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.     

A review of the current scientific and regulatory status of nanomedicines and the challenges ahead

Nanomedicines refer to drugs, medical devices, and health products developed using nanotechnology with the aim of diagnosing, monitoring, and treating diseases at the molecular level. Due to their nano size, nanomedicines offer advantages over conventional medicines, including more effective targeting of difficult-to-reach sites, improved solubility and bioavailability, and reduced adverse effects. Hence, nanomedicines can be used to achieve the same therapeutic effect at smaller doses than their conventional counterparts. Three types of nanomedicines are described: nanocarriers used in drug delivery, nanosuspensions used in the improvement of drug solubility, and nanoparticles used in bioimaging. While nanomedicines offer promising benefits, there are concerns that the inherent properties of nanoparticles such as their size, shape, agglomeration/aggregation potential, and surface chemistry can adversely affect the safety and quality of nanomedicines. Furthermore, there are currently no regulatory guidelines developed specifically for nanomedicines due to limitations including inadequate knowledge regarding nanoparticle behavior, the absence of standardized nomenclature, test methods, and characterization of nanoparticles, as well as difficulty in determining primary jurisdiction for combination products. In addition, a shortage of trained personnel, a lack of a nanomedicine-specific safety protocol, and ineffective control of nanoparticle contamination challenge the current good manufacturing practice requirements governing the manufacture of nanomedicines. Regulatory authorities are in the midst of improving the current framework for controlling the manufacturing processes, product quality, and safety of nanomedicines. This paper proposes improvements through the adaptation of conventional regulations for nanoparticles, implementation of compulsory regulations for presently unregulated nanoparticle-containing products, and the establishment of an online database for efficient retrieval of information relating to nanomedicines by authorities. LAY ABSTRACT: Nanomedicines refer to drugs, medical devices, and health products developed using nanotechnology with the aim of diagnosing, monitoring, and treating diseases at the molecular level. Due to their nano size, nanomedicines offer advantages over conventional medicines, including more effective targeting of difficult-to-reach sites, improved solubility and bioavailability, and better side effect profile. Hence, smaller doses of nanomedicines are needed to achieve the same therapeutic effect. While nanomedicines offer promising benefits, there are concerns that the inherent properties of nanoparticles such as their size, shape, agglomeration/aggregation potential, and surface chemistry can adversely affect the safety and quality of nanomedicines. Standardized test methods and characterization of nanoparticles are lacking. In addition, a shortage of trained personnel, a lack of a nanomedicines-specific safety protocol, and ineffective control of nanoparticle contamination challenge the current good manufacturing practice requirements governing the manufacture of nanomedicines. Regulatory authorities are in the midst of improving the current framework for controlling the manufacturing processes, product quality, and safety of nanomedicines. This paper proposes improvements through the adaptation of conventional regulations for nanoparticles, implementation of compulsory regulations for presently unregulated nanoparticle-containing products, and establishment of an online database for efficient retrieval of information relating to nanomedicines by authorities.     

Nanomedicines and Nanodiagnostics Come of Age

Although the employment of biomedical colloids is not new, modern biomedical colloids, termed nanomedicines and nanodiagnostics, have enhanced functionality, in that the drug compound/diagnostic probe entrapped within the nanoparticle takes on the properties of the encapsulating nanoparticle. The nanoparticle's properties are specifically dictated by its size, shape, and surface chemistry; the net result in the case of medicines is an alteration of the drug's intrinsic pharmacokinetics and eventual drug targeting to the areas of pathology. The first nanomedicines, which really altered the pharmacokinetics of a drug molecule, were licensed in the early-to-mid 1990s. Since this time, these pioneering nanomedicines: liposomal doxorubicin (Doxil) and liposomal amphotericin B (Ambisome), have been followed by medicines such as albumin-stabilised paclitaxel (Abraxane) and biomedical sentinel lymph node nanodiagnostics such as Sienna+. The clinical trials database is heavily populated with nanosystem trials—an indication that these agents are growing in stature and will be utilised in an expanding list of clinical situations. Although the intravenous route is the route of choice for the current nanoparticles, new administration routes such as the pulmonary route are already in clinical testing, and researchers are working on the preclinical development of oral nanomedicines.     

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.     

A Quality by Design Approach to Developing and Manufacturing Polymeric Nanoparticle Drug Products

The translation of nanomedicines from concepts to commercial products has not reached its full potential, in part because of the technical and regulatory challenges associated with chemistry, manufacturing, and controls (CMC) development of such complex products. It is critical to take a quality by design (QbD) approach to developing nanomedicines—using a risk-based approach to identifying and classifying product attributes and process parameters and ultimately developing a deep understanding of the products, processes, and platform. This article exemplifies a QbD approach used by BIND Therapeutics, Inc., to industrialize a polymeric targeted nanoparticle drug delivery platform. The focus of the approach is on CMC affairs but consideration is also given to preclinical, clinical, and regulatory aspects of pharmaceutical development. Processes are described for developing a quality target product profile and designing supporting preclinical studies, defining critical quality attributes and process parameters, building a process knowledge map, and employing QbD to support outsourced manufacturing.     

Nanomedicine(s) under the microscope

Depending on the context, nanotechnologies developed as nanomedicines (nanosized therapeutics and imaging agents) are presented as either a remarkable technological revolution already capable of delivering new diagnostics, treatments for unmanageable diseases, and opportunities for tissue repair or highly dangerous nanoparticles, nanorobots, or nanoelectronic devices that will wreak havoc in the body. The truth lies firmly between these two extremes. Rational design of "nanomedicines" began almost half a century ago, and >40 products have completed the complex journey from lab to routine clinical use. Here we critically review both nanomedicines in clinical use and emerging nanosized drugs, drug delivery systems, imaging agents, and theranostics with unique properties that promise much for the future. Key factors relevant to the design of practical nanomedicines and the regulatory mechanisms designed to ensure safe and timely realization of healthcare benefits are discussed.     

Clinical biomarkers in drug discovery and development

Biomarkers enable the characterization of patient populations and quantitation of the extent to which new drugs reach intended targets, alter proposed pathophysiological mechanisms and achieve clinical outcomes. In genomics, the biomarker challenge is to identify unique molecular signatures in complex biological mixtures that can be unambiguously correlated to biological events in order to validate novel drug targets and predict drug response. Biomarkers can stratify patient populations or quantify drug benefit in primary prevention or disease-modification studies in poorly served areas such as neurodegeneration and cancer. Clinically useful biomarkers are required to inform regulatory and therapeutic decision making regarding candidate drugs and their indications in order to help bring new medicines to the right patients faster than they are today.     

Nanomedicine: clinical applications of polyethylene glycol conjugated proteins and drugs

The intricate problems associated with the delivery and various unnecessary in vivo transitions of proteins and drugs needs to be tackled soon to be able to exploit the myriad of putative therapeutics created by the biotechnology boom. Nanomedicine is one of the most promising applications of nanotechnology in the field of medicine. It has been defined as the monitoring, repair, construction and control of human biological systems at the molecular level using engineered nanodevices and nanostructures. These nanostructured medicines will eventually turn the world of drug delivery upside down. PEGylation (i.e. the attachment of polyethylene glycol to proteins and drugs) is an upcoming methodology for drug development and it has the potential to revolutionise medicine by drastically improving the pharmacokinetic and pharmacodynamic properties of the administered drug. This article provides a total strategy for improving the therapeutic efficacy of various biotechnological products in drug delivery. This article also presents an extensive analysis of most of the PEGylated proteins, peptides and drugs, together with extensive clinical data. Nanomedicines and PEGylation, the latest offshoots of nanotechnology will definitely pave a way in the field of drug delivery where targeted delivery, formulation, in vivo stability and retention are the major challenges.     

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.     

Finding a niche with personalized generics: opportunities from systems-based therapeutic delivery in hypertension

A key principle in earlier eras of drug development was to deliver medicines with clinical benefits for populations. Individual patients frequently did not benefit, or experienced adverse drug reactions, and were at risk of exposure to a prolonged series of treatment trials before effective therapies were found, if available. A personalized medicines approach offers opportunities to select drugs likely to be effective or safer, based on knowledge, for example, of differences in disease-modulating receptors, in drug metabolism, or in drug transporters into cells and across tissue boundaries. This new genetic and phenotypic knowledge allows generics to be revisited and may also help to improve medicine adherence, by reducing predictable adverse effects from unwanted accumulation of a medicine or its metabolites. This review will consider effective population delivery of therapeutics to treat hypertension in order to illustrate the potential and current place of personalizing medicines to improve effective and safe use of therapeutics.     

AI-based language models powering drug discovery and development

The discovery and development of new medicines is expensive, time-consuming, and often inefficient, with many failures along the way. Powered by artificial intelligence (AI), language models (LMs) have changed the landscape of natural language processing (NLP), offering possibilities to transform treatment development more effectively. Here, we summarize advances in AI-powered LMs and their potential to aid drug discovery and development. We highlight opportunities for AI-powered LMs in target identification, clinical design, regulatory decision-making, and pharmacovigilance. We specifically emphasize the potential role of AI-powered LMs for developing new treatments for Coronavirus 2019 (COVID-19) strategies, including drug repurposing, which can be extrapolated to other infectious diseases that have the potential to cause pandemics. Finally, we set out the remaining challenges and propose possible solutions for improvement.     

Biointerface engineering nanoplatforms for cancer-targeted drug delivery

Over the past decade, nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy. Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis. Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery. Keeping in mind the biological framework of the tumor microenvironment, biomembrane-camouflaged nanoplatforms have been a research focus, reflecting their superiority in cancer targeting. In this review, we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancer-targeted drug delivery, which are classified according to the membranes from different cells. The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.     

Early Development Challenges for Drug Products Containing Nanomaterials

The vast majority of drug product candidates in early development fail to progress to clinics. This is true for products containing nanomaterials just as for other types of pharmaceuticals. Early development pathways should therefore place high priority on experiments that help candidates fail faster and less expensively. Nanomedicines fail for many reasons, but some are more avoidable than others. Some of the points of failure are not considerations in the development of small molecules or biopharmaceuticals, and so may be unexpected, even to those with previous experience bringing drug products to the clinic. This article reviews experiments that have proven useful in providing “go/no-go” decision-making data for nanomedicines in early preclinical development. Of course, the specifics depend on the particulars of the drug product and the nanomaterial type, and not every product shares the same development pathway or the same potential points of failure. Here, we focus on challenges that differ from those in the development of traditional small molecule therapeutics, and on experiments that reveal deficiencies that can only be corrected by essentially starting over—altering the nanomedicine to an extent that all previous characterization and proof-of-concept testing must be repeated. Conducting these experiments early in the development process can save significant resources and time and allow developers to focus on derisked candidates with a greater likelihood of ultimate success.     

Antibody-enabled small-molecule drug discovery

Although antibody-based therapeutics have become firmly established as medicines for serious diseases, the value of antibodies as tools in the early stages of small-molecule drug discovery is only beginning to be realized. In particular, antibodies may provide information to reduce risk in small-molecule drug discovery by enabling the validation of targets and by providing insights into the design of small-molecule screening assays. Moreover, antibodies can act as guides in the quest for small molecules that have the ability to modulate protein-protein interactions, which have traditionally only been considered to be tractable targets for biological drugs. The development of small molecules that have similar therapeutic effects to current biologics has the potential to benefit a broader range of patients at earlier stages of disease.     

Polymeric carriers: Preclinical safety and the regulatory implications for design and development of polymer therapeutics

Since the early 1990s polymer–protein conjugates (included PEGylated enzymes and cytokines), polymeric drugs and polymeric sequestrants have been entering the market as innovative polymer-based therapeutics. Initially these products were most frequently developed as novel anticancer agents; indeed they can be considered first generation “nanomedicines”. More recently, a much broader range of life-threatening and debilitating diseases (e.g. viral infections, arthritis, multiple sclerosis and hormone abnormalities) have been targeted via intravenous (i.v.), subcutaneous (s.c.) or oral routes of administration. Given the increasing novelty of polymeric materials proposed for development as second-generation polymer therapeutics (with increasing complexity of conjugate composition), and the growing debate as to the safety of nanomedicines per se, the need for evolution of an appropriate regulatory framework is at the forefront of the scientific discussion. The adequacy of the current tests and models used to define safety are also constantly being reviewed. Here we describe the current status and future challenges in relation to these issues.     

Current approaches of nanomedicines in the market and various stage of clinical translation

Compared with traditional drug therapy, nanomedicines exhibit intriguing biological features to increase therapeutic efficiency, reduce toxicity and achieve targeting delivery. This review provides a snapshot of nanomedicines that have been currently launched or in the clinical trials, which manifests a diversified trend in carrier types, applied indications and mechanisms of action. From the perspective of indications, this article presents an overview of the applications of nanomedicines involving the prevention, diagnosis and treatment of various diseases, which include cancer, infections, blood disorders, cardiovascular diseases, immuno-associated diseases and nervous system diseases, etc. Moreover, the review provides some considerations and perspectives in the research and development of nanomedicines to facilitate their translations in clinic.     

Protein-based nanoparticles as a drug delivery system: chances,risks, perspectives

This review aims to provide a broad overview of the development of drug delivery nanoparticulate systems, their classification by basic material, preparation method and administration route while focusing on recent trends in the field of protein-based nanoparticles. Literature on drug delivery by nanotechnology was reviewed in the light of previous and ongoing research. Potentials and challenges including regulatory issues are discussed in the context of possible applications of the miscellaneous nanoparticle devices. Over the past years homogeneous and clearly size-defined nanoparticles have been successfully designed from a large variety of starting materials. These nanoparticles offered diverse targeting or imaging properties in order to either enhance pharmacodynamic efficiency or reduce side effects of the delivered drug substance or to monitor the system’s fate in vivo. The latter is considered especially crucial when it comes to finally guiding nanoparticulate formulations through the clinical phase and its use for the patient’s benefit in the end. If the clinical requirements can be met, the main promises of the new nanoparticulate formulations and associated new routes of drug delivery can be met (a) to enable new types of medicines to be carried to previously inaccessible sites within the body or (b) to reduce risks in delivering already established drugs.     

The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity

Biomarkers are biometric measurements that provide critical quantitative information about the biological condition of the animal or individual being tested. In drug safety studies, established toxicity biomarkers are used along with other conventional study data to determine dose-limiting organ toxicity, and to define species sensitivity for new chemical entities intended for possible use as human medicines. A continuing goal of drug safety scientists in the pharmaceutical industry is to discover and develop better trans-species biomarkers that can be used to determine target organ toxicities for preclinical species in short-term studies at dose levels that are some multiple of the intended human dose and again later in full development for monitoring clinical trials at lower therapeutic doses. Of particular value are early, predictive, noninvasive biomarkers that have in vitro, in vivo, and clinical transferability. Such translational biomarkers bridge animal testing used in preclinical science and human studies that are part of subsequent clinical testing. Although suitable for in vivo preclinical regulatory studies, conventional hepatic safety biomarkers are basically confirmatory markers because they signal organ toxicity after some pathological damage has occurred, and are therefore not well-suited for short-term, predictive screening assays early in the discovery-to-development progression of new chemical entities (NCEs) available in limited quantities. Efforts between regulatory agencies and the pharmaceutical industry are underway for the coordinated discovery, qualification, verification and validation of early predictive toxicity biomarkers. Early predictive safety biomarkers are those that are detectable and quantifiable prior to the onset of irreversible tissue injury and which are associated with a mechanism of action relevant to a specific type of potential hepatic injury. Potential drug toxicity biomarkers are typically endogenous macromolecules in biological fluids with varying immunoreactivity which can present bioanalytical challenges when first discovered. The potential success of these efforts is greatly enhanced by recent advances in two closely linked technologies, toxicoproteomics and targeted, quantitative mass spectrometry. This review focuses on the examination of the current status of these technologies as they relate to the discovery and development of novel preclinical biomarkers of hepatotoxicity. A critical assessment of the current literature reveals two distinct lines of safety biomarker investigation, (1) peripheral fluid biomarkers of organ toxicity and (2) tissue or cell-based toxicity signatures. Improved peripheral fluid biomarkers should allow the sensitive detection of potential organ toxicity prior to the onset of overt organ pathology. Advancements in tissue or cell-based toxicity biomarkers will provide sensitive in vitro or ex vivo screening systems based on toxicity pathway markers. An examination of the current practices in clinical pathology and the critical evaluation of some recently proposed biomarker candidates in comparison to the desired characteristics of an ideal toxicity biomarker lead this author to conclude that a combination of selected biomarkers will be more informative if not predictive of potential animal organ toxicity than any single biomarker, new or old. For the practical assessment of combinations of conventional and/or novel toxicity biomarkers in rodent and large animal preclinical species, mass spectrometry has emerged as the premier analytical tool compared to specific immunoassays or functional assays. Selected and multiple reaction monitoring mass spectrometry applications make it possible for this same basic technology to be used in the progressive stages of biomarker discovery, development, and more importantly, routine study applications without the use of specific antibody reagents. This technology combined with other “omics” technologies can provide added selectivity and sensitivity in preclinical drug safety testing.     

Modulation of gene expression by antisense and antigene oligodeoxynucleotides and small interfering RNA

Antisense oligodeoxynucleotides, triplex-forming oligodeoxynucleotides and double-stranded small interfering RNAs have great potential for the treatment of many severe and debilitating diseases. Concerted efforts from both industry and academia have made significant progress in turning these nucleic acid drugs into therapeutics, and there is already one FDA-approved antisense drug in the clinic. Despite the success of one product and several other ongoing clinical trials, challenges still exist in their stability, cellular uptake, disposition, site-specific delivery and therapeutic efficacy. The principles, strategies and delivery consideration of these nucleic acids are reviewed. Furthermore, the ways to overcome the biological barriers are also discussed so that therapeutic concentrations at their target sites can be maintained for a desired period.     

Developing paediatric medicines: identifying the needs and recognizing the challenges

There is a significant need for research and development into paediatric medicines. Only a small fraction of the drugs marketed and utilized as therapeutic agents in children have been clinically evaluated. The majority of marketed drugs are either not labelled, or inadequately labelled, for use in paediatric patients. The absence of suitable medicines or critical safety and efficacy information poses significant risks to a particularly vulnerable patient population. However, there are many challenges associated with developing medicines for the paediatric population and this review paper is intended to highlight these. The paediatric population is made up of a wide range of individuals of substantially varied physical size, weight and stage of physiological development. Experimentation on children is considered by many to be unethical, resulting in difficulties in obtaining critical safety data. Clinical trials are subject to detailed scrutiny by the various regulatory bodies who have recently recognized the need for pharmaceutical companies to invest in paediatric medicines. The costs associated with paediatric product development could result in poor or negative return on investment and so incentives have been proposed by the EU and US regulatory bodies. Additionally, some commonly used excipients may be unsuitable for use in children; and some dosage forms may be undesirable to the paediatric population.