Recent Advances in Preclinical Research Using PAMAM Dendrimers for Cancer Gene Therapy.

Carriers of genetic material are divided into vectors of viral and non-viral origin. Viral carriers are already successfully used in experimental gene therapies, but despite advantages such as their high transfection efficiency and the wide knowledge of their practical potential, the remaining disadvantages, namely, their low capacity and complex manufacturing process, based on biological systems, are major limitations prior to their broad implementation in the clinical setting. The application of non-viral carriers in gene therapy is one of the available approaches. Poly(amidoamine) (PAMAM) dendrimers are repetitively branched, three-dimensional molecules, made of amide and amine subunits, possessing unique physiochemical properties. Surface and internal modifications improve their physicochemical properties, enabling the increase in cellular specificity and transfection efficiency and a reduction in cytotoxicity toward healthy cells. During the last 10 years of research on PAMAM dendrimers, three modification strategies have commonly been used: (1) surface modification with functional groups; (2) hybrid vector formation; (3) creation of supramolecular self-assemblies. This review describes and summarizes recent studies exploring the development of PAMAM dendrimers in anticancer gene therapies, evaluating the advantages and disadvantages of the modification approaches and the nanomedicine regulatory issues preventing their translation into the clinical setting, and highlighting important areas for further development and possible steps that seem promising in terms of development of PAMAM as a carrier of genetic material.

Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls.

Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Nanomedicines and Nanosimilars: Looking for a New and Dynamic Regulatory "Astrolabe" Inspired System.

The application of the nanotechnology in medicine and pharmaceutics opens new horizons in therapeutics. Several nanomedicines are in the market and an increasing number is in clinical trials. But which is the advantage of the medicines in nanoscale? The scientists and the regulatory authorities agree that the size and consequently the physiochemical/biological properties of nanomaterials play a key role in their safety and effectiveness. Additionally, all of them agree that a new scientific-based regulatory landscape is required for the establishment of nanomedicines in the market. The aim of this review is to investigate the parameters that the scientists and the regulatory authorities should take into account in order to build up a dynamic regulatory landscape for nanomedicines. For this reason, we propose an "astrolabe-like system" as the guide for establishing the regulatory approval process. Its function is based on the different physicochemical/biological properties in comparison to low molecular weight drugs.

Reflexões bioéticas acerca da inovação em Nanomedicamentos / Reflexiones bioéticsa acerca de la innovación en Nanomedicamentos / Bioethical Reflections on Innovation in Nanomedicines / Reflexions bioètiques sobre la innovació en nanomedicaments

A nanotecnologia vem se desenvolvendo de forma exponencial na área farmacêutica, prometendo grandes benefícios, entretanto, pode estar sujeita a riscos intrínsecos relacionados a esta ciência. Neste artigo é realizada uma reflexão acerca dos desafios enfrentados pelos órgãos regulatórios em função da ausência, ou ainda, incipiente legislação, especialmente no Brasil, visto que os documentos disponíveis em relação a regulamentação, não incluem especificações para nanomedicamentos, os quais apresentam alterações na dimensão e constituição, e consequentemente comportamento diferente de medicamentos convencionais. A contingência envolvendo o desenvolvimento de nanomedicamentos e a gestão dos riscos para a vida humana e o meio ambiente fazem com que a bioética seja invocada de forma a analisar quais os impactos decorrem deste proceso

Nanotechnology has been developing exponentially in the pharmaceutical area, promising great benefits, however, it may be subject to intrinsic risks related to this science. In this article, a reflection is made on the challenges faced by regulatory agencies due to the absence or incipient legislation, especially in Brazil, since the available documents in relation to regulation do not include specifications for nanomedicine, which present changes in the dimension and constitution, and consequently different behavior of conventional drugs. The contingency involving the development of nanomedicine and the management of the risks for human life and the environment, cause bioethics to be invoked in order to analyze the impacts of this process

La nanotecnología se está desarrollando de forma exponencial en el área farmacéutica, prometiendo grandes beneficios, sin embargo, puede estar sujeta a riesgos intrínsecos relacionados a esta ciencia. En este artículo se reflexiona sobre los desafíos enfrentados por los órganos regulatorios en función de la ausencia, o aún incipiente legislación, especialmente en Brasil, ya que los documentos disponibles en relación a la reglamentación, no incluyen especificaciones para nanomedicamentos, los cuales presentan alteraciones en la dimensión y la constitución, y consecuentemente un comportamiento diferente de los medicamentos convencionales. La contingencia que involucra el desarrollo de nanomedicamentos y la gestión de los riesgos para la vida humana y el medio ambiente hacen que la bioética sea invocada para analizar qué impactos se derivan de este proceso

La nanotecnologia s'està desenvolupant de forma exponencial en l'àrea farmacèutica, prometent grans beneficis; no obstant això, pot estar subjecta a riscos intrínsecs relacionats amb aquesta ciència. En aquest article es reflexiona sobre els desafiaments que enfronten els òrgans reguladors en funció de l'absència, o d’una legislació incipient, especialment al Brasil, ja que els documents disponibles en relació a la reglamentació no inclouen especificacions per a nanomedicaments, els quals presenten alteracions en la seva dimensió i constitució, i conseqüentment presenten un comportament diferent al dels medicaments convencionals. La contingència que involucra el desenvolupament de nanomedicaments i la gestió dels riscos per a la vida humana i el medi ambient fan que la bioètica hagi de jugar un paper a fi d’analitzar quins impactes es deriven d'aquest procés

Preclinical hazard evaluation strategy for nanomedicines.

The increasing nanomedicine usage has raised concerns about their possible impact on human health. Present evaluation strategies for nanomaterials rely on a case-by-case hazard assessment. They take into account material properties, biological interactions, and toxicological responses. Authorities have also emphasized that exposure route and intended use should be considered in the safety assessment of nanotherapeutics. In contrast to an individual assessment of nanomaterial hazards, we propose in the present work a novel and unique evaluation strategy designed to uncover potential adverse effects of such materials. We specifically focus on spherical engineered nanoparticles used as parenterally administered nanomedicines. Standardized assay protocols from the US Nanotechnology Characterization Laboratory as well as the EU Nanomedicine Characterisation Laboratory can be used for experimental data generation. We focus on both cellular uptake and intracellular persistence as main indicators for nanoparticle hazard potentials. Based on existing regulatory specifications defined by authorities such as the European Medicines Agency and the United States Food and Drug Administration, we provide a robust framework for application-oriented classification paired with intuitive decision making. The Hazard Evaluation Strategy (HES) for injectable nanoparticles is a three-tiered concept covering physicochemical characterization, nanoparticle (bio)interactions, and hazard assessment. It is cost-effective and can assist in the design and optimization of nanoparticles intended for therapeutic use. Furthermore, this concept is designed to be adaptable for alternative exposure and application scenarios. To the knowledge of the authors, the HES is unique in its methodology based on exclusion criteria. It is the first hazard evaluation strategy designed for nanotherapeutics.

Mapping of the available standards against the regulatory needs for nanomedicines.

Appropriate documentary standards and reference materials are crucial building blocks for the development of innovative products. In order to support the emerging sector of nanomedicine, relevant standards must be identified and/or developed before the products will enter into the regulatory approval process. The anticipation of standardization needs requires a good understanding on the regulatory information requirements that can be triggered by the particularities of nanomedicines. However, robust datasets allowing firm conclusions on regulatory demands are not yet available due to a lack of regulatory experience with innovative products. Such a catch-22 situation can only be advanced in an iterative process by monitoring continuously the scientific evidence and by promoting intensive knowledge exchange between all involved stakeholders. In this study, we have compiled information requirements released by regulatory scientists so far and mapped it against available standards that could be of relevance for nanomedicines. Our gap analysis clearly demonstrated that for some endpoints such as drug release/loading and the interaction of nanomedicines with the immune system no standards are available so far. The emerging nanomedicine sector could benefit from cross-sector collaboration and review the suitability of standards that have been developed for nanomaterials used for other industrial applications. Only a concerted action of all parties can lead to a smooth translation of nanomedicines to clinical application and to the market. This is in particular important because nanotechnology-based drug delivery systems are key for the development and implementation of personalized medicine. This article is characterized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

Reflections on FDA Draft Guidance for Products Containing Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for Nanomedicines?

The US Food and Drug Administration (FDA) recently released a draft guidance for industry titled "Drug Products, Including Biological Products, that Contain Nanomaterials." The FDA's attention to the unique safety and efficacy aspects of drugs containing nanomaterials is commendable. This Draft Guidance succeeds in acknowledging the complexity of these products, as well as the challenges associated with approving safe and therapeutically equivalent complex generic versions. However, the challenge posed by the manufacturing process for drugs containing nanomaterials is insufficiently addressed. The critical quality attributes of such products cannot be properly defined, and therefore it is not possible to design informative comparative physicochemical assessments for equivalence. As a consequence, the 505(j) Abbreviated New Drug Application (ANDA) pathway, currently advised as the standard from the FDA, is not suitable for the approval of complex generic products. Drawing from the successful story of biologics, we propose instead a stepwise totality-of-evidence approach, demonstrating similarity and including clinical studies when deemed necessary, as an appropriate alternative to the 505(j) ANDA pathway.

Current State of Nanomedicines in the Treatment of Topical Infectious Disorders.

BACKGROUND: Topical infections, involving a number of diseases such as impetigo, eczema, pustular acne, psoriasis and infected seborrheic dermatitis are one among the many challenges to health which stand out for their profound impact on human species. The treatment of topical infections has always been a difficult proposition because of the lack of efficacy of existing anti-infectives, longer period of treatment and yet incomplete recovery. The increasing emergence of antibiotic resistant bacterial strains like Staphylococcus aureus, Methicillin-Resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa undermines the need for the development of new delivery systems to enhance the therapeutic efficacy of existing topical anti-infectives. METHODS: The application of nanotechnology to medicine, or nanomedicine, is rapidly becoming a major driving force behind ongoing changes in the anti-infective field because of its interaction at the sub-atomic level with the skin tissue. The latter, in the current scenario, points towards vesicular carriers like liposomes, lipidic nanoparticles and silver nanoparticles. as the most promising drug delivery solutions for topical infection disorders. These have exhibited immense significance owing to their uniqueness to facilitate the interactions at interfaces with the barrier membranes. RESULTS: The present review summarizes the emerging efforts in combating topical infections particularly using nanomedicine based delivery systems as new tools to tackle the current challenges in treating infectious diseases. Besides, compiling various research reports, this article also includes formulation considerations, mechanisms of penetration and patents reported. CONCLUSION: Despite the new emerging technologies and delivery systems, efforts are still needed in the right direction to combat this global challenge.

Patented and Approval Scenario of Nanopharmaceuticals with Relevancy to Biomedical Application, Manufacturing Procedure and Safety Aspects.

BACKGROUND: Nanopharmaceutical is the field that arises gradually but many challenges are also still there. This review aims to identify these challenges and give the focus on their rectification. METHODS: In this paper, we memorize the safety issues, patented manufacturing procedure, applications and regulatory aspects of the nanopharmaceuticals by using the peer-reviewed research literatures. All the screened literatures described the quality content of nanopharmaceuticals with relevancy to biomedical and pharmaceutical field. RESULTS: Nanopharmaceuticals have great potential to resolve the different issues such as; site specific drug delivery however, many challenges are also arising in their commercialization. In the recent years, some nanopharmaceuticals have the desired quality and safety for the public, have been approved by the regulatory agencies but this field is still a thrust area that demands a lot of attention. CONCLUSION: The present review article confirms the importance of nanopharmaceuticals and impart the knowledge for making the significant approaches and strategies to overcome the manufacturing, safety, legal and regulatory issues related to nanopharmaceuticals.

Régimen jurídico de la Nanomedicina en España / No disponnible

El devenir de los tiempos ha favorecido el desarrollo de tecnologías aplicadas a dispositivos, materiales, procedimientos médicos y modalidades terapéuticas desarrolladas, en algunos casos, mediante la convergencia de materiales vivos e inertes, dando lugar al descubrimiento de nuevos tratamientos médicos beneficiosos para la salud y la mejora de la calidad de vida de nuestra especie. En base a estos presupuestos metodológicos el objeto de este trabajo ha consistido en analizar cuáles son los avances más notorios que se han producido en este campo durante los últimos años y cuales es el mapa jurídico de los sistemas de Nanomedicina en un país como España inmerso, actualmente, en una desoladora época de crisis gestionada por las instancias públicas en base a recortes en el ámbito de la salud pública

The evolution has favored the development of technologies applied to devices, materials, medical procedures and therapeutic modalities developed, in some cases, by the convergence of living and inert materials, leading to the discovery of new medical treatments beneficial to health and the improvement of the quality of life of our species. Based on these methodological assumptions the objective of this work has been to analyze which are the most notorious advances that have occurred in this field during the last years and what is the legal map of the systems of Nanomedicine in a country like immersed Spain, Currently, in a bleak era of crisis managed by public bodies based on cuts in the field of public health

[Nano materials need stricter EU regulation]. / Nanomaterial måste EU-regleras bättre - Risk att bristen på lagstiftning stör teknikutvecklingen och skapar misstro för nanotekniken hos allmänheten.

Nano materials need stricter EU regulation REACH is the EU regulation adopted to protect health and environment from the risks that can be posed by chemicals. Companies have the responsibility of collecting information on the uses of manufactured or imported substances above one tonne per year. They also have to make an assessment of the potential risks presented by the substance. Nanomaterials contain chemical substances which are regulated by REACH. However, nanomaterials have unique characteristics and are manufactured and used on a very small scale. Therefore, REACH is at present not well adjusted to regulate nanomaterials. Neither is the approval process for new drugs well adjusted for compounds containing nanomaterial. Improvement of the European medical technology regulation that takes nanomaterial into consideration is under way although it is delayed. There is a lack of data on the degree of exposure to nanomaterial and effects on human health and environment. Such information is needed to obtain adequate regulation.

Updated Regulatory Considerations for Nanomedicines.

BACKGROUND: Nanomedicine is a branch which deals with medicinal products, devices, nonbiological complex drugs and antibody-nanoparticle conjugates and general health products that are manufactured using nanotechnology. OBJECTIVE: Nano-medicine provides the same efficacies as traditional medicines owing to their improved solubility and bioavailability with reduced dosages. However, there are currently safety concerns due to the difficulties related to nanomaterial characterization; this might be the reason for unawareness of such medicines among the patients. The absence of clear regulatory guidelines further complicates matters, as it makes the path to registering them with regulatory bodies difficult. However, some products have overcome these obstacles and have been registered. While there are many international initiatives to harmonize the regulatory requirements and helps the industry to determine the most important characteristics that influence in vivo product performance. CONCLUSION: This review focuses on the various types of nanopharmaceuticals, and developments process with strategies tailored to upcoming regulations may satisfy the patients' needs.

Ethical issues in nanomedicine: Tempest in a teapot?

Nanomedicine offers remarkable options for new therapeutic avenues. As methods in nanomedicine advance, ethical questions conjunctly arise. Nanomedicine is an exceptional niche in several aspects as it reflects risks and uncertainties not encountered in other areas of medical research or practice. Nanomedicine partially overlaps, partially interlocks and partially exceeds other medical disciplines. Some interpreters agree that advances in nanotechnology may pose varied ethical challenges, whilst others argue that these challenges are not new and that nanotechnology basically echoes recurrent bioethical dilemmas. The purpose of this article is to discuss some of the ethical issues related to nanomedicine and to reflect on the question whether nanomedicine generates ethical challenges of new and unique nature. Such a determination should have implications on regulatory processes and professional conducts and protocols in the future.

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.

Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?

Nanotechnology offers several attractive design features that have prompted its exploration for cancer diagnosis and treatment. Nanosized drugs have a large loading capacity, the ability to protect the payload from degradation, a large surface on which to conjugate targeting ligands, and controlled or sustained release. Nanosized drugs also leak preferentially into tumor tissue through permeable tumor vessels and are then retained in the tumor bed due to reduced lymphatic drainage. This process is known as the enhanced permeability and retention (EPR) effect. However, while the EPR effect is widely held to improve delivery of nanodrugs to tumors, it in fact offers less than a 2-fold increase in nanodrug delivery compared with critical normal organs, resulting in drug concentrations that are not sufficient for curing most cancers. In this Review, we first overview various barriers for nanosized drug delivery with an emphasis on the capillary wall's resistance, the main obstacle to delivering drugs. Then, we discuss current regulatory issues facing nanomedicine. Finally, we discuss how to make the delivery of nanosized drugs to tumors more effective by building on the EPR effect.

A comparison of immunotoxic effects of nanomedicinal products with regulatory immunotoxicity testing requirements.

Nanomaterials (NMs) are attractive for biomedical and pharmaceutical applications because of their unique physicochemical and biological properties. A major application area of NMs is drug delivery. Many nanomedicinal products (NMPs) currently on the market or in clinical trials are most often based on liposomal products or polymer conjugates. NMPs can be designed to target specific tissues, eg, tumors. In virtually all cases, NMPs will eventually reach the immune system. It has been shown that most NMs end up in organs of the mononuclear phagocytic system, notably liver and spleen. Adverse immune effects, including allergy, hypersensitivity, and immunosuppression, have been reported after NMP administration. Interactions of NMPs with the immune system may therefore constitute important side effects. Currently, no regulatory documents are specifically dedicated to evaluate the immunotoxicity of NMs or NMPs. Their immunotoxicity assessment is performed based on existing guidelines for conventional substances or medicinal products. Due to the unique properties of NMPs when compared with conventional medicinal products, it is uncertain whether the currently prescribed set of tests provides sufficient information for an adequate evaluation of potential immunotoxicity of NMPs. The aim of this study was therefore, to compare the current regulatory immunotoxicity testing requirements with the accumulating knowledge on immunotoxic effects of NMPs in order to identify potential gaps in the safety assessment. This comparison showed that immunotoxic effects, such as complement activation-related pseudoallergy, myelosuppression, inflammasome activation, and hypersensitivity, are not readily detected by using current testing guidelines. Immunotoxicity of NMPs would be more accurately evaluated by an expanded testing strategy that is equipped to stratify applicable testing for the various types of NMPs.

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date.

In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clinical trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biologic. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clinical trials, with ~40% of trials listed in clinicaltrials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorganic and metallic particles in clinical trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clinical trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials ("theranostics") and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what additional testing (e.g. safety and toxicity) is required before products become available.

Naming it 'nano': Expert views on 'nano' terminology in informed consent forms of first-in-human nanomedicine trials.

BACKGROUND: Obtaining valid informed consent (IC) can be challenging in first-in-human (FIH) trials in nanomedicine due to the complex interventions, the hype and hope concerning potential benefits, and fear of harms attributed to 'nano' particles. AIM: We describe and analyze the opinions of expert stakeholders involved in translational nanomedicine regarding explicit use of 'nano' terminology in IC documents. METHODS: We draw on content analysis of 46 in-depth interviews with European and North American stakeholders. RESULTS: We received a spectrum of responses (reluctance, ambivalence, absolute insistence) on explicit mention of 'nano' in IC forms with underlying reasons. CONCLUSION: We conclude that consistent, clear and honest communication regarding the 'nano' dimension of investigational product is critical in IC forms of FIH trials.

Safety of Nanoparticles in Medicine.

Nanomedicine involves the use of nanoparticles for therapeutic and diagnostic purposes. During the past two decades, a growing number of nanomedicines have received regulatory approval and many more show promise for future clinical translation. In this context, it is important to evaluate the safety of nanoparticles in order to achieve biocompatibility and desired activity. However, it is unwarranted to make generalized statements regarding the safety of nanoparticles, since the field of nanomedicine comprises a multitude of different manufactured nanoparticles made from various materials. Indeed, several nanotherapeutics that are currently approved, such as Doxil and Abraxane, exhibit fewer side effects than their small molecule counterparts, while other nanoparticles (e.g. metallic and carbon-based particles) tend to display toxicity. However, the hazardous nature of certain nanomedicines could be exploited for the ablation of diseased tissue, if selective targeting can be achieved. This review discusses the mechanisms for molecular, cellular, organ, and immune system toxicity, which can be observed with a subset of nanoparticles. Strategies for improving the safety of nanoparticles by surface modification and pretreatment with immunomodulators are also discussed. Additionally, important considerations for nanoparticle safety assessment are reviewed. In regards to clinical application, stricter regulations for the approval of nanomedicines might not be required. Rather, safety evaluation assays should be adjusted to be more appropriate for engineered nanoparticles.