseases; it is especially strong in other cancers in a platform-independent manner, and less severe, but present nonetheless, in nonproliferative diseases.
Bioinformatics-based tools in drug discovery: the cartography from single gene to integrative biological networks Drug. Discov. Today (IF 6.369) Pub Date : 2018-06-01 Pritika Ramharack, Mahmoud E.S. Soliman
Originally developed for the analysis of biological sequences, bioinformatics has advanced into one of the most widely recognized domains in the scientific community. Despite this technological evolution, there is still an urgent need for nontoxic and efficient drugs. The onus now falls on the ‘omics domain to meet this need by implementing bioinformatics techniques that will allow for the introduction of pioneering approaches in the rational drug design process. Here, we categorize an updated list of informatics tools and explore the capabilities of integrative bioinformatics in disease control. We believe that our review will serve as a comprehensive guide toward bioinformatics-oriented disease and drug discovery research.
Mesenteric ischemia-reperfusion: an overview of preclinical drug strategies Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-29 Simona Bertoni, Vigilio Ballabeni, Elisabetta Barocelli, Massimiliano Tognolini
Mesenteric ischemia is a surgical emergency caused by a transient reduction in blood perfusion to the bowel. Despite accounting for only 0.1% of hospital admissions and 1–2% of gastrointestinal diseases, its elusive symptoms often lead to dramatically high morbidity and mortality rates. The complex cascade of inflammatory events and mediators triggered by mesenteric ischemia-reperfusion (I/R) accounts for the plethora of proposed pharmacological targets and for the current lack of an efficacious drug strategy for its management. It is hoped that a deeper understanding of its pathogenesis and the preclinical therapeutic strategies identified to date and described herein will improve the translation into the clinical setting of the pharmacological armamentarium against a life-threatening disorder that is currently mainly managed surgically.
microRNAs and cardiac stem cells in heart development and disease Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-28 Bo Li, Xianmei Meng, Lubo Zhang
Cumulative evidence has proven that proliferation, differentiation and migration of cardiac stem cells (CSCs) dominate early heart development and contribute to the later occurrence of heart disease. Among other mechanisms, microRNAs work as the ‘fine-tuning’ to modulate the levels of target genes in a specific cell type. The distinct microRNA signatures in CSCs reveal the stages and functions of CSCs. The focus of this review is to summarize recent knowledge advances in CSC proliferation, differentiation and migration and to discuss how microRNAs regulate these processes during heart development and in heart disease. Better understanding of microRNA regulation on CSCs under different situations will enable the unveiling of the mechanisms of heart disease and open new avenues in the therapeutic potentials of microRNA modulation to treat heart disease.
Drug metabolism and pharmacokinetic strategies for oligonucleotide- and mRNA-based drug development Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-28 Shalini Andersson, Madeleine Antonsson, Marie Elebring, Rasmus Jansson-Löfmark, Lars Weidolf
Host-defense peptides and their potential use as biomarkers in human diseases Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-24 Osmar N. Silva, William F. Porto, Suzana M. Ribeiro, Ingrid Batista, Octavio Luiz Franco
Since the early 19th century, it has been known that host-defense peptides (HDPs) have a crucial role in innate host defense. Subsequent work has demonstrated their role in adaptive immunity as well as their involvement in different inflammatory diseases, autoimmune diseases, and cancer. In addition to these multiple functional activities, several studies have shown that HDP accumulation might be correlated with various human diseases and, therefore, could be used as a biomarker of such diseases. Thus, research has aimed to validate the clinical use of HDPs for diagnosis, prognosis, and further treatment. In this review, we outline the most recent findings related to the use of HDPs as biomarkers, their clinical and epidemiological value, and the techniques used to determine the levels of HDPs.
Bioactive glasses entering the mainstream Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-24 Saeid Kargozar, Francesco Baino, Sepideh Hamzehlou, Robert G. Hill, Masoud Mozafari
Over the past decade, the extended research on bioactive glasses (BGs) has drastically grown because of their bioactive nature and unique ability to deliver therapeutics in tissue engineering, regenerative medicine and even cancer research. These strategies mostly rely on the inherent potential of BGs regarding bonding to the living tissues and accelerating the healing process. All the possibilities are strongly associated with releasing various therapeutic ions from the BG structures into the biological environment. Additionally, some types of glasses [i.e., mesoporous bioactive glasses (MBGs)] can serve as suitable platforms for the delivery of various small molecules and pharmaceutical agents. This class of biomaterials is recognised as a highly versatile delivery system, playing a crucial part in the future of medicine.
Progress in the development of nanosensitizers for X-ray-induced photodynamic therapy Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-24 Xu-Dong Ren, Xiu-Yun Hao, Hong-Cai Li, Mei-Rong Ke, Bi-Yuan Zheng, Jian-Dong Huang
The Clinical Innovation Network: a policy for promoting development of drugs and medical devices in Japan Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-24 Shunsuke Matsushita, Keisuke Tachibana, Masuo Kondoh
The continuous increase in the costs of developing new drugs and medical devices drives increases in medical expenses. Seventy to ninety percent of these costs are associated with clinical trials. Therefore, the development of cost-effective methods to perform clinical trials remains a challenge. One approach is to use patient registries, collections of data related to patients with a specific diagnosis, condition, or procedure. Patient registries are used in Denmark, Sweden, and the USA for the enrollment of patients into clinical trials, and to evaluate endpoints. In Japan, a national project for registry-oriented clinical research, termed the ‘Clinical Innovation Network’ (CIN), was initiated in 2016. Here, we provide an overview of the CIN and discuss its impact on drug and device development in Japan.
Reshaping drug development using 3D printing Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-24 Atheer Awad, Sarah J. Trenfield, Alvaro Goyanes, Simon Gaisford, Abdul W. Basit
The pharmaceutical industry stands on the brink of a revolution, calling for the recognition and embracement of novel techniques. 3D printing (3DP) is forecast to reshape the way in which drugs are designed, manufactured, and used. Although a clear trend towards personalised fabrication is perceived, here we accentuate the merits and shortcomings of each technology, providing insights into aspects such as the efficiency of production, global supply, and logistics. Contemporary opportunities for 3DP in drug discovery and pharmaceutical development and manufacturing are unveiled, offering a forward-looking view on its potential uses as a digitised tool for personalised dispensing of drugs.
Understanding drug targets: no such thing as bad news Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-24 Ruth A. Roberts
How can small-to-medium pharma and biotech companies enhance the chances of running a successful drug project and maximise the return on a limited number of assets? Having a full appreciation of the safety risks associated with proposed drug targets is a crucial element in understanding the unwanted side-effects that might stop a project in its tracks. Having this information is necessary to complement knowledge about the probable efficacy of a future drug. However, the lack of data-rich insight into drug-target safety is one of the major causes of drug-project failure today. Conducting comprehensive target-safety reviews early in the drug discovery process enables project teams to make the right decisions about which drug targets to take forward.
Next-generation sequencing in drug development: target identification and genetically stratified clinical trials Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-24 Abolfazl Doostparast Torshizi, Kai Wang
Next-generation sequencing (NGS) enabled high-throughput analysis of genotype–phenotype relationships on human populations, ushering in a new era of genetics-informed drug development. The year 2017 was remarkable, with the first FDA-approved gene therapy for cancer (Kymriah™) and for inherited diseases (LUXTURNA™), the first multiplex NGS panel for companion diagnostics (MSK-IMPACT™) and the first drug targeting a genetic signature rather than a disease (Keytruda®). We envision that population-scale NGS with paired electronic health records (EHRs) will become a routine measure in the drug development process for the identification of novel drug targets, and that genetically stratified clinical trials could be widely adopted to improve power in precision-medicine-guided drug development.
Recent advances in intra-articular drug delivery systems for osteoarthritis therapy Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-21 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.
Nanogels as potential drug nanocarriers for CNS drug delivery Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-20 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.
Current approaches to the discovery of novel inhaled medicines Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-20 Peter Strong, Kazuhiro Ito, John Murray, Garth Rapeport
Bioorthogonal chemistry in bioluminescence imaging Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-18 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.
Corticosteroids and perinatal hypoxic-ischemic brain injury Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-17 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.
Renal Pre-Competitive Consortium (RPC2): discovering therapeutic targets together Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-18 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.
Structural basis for selective inhibition of antibacterial target MraY, a membrane-bound enzyme involved in peptidoglycan synthesis Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-18 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.
Targeting HIF-2α as therapy for advanced cancers Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-16 Thanabal Murugesan, Gurukumari Rajajeyabalachandran, Swetha Kumar, Shruthi Nagaraju, Sooriya Kumar
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.
Prolyl hydroxylase 2: a promising target to inhibit hypoxia-induced cellular metabolism in cancer cells Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-14 Lakhveer Singh, Sara Aldosary, Abdulaziz S. Saeedan, M. 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.
Translation of innovative chemistry into screening libraries: an exemplar partnership from the European Lead Factory Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-09 Remy Morgentin, Mark Dow, Anthony Aimon, George Karageorgis, Tuomo Kalliokoski, Didier Roche, Stephen Marsden, Adam S. 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 21 119 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.
Machine learning in chemoinformatics and drug discovery Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-08 Yu-Chen Lo, Stefano E. Rensi, Wen Torng, Russ B. Altman
2017 in review: FDA approvals of new molecular entities Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-08 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.
Real-world evidence approach to traditional herbal medicinal products Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-07 Xinyu Weng
There are tens of thousands of traditional herbal medicinal products (THMPs) on the market worldwide but few of them have gone through tests for efficacy and safety in randomized controlled trials (RCTs). THMP regulation is a global challenge. Many countries are faced with this dilemma: a looser regulation could present a significant risk to the public, whereas a tougher regulation might limit the availability of THMPs to the public. In the past two decades, the USA, the European Union (EU), China and other countries have enacted different provisions for THMPs. Different regulatory approaches reflect different cultures, ideology and experience in the regulation of THMPs, and none of them lacks controversy.
Dual-therapy strategy for modification of adiponectin receptor signaling in aging-associated chronic diseases Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-07 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.
Is the adenosine A2B ‘biased’ receptor a valuable target for the treatment of pulmonary arterial hypertension? Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-07 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.
The extent and effects of patient involvement in pictogram design for written drug information: a short systematic review Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-07 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.
Bioinspired bone therapies using naringin: applications and advances Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-07 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.
Cochlear hair cell regeneration: an emerging opportunity to cure noise-induced sensorineural hearing loss Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-04 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, much research is focusing 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 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 through the activation of the NOTCH 1 pathway.
When fragments link: a bibliometric perspective on the development of fragment-based drug discovery Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-05 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.
Protein–peptide docking: opportunities and challenges Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-04 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.
Applying the 3Rs to neuroscience research involving nonhuman primates Drug. Discov. Today (IF 6.369) Pub Date : 2018-05-04 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. 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.
Circulatory-cell-mediated nanotherapeutic approaches in disease targeting Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-14 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.
Strategies for the enhanced intracellular delivery of nanomaterials Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-15 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.
Carbon nanomaterials in oncology: an expanding horizon Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-28 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.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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