The nanomedicines alliance: an industry perspective on nanomedicines

The field of nanomedicines has expanded significantly in recent years in the breadth of compounds under development as well as in the types of technology that are being applied to generate nanomedicines. The pathway to licensure of new nanomedicines is sufficiently well defined by existing regulations and guidance. The future of nanomedicines requires collaboration between industry and regulatory agencies to ensure that safe and effective nanomedicines emerge from this field.From the Clinical EditorWith the expansion of translational nanomedicine research, the “last steps” of translation, such as making sure all regulatory approvals are met, the availability of appropriate larger-scale production technologies, are becoming critically important. This review provides a perspective from the biomedical and pharmaceutical industry on the above issues.     

纳米药物粒度分析方法

纳米药物在研究和应用领域都在快速发展,根据具体纳米药物的特性,运用合理的分析方法来建立质量标准是一项需要深入研究的重要课题。本文综述了可用于纳米药物质量控制的粒度分析方法,考察了几种重要技术的原理、适用范围、优点和不足。结合不同剂型纳米药物的特性,讨论了各方法在纳米药物分析中的应用,为纳米药物的检测和监管提供借鉴。     

PEGylated nanomedicines: recent progress and remaining concerns

Introduction: Recent biopharma deals related to nanocarrier drug delivery technologies highlight the emergence of nanomedicine. This is perhaps an expected culmination of many years of research demonstrating the potential of nanomedicine as the next generation of therapeutics with improved performance. PEGylated nanocarriers play a key role within this field.

Areas covered: The drug delivery advantages of nanomedicines in general are discussed, focusing on nanocarriers and PEGylated nanomedicines, including products under current development/clinical evaluation. Well-established drug delivery benefits of PEGylation (e.g., prolonged circulation) are only briefly covered. Instead, attention is deliberately made to less commonly reported advantages of PEGylation, including mucosal delivery of nanomedicines. Finally, some of the issues related to the safety of PEGylated nanomedicines in clinical application are discussed.

Expert opinion: The advent of nanomedicine providing therapeutic options of refined performance continues. Although PEGylation as a tool to improve the pharmacokinetics of nanomedicines is well established and is used clinically, other benefits of ‘PEGnology', including enhancement of physicochemical properties and/or biocompatibility of actives and/or drug carriers, as well as mucosal delivery, have attracted less attention. While concerns regarding the clinical use of PEGylated nanomedicines remain, evidence suggests that at least some safety issues may be controlled by adequate designs of nanosystems.     

Nanomedicines: From Bench to Bedside and Beyond

Advancing nanomedicines from concept to clinic requires integration of new science with traditional pharmaceutical development. The medical and commercial success of nanomedicines is greatly facilitated when those charged with developing nanomedicines are cognizant of the unique opportunities and technical challenges that these products present. These individuals must also be knowledgeable about the processes of clinical and product development, including regulatory considerations, to maximize the odds for successful product registration. This article outlines these topics with a goal to accelerate the combination of academic innovation with collaborative industrial scientists who understand pharmaceutical development and regulatory approval requirements—only together can they realize the full potential of nanomedicines for patients.     

Endocytosis and intracellular trafficking as gateways for nanomedicine delivery: opportunities and challenges

More than 40 nanomedicines are already in routine clinical use with a growing number following in preclinical and clinical development. The therapeutic objectives are often enhanced disease-specific targeting (with simultaneously reduced access to sites of toxicity) and, especially in the case of macromolecular biotech drugs, improving access to intracellular pharmacological target receptors. Successful navigation of the endocytic pathways is usually a prerequisite to achieve these goals. Thus a comprehensive understanding of endocytosis and intracellular trafficking pathways in both the target and bystander normal cell type(s) is essential to enable optimal nanomedicine design. It is becoming evident that endocytic pathways can become disregulated in disease and this, together with the potential changes induced during exposure to the nanocarrier itself, has the potential to significantly impact nanomedicine performance in terms of safety and efficacy. Here we overview the endomembrane trafficking pathways, discuss the methods used to determine and quantitate the intracellular fate of nanomedicines, and review the current status of lysosomotropic and endosomotropic delivery. Based on the lessons learned during more than 3 decades of clinical development, the need to use endocytosis-relevant clinical biomarkers to better select those patients most likely to benefit from nanomedicine therapy is also discussed.     

Summary Report of PQRI Workshop on Nanomaterial in Drug Products: Current Experience and Management of Potential Risks

At the Product Quality Research Institute (PQRI) Workshop held last January 14–15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Representatives from the US Food and Drug Administration (USFDA), Health Canada, and European Medicines Agency (EMA) presented information about the diversity of nanomaterials in approved and newly developed drug products. USFDA, Health Canada, and EMA regulators discussed the applicability of current regulatory policies in presentations and open discussion. Information contained in several of the recent EMA reflection papers was discussed in detail, along with their scope and intent to enhance scientific understanding about disposition, efficacy, and safety of nanomaterials introduced in vivo and regulatory requirements for testing and market authorization. Opportunities for interaction with regulatory agencies during the lifecycle of nanomedicines were also addressed at the meeting. This is a summary of the workshop presentations and discussions, including considerations for future regulatory guidance on drug products containing nanomaterials.KEY WORDS: nanomaterials, nanomedicine, nanotechnology, PQRI, risk management, USFDA     

Nanomedicine Drug Development: A Scientific Symposium Entitled “Charting a Roadmap to Commercialization”

The use of nanotechnology in medicine holds great promise for revolutionizing a variety of therapies. The past decade witnessed dramatic advancements in scientific research in nanomedicines, although significant challenges still exist in nanomedicine design, characterization, development, and manufacturing. In March 2013, a two-day symposium “Nanomedicines: Charting a Roadmap to Commercialization,” sponsored and organized by the Nanomedicines Alliance, was held to facilitate better understanding of the current science and investigative approaches and to identify and discuss challenges and knowledge gaps in nanomedicine development programs. The symposium provided a forum for constructive dialogue among key stakeholders in five distinct areas: nanomedicine design, preclinical pharmacology, toxicology, CMC (chemistry, manufacturing, and control), and clinical development. In this meeting synopsis, we highlight key points from plenary presentations and focus on discussions and recommendations from breakout sessions of the symposium.     

Structure and biological activity of pathogen-like synthetic nanomedicines

Here we characterize the structure, stability and intracellular mode of action of DermaVir nanomedicine that is under clinical development for the treatment of HIV/AIDS. This nanomedicine comprises pathogen-like pDNA/PEIm nanoparticles (NPs) having the structure and function resembling spherical viruses that naturally evolved to deliver nucleic acids to the cells. Atomic force microscopy demonstrated spherical 100 - 200 nm NPs with a smooth polymer surface protecting the pDNA in the core. Optical absorption determined both the NP structural stability and biological activity relevant to their ability to escape from the endosome and release the pDNA at the nucleus. Salt, pH and temperature influence nanomedicine shelf-life and intracellular stability. This approach facilitates the development of diverse polyplex nanomedicines where the delivered pDNA-expressed antigens induce immune responses to kill infected cells. FROM THE CLINICAL EDITOR: The authors investigated DermaVir nanomedicine comprised of pathogen-like pDNA/PEIm nanoparticles with structure and function resembling spherical viruses. DermaVir delivery of pDNA expresses antigens that induce immune responses to kill HIV infected cells.     

“Pincer movement”: Reversing cisplatin resistance based on simultaneous glutathione depletion and glutathione S-transferases inhibition by redox-responsive degradable organosilica hybrid nanoparticles

The therapeutic efficacy of cisplatin has been restricted by drug resistance of cancers. Intracellular glutathione (GSH) detoxification of cisplatin under the catalysis of glutathione S-transferases (GST) plays important roles in the development of cisplatin resistance. Herein, a strategy of “pincer movement” based on simultaneous GSH depletion and GST inhibition is proposed to enhance cisplatin-based chemotherapy. Specifically, a redox-responsive nanomedicine based on disulfide-bridged degradable organosilica hybrid nanoparticles is developed and loaded with cisplatin and ethacrynic acid (EA), a GST inhibitor. Responding to high level of intracellular GSH, the hybrid nanoparticles can be gradually degraded due to the break of disulfide bonds, which further promotes drug release. Meanwhile, the disulfide-mediated GSH depletion and EA-induced GST inhibition cooperatively prevent cellular detoxification of cisplatin and reverse drug resistance. Moreover, the nanomedicine is integrated into microneedles for intralesional drug delivery against cisplatin-resistant melanoma. The in vivo results show that the nanomedicine-loaded microneedles can achieve significant GSH depletion, GST inhibition, and consequent tumor growth suppression. Overall, this research provides a promising strategy for the construction of new-type nanomedicines to overcome cisplatin resistance, which extends the biomedical application of organosilica hybrid nanomaterials and enables more efficient chemotherapy against drug-resistant cancers.KEY WORDS: Cancer therapy, Cisplatin, Drug resistance, Glutathione depletion, Glutathione S-transferases, Disulfide bonds, Organosilica hybrid nanoparticles, Ethacrynic acid     

European Commission-supported development of targeted nanomedicines: did MediTrans make a difference?

Nanotechnology-inspired approaches to particle design and formulation, an improved understanding of (patho) physiological processes and biological barriers to drug targeting, as well as the limited input of new chemical entities in the 'pipeline' of pharmaceutical companies, suggest a bright future for targeted nanomedicines as pharmaceuticals. There is an increased consensus to the view that a major limitation hampering the entry of targeted delivery systems into the clinic is that new concepts and innovative research ideas within academia are not being developed and exploited in close collaboration with the pharmaceutical industry. Thus, an integrated 'bench-to-clinic' approach realized within a structural collaboration between industry and academia, will facilitate and promote the progression of targeted nanomedicines towards clinical application. The MediTrans project performed under the EU Framework Program 6, was designed to contribute to this ambition. The objectives of this collaborative initiative were: to apply nanotechnology for development of innovative targeted drug-delivery systems; to optimize targeted nanomedicines by using imaging guidance; to promote structural collaboration between industry and academia; and to forward targeted nanomedicines towards the clinic and the market. In this article, we will briefly address the research content, outcome and impact of the MediTrans project.     

Perspectives and opportunities for nanomedicine in the management of atherosclerosis

The use of nanotechnology for medical purposes--nanomedicine--has grown exponentially over the past few decades. This is exemplified by the US Food and Drug Administration's approval of several nanotherapies for various conditions, as well as the funding of nanomedical programmes worldwide. Although originally the domain of anticancer therapy, recent advances have illustrated the considerable potential of nanomedicine in the diagnosis and treatment of atherosclerosis. This Review elaborates on nanoparticle-targeting concepts in atherosclerotic disease, provides an overview of the use of nanomedicine in atherosclerosis, and discusses potential future applications and clinical benefits.     

Can nanomedicines kill cancer stem cells?

Most tumors are heterogeneous and many cancers contain small population of highly tumorigenic and intrinsically drug resistant cancer stem cells (CSCs). Like normal stem cell, CSCs have the ability to self-renew and differentiate to other tumor cell types. They are believed to be a source for drug resistance, tumor recurrence and metastasis. CSCs often overexpress drug efflux transporters, spend most of their time in non-dividing G₀ cell cycle state, and therefore, can escape the conventional chemotherapies. Thus, targeting CSCs is essential for developing novel therapies to prevent cancer relapse and emerging of drug resistance. Nanocarrier-based therapeutic agents (nanomedicines) have been used to achieve longer circulation times, better stability and bioavailability over current therapeutics. Recently, some groups have successfully applied nanomedicines to target CSCs to eliminate the tumor and prevent its recurrence. These approaches include 1) delivery of therapeutic agents (small molecules, siRNA, antibodies) that affect embryonic signaling pathways implicated in self-renewal and differentiation in CSCs, 2) inhibiting drug efflux transporters in an attempt to sensitize CSCs to therapy, 3) targeting metabolism in CSCs through nanoformulated chemicals and field-responsive magnetic nanoparticles and carbon nanotubes, and 4) disruption of multiple pathways in drug resistant cells using combination of chemotherapeutic drugs with amphiphilic Pluronic block copolymers. Despite clear progress of these studies the challenges of targeting CSCs by nanomedicines still exist and leave plenty of room for improvement and development. This review summarizes biological processes that are related to CSCs, overviews the current state of anti-CSCs therapies, and discusses state-of-the-art nanomedicine approaches developed to kill CSCs.     

Preparing for the new millennium

Since being introduced to the field of drug discovery at Zeneca Pharmaceuticals in 1991, it has become apparent to me that a blizzard of revolutionary novel approaches has swept through the pharmaceutical industry. Now, the discovery process has become completely transformed and the race to develop commercially successful drugs is now taking place in a very different realm. Rapid advances in automation, combinatorial chemistry, high-throughput screening (HTS), genomics, proteomics and bioinformatics appear to be principally responsible for driving such a rapidly evolving discovery process. In these exciting times for pharmaceutical R&D, it is a delight for me to take over the Editor's reins of Drug Discovery Today.     

Nanomedicine therapeutic approaches to overcome cancer drug resistance

Nanomedicine is an emerging form of therapy that focuses on alternative drug delivery and improvement of the treatment efficacy while reducing detrimental side effects to normal tissues. Cancer drug resistance is a complicated process that involves multiple mechanisms. Here we discuss the major forms of drug resistance and the new possibilities that nanomedicines offer to overcome these treatment obstacles. Novel nanomedicines that have a high ability for flexible, fast drug design and production based on tumor genetic profiles can be created making drug selection for personal patient treatment much more intensive and effective. This review aims to demonstrate the advantage of the young medical science field, nanomedicine, for overcoming cancer drug resistance. With the advanced design and alternative mechanisms of drug delivery known for different nanodrugs including liposomes, polymer conjugates, micelles, dendrimers, carbon-based, and metallic nanoparticles, overcoming various forms of multi-drug resistance looks promising and opens new horizons for cancer treatment.     

Paradigm shift in bacteriophage-mediated delivery of anticancer drugs: from targeted ‘magic bullets’ to self-navigated ‘magic missiles’

Introduction: New phage-directed nanomedicines have emerged recently as a result of the in-depth study of the genetics and structure of filamentous phage and evolution of phage display and phage nanobiotechnology. This review focuses on the progress made in the development of the cancer-targeted nanomaterials and discusses the trends in using phage as a bioselectable molecular navigation system.

Areas covered: The merging of phage display technologies with nanotechnology in recent years has proved promising in different areas of medicine and technology, such as medical diagnostics, molecular imaging, vaccine development and targeted drug/gene delivery, which is the focus of this review. The authors used data obtained from their research group and sourced using Science Citation Index (Web of Science) and NCBI PubMed search resources.

Expert opinion: First attempts of adapting traditional concepts of direct targeting of tumor using phage-targeted nanomedicines has shown minimal improvements. With discovery and study of biological and technical barriers that prevent anti-tumor drug delivery, a paradigm shift from traditional drug targeting to nanomedicine navigation systems is required. The advanced bacteriophage-driven self-navigation systems are thought to overcome those barriers using more precise, localized phage selection methods, multi-targeting ‘promiscuous’ ligands and advanced multifunctional nanomedicine platforms.     

浅谈“新医改”政策下的我院药学服务

目的:贯彻"新医改"政策,促进我院药学服务工作的开展。方法:结合"新医改"政策,分析促进我院药学服务工作开展的具体实施方法。结果与结论:在"新医改"政策下,药学服务应利用处方点评制度,间接为临床服务;还应走入病区,直接为临床服务;应积极参与、督导抗菌药物使用及开展药物宣传,编写《临床药讯》;开展药品不良反应监测等方法贯彻"新医改"政策,促进我院药学服务工作的开展。     

Role of nanotechnology in targeted drug delivery and imaging: a concise review

The use of nanotechnology in drug delivery and imaging in vivo is a rapidly expanding field. The emphases of this review are on biophysical attributes of the drug delivery and imaging platforms as well as the biological aspects that enable targeting of these platforms to injured and diseased tissues and cells. The principles of passive and active targeting of nanosized carriers to inflamed and cancerous tissues with increased vascular leakiness, overexpression of specific epitopes, and cellular uptake of these nanoscale systems are discussed. Preparation methods-properties of nanoscale systems including liposomes, micelles, emulsions, nanoparticulates, and dendrimer nanocomposites, and clinical indications are outlined separately for drug delivery and imaging in vivo. Taken together, these relatively new and exciting data indicate that the future of nanomedicine is very promising, and that additional preclinical and clinical studies in relevant animal models and disease states, as well as long-term toxicity studies, should be conducted beyond the "proof-of-concept" stage. Large-scale manufacturing and costs of nanomedicines are also important issues to be addressed during development for clinical indications.     

希美加群药品风险管理的案例简析

药品风险管理适用于药品从前体化合物筛选、新药审批、上市后监控以及药品撤出市场的整个过程。通过介绍阿斯利康公司生产的新一代抗凝血药物希美加群（Exanta。）从新药审批上市到撤出市场的风险管理相关事件,以期为我国抗凝药物的监测和安全管理工作提供借鉴,从而更好地规范我国的药品市场。