Issues In Nanomedicine Research Articles

Endotoxin contamination in ovalbumin as viewed from a nano-immunotherapy perspective.

Ovalbumin (OVA) is a model antigen commonly incorporated in smartly designed nanoparticles for delivery into antigen-presenting cells (APC), aiming to investigate the immune activity and therapeutic efficacy of nanoparticles that contain immunoregulatory compounds. However, the immunoresponse observed in nano-immunotherapy may unexpectedly arise from endotoxin impurity of OVA in the nanoparticles. Literature review shows that most researchers did not notice the importance of endotoxin-free OVA when used in nano-immunotherapy studies. Concentration at as low as 5μg/ml OVA from Sigma-Aldrich (contains 0.625 ng/ml endotoxin) was able to activate APC such as dendritic cells and macrophages. Here, we proposed that the endotoxin impurity in OVA or the finished nanoproducts should be determined by both Limulus Amebocyte Lysate (LAL) and cell-based assay, to ensure the endotoxin-free quality of the nanoparticles. The endotoxin in OVA can be removed by endotoxin removal column and phase separation methods and endotoxin-free OVA can be purchased. This perspective alerts the researchers of endotoxin impurity of OVA that may transfer into the finished nanoparticles and introduce an unfavorable immunoregulatory function with false-positive results. OVA with minimal endotoxin level should be used in nano-immunotherapy studies to accurately reflect the true effects of nanoparticles on the immune system. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Co-Adjuvant Nanoparticles for Radiotherapy Treatments of Oncological Diseases

Nanomedicine is emerging as promising approach for the implementation of oncological methods. In this review, we describe the most recent methods exploiting heavy nanoparticles and hybrid nanomaterials aiming at improving the traditional X-rays-based treatments. High-Z nanoparticles are proposed as radiosensitizers due to their ability to stop the ionizing radiation and to increase the locally delivered therapeutic dose. Other nanoparticles working as catalysts can generate reactive oxygen species upon X-rays exposure. Thanks to their high toxicity and reactivity, these species promote DNA cancer cells damage and apoptosis. Hybrid nanoparticles, composed by scintillators coupled to organic molecules, are suitable in X-rays activated photodynamic therapy. This work highlights the roles played by the diverse nanoparticles, upon ionizing radiation irradiation, according to their physico-chemical properties, surface functionalization, and targeting strategies. The description of nanoparticle qualities demanded by the oncological nanomedicine is presented in relation to the processes occurring in biological medium when X-ray radiation interacts with heavy nanoparticles, including the scintillation mechanisms, the stopping power amplification, and the disputed modeling of the effective deposit of energy within nanomaterials. The comprehension of these issues in nanomedicine drives the strategies of nanoparticles engineering and paves the way for the development of advanced medical therapies.

Endotoxin contamination of engineered nanomaterials: Overcoming the hurdles associated with endotoxin testing.

Nanomaterials are highly susceptible to endotoxin contamination due their large surface-to-volume ratios and endotoxins propensity to associate readily to hydrophobic and cationic surfaces. Additionally, the stability of endotoxin ensures it cannot be removed efficiently through conventional sterilization techniques such as autoclaving and ionizing radiation. In recent times, the true significance of this hurdle has come to light with multiple reports from the United States Nanotechnology Characterization Laboratory, in particular, along with our own experiences of endotoxin testing from multiple Horizon 2020-funded projects which highlight the importance of this issue for the clinical translation of nanomaterials. Herein, we provide an overview on the topic of endotoxin contamination of nanomaterials intended for biomedical applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

In vitro dissolution considerations associated with nano drug delivery systems.

Nano drug delivery systems (NDDS) offer promising solution for the translation of future nanomedicines. As bioavailability and therapeutic outcomes can be improved by altering the drug release from these NDDS, it becomes essential to thoroughly understand their drug release kinetics. Moreover, U.S. Food and Drug Administration requires critical evaluation of potential safety, efficacy, and public health impacts of nanomaterials. Spiraling up market share of NDDS has also stimulated the pharmaceutical industry to develop their cost-effective generic versions after the expiry of patent and associated exclusivity. However, unlike the conventional dosage forms, the in vivo disposition of NDDS is highly intricate and different from their in vitro behavior. Significant challenges exist in the establishment of in vitro-in vivo correlation (IVIVC) due to incomplete understanding of nanoparticles' in vivo biofate and its impact on in vitro experimental protocols. A rational design of dissolution may serve as quality and quantity control tool and help develop a meaningful IVIVC for favorable economic implications. Clinically relevant drug product specifications (critical quality attributes) can be identified by establishing a link between in vitro performance and in vivo exposure. In vitro dissolution may also play a pivotal role to understand the dissolution-mediated clearance and safety of NDDS. Prevalent in vitro dissolution methods for NDDS and their limitations are discussed in this review, among which USP 4 is gaining more interest recently. Researchers are working diligently to develop biorelevant in vitro release assays to ensure optimal therapeutic performance of generic versions of these NDDS. This article focuses on these studies and presents important considerations for the future development of clinically relevant in vitro release methods. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

The effects of gene × environment interactions on silver nanoparticle toxicity in the respiratory system: An adverse outcome pathway.

The Adverse Outcome Pathway (AOP) framework is serving as a basis to integrate new data streams in order to enhance the power of predictive toxicology. AOP development for engineered nanomaterials (ENM), including silver nanoparticles (AgNP), is currently lagging behind other chemicals of regulatory interest due to our limited understanding of the mechanism by which underlying genetics or diseases directly modify host response to AgNP exposures. This also highlights the importance of considering the Aggregate Exposure Pathway (AEP) framework, which precedes the AOP framework and outlines source to target site exposure. The AEP and AOP frameworks interface at the target site, where a molecular initiating event (MIE) occurs and is followed by key events (KE) for adverse cellular and organ responses along a biological pathway and ends with the adverse organism response. The primary goal of this study is to use AgNP to interrogate the AEP-AOP framework by organizing and integrating in vitro dose-response data and in vivo exposure-response data from previous studies to evaluate the effects of interactions between host genetic and acquired factors, or gene × environment interactions (G × E), on AgNP toxicity in the respiratory system. Using this framework will help us to identify plausible key event relationships (KER) between MIE and adverse organism responses when KE are not measured using the same assay in order to derive future predictive models, guide research, and support development of tools for making risk-based, regulatory decisions on ENM. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

Nanomaterials for Agricultural and Ecological Defense Applications: Active Agents and Sensors.

The world we live in today is overpopulated with an unprecedented number of people competing for fewer and fewer precious resources. The struggle to efficiently steward and manage these resources is a global problem in need of concrete and urgent solutions. Nanomaterials have driven innovation in diverse industrial sectors including military, aviation, electronic, and medical among others. Nanoscale materials possess unique surfaces and exquisite opto-electronic properties that make them uniquely suited to environmental, biological, and ecological defense applications. A tremendous upsurge of research activity in these areas is evident from the exponential increase in publications worldwide. Here we review recent applications of nanomaterials toward soil health and management, abiotic and biotic stress management, plant defense, delivery of the RNA Interference (RNAi), plant growth, manufacture of agro-products, and ecological investigations related to farming. For example, nanomaterial constructs have been used to counter environmental stresses and in plant defense and disease diagnosis. Nanosensor chemistries have been developed to monitor water quality and measure specific pollutant levels. Specific nanomaterials such as silver, iron oxide, and zinc oxide proffer protection to plants from pathogens. This review describes progress in nanomaterial-based agricultural and ecological defense and seeks to identify factors that would enable their wider commercialization and deployment. This article is categorized under: Diagnostic Tools > Biosensing Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Diagnostic Tools > Diagnostic Nanodevices.

Silver nanoparticles as a potential treatment against SARS-CoV-2: A review.

Several human coronaviruses (HCoVs) are distinguished by the ability to generate epidemics or pandemics, with their corresponding diseases characterized by severe respiratory illness, such as that which occurs in severe acute respiratory syndrome (SARS‐CoV), Middle East respiratory syndrome (MERS‐CoV), and, today, in SARS‐CoV‐2, an outbreak that has struck explosively and uncontrollably beginning in December 2019 and has claimed the lives of more than 1.9 M people worldwide as of January 2021. The development of vaccines has taken one year, which is why it is necessary to investigate whether some already‐existing alternatives that have been successfully developed in recent years can mitigate the pandemic's advance. Silver nanoparticles (AgNPs) have proved effective in antiviral action. Thus, in this review, several in vitro and in vivo studies of the effect of AgNPs on viruses that cause respiratory diseases are analyzed and discussed to promote an understanding of the possible interaction of AgNPs with SARS‐CoV‐2. The study focuses on several in vivo toxicological studies of AgNPs and a dose extrapolation to humans to determine the chief avenue of exposure. It can be concluded that the use of AgNPs as a possible treatment for SARS‐CoV‐2 could be viable, based on comparing the virus' behavior to that of similar viruses in in vivo studies, and that the suggested route of administration in terms of least degree of adverse effects is inhalation.This article is categorized under:Nanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory DiseaseToxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

The evolution of polymer conjugation and drug targeting for the delivery of proteins and bioactive molecules.

Polymer conjugation can be considered one of the leading approaches within the vast field of nanotechnology-based drug delivery systems. In fact, such technology can be exploited for delivering an active molecule, such as a small drug, a protein, or genetic material, or it can be applied to other drug delivery systems as a strategy to improve their in vivo behavior or pharmacokinetic activities such as prolonging the half-life of a drug, conferring stealth properties, providing external stimuli responsiveness, and so on. If on the one hand, polymer conjugation with biotech drug is considered the linchpin of the protein delivery field boasting several products in clinical use, on the other, despite dedicated research, conjugation with low molecular weight drugs has not yet achieved the milestone of the first clinical approval. Some of the primary reasons for this debacle are the difficulties connected to achieving selective targeting to diseased tissue, organs, or cells, which is the main goal not only of polymer conjugation but of all delivery systems of small drugs. In light of the need to achieve better drug targeting, researchers are striving to identify more sophisticated, biocompatible delivery approaches and to open new horizons for drug targeting methodologies leading to successful clinical applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

Intracellular and extracellular targets as mechanisms of cancer therapy by nanomaterials in relation to their physicochemical properties.

Cancer nanomedicine has evolved in recent years and is only expected to increase due to the ease with which nanomaterials (NMs) may be manipulated to the advantage of the cancer patient. The success of nanomedicine is dependent on the cell death mechanism, which in turn is dependent on the organelle initially targeted. The success of cancer nanomedicine is also dependent on other cellular mechanisms such as the induction of autophagy dysfunction, manipulation of the tumor microenvironment (TME) and secretome or induction of host immune responses. Current cancer phototherapies for example, photothermal‐ or photodynamic therapies as well as radio enhancement also form a major part of cancer nanomedicine. In general, cancer nanomedicine may be grouped into those NMs exhibiting inherent anti‐cancer properties that is, self‐therapeutic NMs (Group 1), NMs leading to localization of phototherapies or radio‐enhancement (Group 2), and NMs as nanocarriers in the absence or presence of external radiation (Group 3). The recent advances of these three groups, together with their advantages and disadvantages as well as their cellular mechanisms and ultimate outcomes are summarized in this review. By exploiting these different intracellular mechanisms involved in initiating cell death pathways, it is possible to synthesize NMs that may have the desirable characteristics to maximize their efficacy in cancer therapy. Therefore, a summary of these important physicochemical characteristics is also presented that need to be considered for optimal cancer cell targeting and initiation of mechanisms that will lead to cancerous cell death.This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseToxicology and Regulatory Issues in Nanomedicine > Toxicology of NanomaterialsToxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine

Challenges in the development of nanoparticle‐based imaging agents: Characterization and biology

Despite imaging agents being some of the earliest nanomedicines in clinical use, the vast majority of current research and translational activities in the nanomedicine field involves therapeutics, while imaging agents are severely underrepresented. The reasons for this lack of representation are several fold, including difficulties in synthesis and scale-up, biocompatibility issues, lack of suitable tissue/disease selective targeting ligands and receptors, and a high bar for regulatory approval. The recent focus on immunotherapies and personalized medicine, and development of nanoparticle constructs with better tissue distribution and selectivity, provide new opportunities for nanomedicine imaging agent development. This manuscript will provide an overview of trends in imaging nanomedicine characterization and biocompatibility, and new horizons for future development. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

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 NanomedicineToxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

Impact of the protein corona on nanomaterial immune response and targeting ability.

Over the last decade nanomaterials have had a major impact on human health for the early detection and treatment of many diseases. The future success of clinically translatable nanomaterials lies in the combination of several functionalities to realize a personalized medical experience for patients. To maintain promises, concerns arising from toxic potential and off-target accumulation of nanomaterials must be addressed first. Upon introduction to a complex biological system (e.g., following systemic administration), nanomaterials interact with all the encountered biomolecules and form the protein corona, a complex coating of plasma proteins that provides them with a totally new biological identity. As the protein corona controls the nanomaterial behavior in vivo, a precise knowledge of the relationship between biological identity and physiological response is needed but not yet achieved. Based on impressive progress made thus far, this review critically discusses how the protein corona activates immune response and influences the targeted delivery of nanomaterials. Furthermore, we comment on emerging strategies to manipulate protein binding in order to promote formation of designer artificial coronas and achieve a desired therapeutic outcome. We conclude by debating challenges that must be overcome to obtain widespread clinical adoption of nanomaterials. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Biocorona-induced modifications in engineered nanomaterial-cellular interactions impacting biomedical applications.

When nanoparticles (NPs) enter a physiological environment, a complex coating of biomolecules is absorbed onto their surface, known as the biocorona (BC). This coating alters nanomaterial physical properties, modulating cellular viability, internalization, and immune responses. To safely utilize NPs within medical settings, it is necessary to understand the influence of the BC on cellular responses. Due to the variety of cell types, NPs, and physiological environments, responses are variable; though trends do exist. This review article critically evaluates the currently available literature regarding the influence of the BC on NP interactions with prominent cell types that they are likely to encounter during biomedical applications. Specifically, we will examine responses related to interactions with endothelial cells, macrophages, and epithelial cells of the digestive tract and lung. Further, we will evaluate how the BC may influence interactions with bacteria and fungi, as NPs have been proposed as antimicrobial agents in medical settings. The information reviewed and discussed here may enhance the development of effective of NP-based therapeutics and diagnostic tools. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Diagnostic Tools > Diagnostic Nanodevices.

The potential anti-infective applications of metal oxide nanoparticles: A systematic review.

Microbial infections present a major global healthcare challenge, in large part because of the development of microbial resistance to the currently approved antimicrobial drugs. This demands the development of new antimicrobial agents. Metal oxide nanoparticles (MONPs) are a class of materials that have been widely explored for diagnostic and therapeutic purposes. They are reported to have wide-ranging antimicrobial activities and to be potent against bacteria, viruses, and protozoans. The use of MONPs reduces the possibility of resistance developing because they have multiple mechanisms of action (including via reactive oxygen species generation), simultaneously attacking many sites in the microorganism. However, despite this there are to date no MONPs clinically approved for antimicrobial therapy. This review explores the recent literature in this area, discusses the mechanisms of MONP action against microorganisms, and considers the barriers faced to the use of MONPs in humans. These include biological challenges, of which the potential for an immune response and off-target toxicity are key. We explore in detail the possible benefits/disbenefits of an immune response being initiated, and consider the effect of production method (chemical vs. green synthesis) on cytotoxicity. There are also a number of technical and manufacturing challenges hindering MONP translation to the clinic which are additionally discussed in depth. In the short term, there are potentially some "quick wins" from the repurposing of already-approved nanoparticle-based medicines for anti-infective applications, but a number of hurdles, both technical and biological, lie in the path to long-term clinical translation of new MONP-based formulations. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Biocompatibility in regenerative nanomedicine.

Biocompatibility is a very common word that is used within biomaterial science and used for description of the interactions between the foreign material and the body. However, the meaning of biocompatibility as well as the mechanisms that collectively constitutes is still unclear. With the advance of nanotechnology, new concerns have been observed related to biocompatibility of these biomaterials. Due to their small size and variability of their physical and chemical properties, nanoparticles' (NP) distribution within the body and interactions with the target cells and tissues are highly variable. Here, we tried to provide an overview about NPs, the concept of biocompatibility and biocompatibility-related issues in nanomedicine and several different NPs.

The role of sex in particle-induced inflammation and injury.

The use of engineered nanomaterials within various applications such as medicine, electronics, and cosmetics has been steadily increasing; therefore, the rate of occupational and environmental exposures has also increased. Inhalation is an important route of exposure to nanomaterials and has been shown to cause various respiratory diseases in animal models. Human lung disease frequently presents with a sex/gender-bias in prevalence or severity, but investigation of potential sex-differences in the adverse health outcomes associated with nanoparticle inhalation is greatly lacking. Only ~20% of basic research in the general sciences use both male and female animals and a substantial percentage of these do not address differences between sexes within their analyses. This has prevented researchers from fully understanding the impact of sex-based variables on health and disease, particularly the pathologies resulting from the inhalation of particles. The mechanisms responsible for sex-differences in respiratory disease remain unclear, but could be related to a number of variables including sex-differences in hormone signaling, lung physiology, or respiratory immune function. By incorporating sex-based analysis into respiratory nanotoxicology and utilizing human data from other relevant particles (e.g., asbestos, silica, particulate matter), we can improve our understanding of sex as a biological variable in nanoparticle exposures. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Integration of gadolinium in nanostructure for contrast enhanced-magnetic resonance imaging.

Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics, which is further enhanced with the use of contrast agents (CAs). The most commonly used CAs are gadolinium-based contrast agents (GBCAs), in which gadolinium (Gd) is chelated with organic chelating agents (linear or cyclic). However, the use of GBCA is related to toxic side effect due to the release of free Gd3+ ions from the chelating agents. The repeated use of GBCAs has led to Gd deposition in various major organs including bone, brain, and kidneys. As a result, the use of GBCA has been linked to the development of nephrogenic systemic fibrosis (NSF). Due to the GBCA associated toxicities, some clinically approved GBCAs have been limited or revoked recently. Therefore, there is an urgent need for the development of new strategies to chelate and stabilize Gd3+ ions for contrast enhancement, safety profile, and selective imaging of a pathological site. Toward this endeavor, GBCAs have been engineered using different nanoparticulate systems to improve their stability, biocompatibility, and pharmacokinetics. Throughout this review, some of the important strategies for engineering small molecular Gd3+ chelates into a nanoconstruct is discussed. We focus on the development of GBCAs as liposomes, mesoporous silica nanoparticles (MSNs), polymeric nanocarriers, and plasmonic nanoparticles-based design strategies to improve safety and contrast enhancement for contrast enhanced-magnetic resonance imaging (Ce-MRI). We also discuss the in-vitro/in-vivo properties of strategically designed nanoscale MRI CAs, its potentials, and limitations. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Diagnostic Tools > Diagnostic Nanodevices Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

National Cancer Institute Alliance for nanotechnology in cancer-Catalyzing research and translation toward novel cancer diagnostics and therapeutics.

Nanotechnology has been a burgeoning research field, which is finding compelling applications in several practical areas of everyday life. It has provided novel, paradigm shifting solutions to medical problems and particularly to cancer. In order to accelerate integration of nanotechnology into cancer research and oncology, the National Cancer Institute (NCI) of the National Institutes of Health (NIH) established the NCI Alliance for Nanotechnology in Cancer program in 2005. This effort brought together scientists representing physical sciences, chemistry, and engineering working at the nanoscale with biologists and clinicians working on cancer to form a uniquely multidisciplinary cancer nanotechnology research community. The last 14 years of the program have produced a remarkable body of scientific discovery and demonstrated its utility to the development of practical cancer interventions. This paper takes stock of how the Alliance program influenced melding of disparate research disciplines into the field of nanomedicine and cancer nanotechnology, has been highly productive in the scientific arena, and produced a mechanism of seamless transfer of novel technologies developed in academia to the clinical and commercial space. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging.

The consolidation of nanomedicine.

Over the past two decades, nanomedicine has grown steadily, however, without inducing a palpable shift in the diagnosis and treatment of diseases so far. While this may simply be a consequence of the slow, incremental nature that characterizes many modern technologies, this article posits that there is another set of significant factors harboring explanatory power. Uncertainties concerning safety, regulatory, and ethical requirements may have prompted innovators to stay close to the known and approved, eventually at the cost of innovating in unexplored alleys. Network analysis of all nanomedicine patents in the United States reveals that nanomedicine has indeed rather consolidated than expanded. We detail a set of recommendations that would reduce the uncertainty prevailing in nanomedicine and could contribute to pushing new boundaries.This article is categorized under:Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine

Drug-free mannosylated liposomes inhibit tumor growth by promoting the polarization of tumor-associated macrophages.

Background: Tumor-associated macrophages (TAMs) are critical in tumor progression and metastasis. Selective targeting of TAMs holds great potential to ameliorate the immunosuppressive tumor microenvironment and enhance the efficacy of antitumor therapy. Various liposomes have been developed to target TAMs via cell-specific surface receptors either to deplete or re-educate TAMs. Since immuno-stimulation often initiates with the interaction of nanocarriers with the innate immunity cells such as macrophages, the intrinsic impact of drug-free liposomes on macrophage activation and polarization via cell interaction is one of the most critical issues in nanomedicine for promoting effective immunotherapy.Methods: In this study, conventional bare liposomes, PEGylated liposomes, and mannosylated liposomes were developed and the cytotoxicity, cellular internalization, immunostimulatory activity, targeting efficiency, antitumor efficacy, and mechanism were evaluated in vitro and in vivo.Results: All liposomes displayed an ideal particle size, good biocompatibility, and controlled release behavior. Mannosylated liposomes exhibited superior in vitro cellular internalization and tumor spheroid penetration with the aid of the mannose receptor-mediated TAMs-targeting effects. In particular, mannosylated liposomes promoted the polarization of both M0 and M2 to the M1 phenotype by enhancing the expression ratio of CD86/CD206 in vitro. Of note, mannosylated liposomes could inhibit G422 glioma tumor growth, which may be attributed to the polarization of TAMs, as evidenced by the reduction in expression level of the TAMs surface marker.Conclusion: These results indicate the potential value of mannosylated liposomes in the design of a rational delivery system to enhance the antitumor immune efficacy of immunomodulators by inducing a shift from the M2 to the M1 phenotype.