Regulatory Science Perspective on the Analysis of Microplastics and Nanoplastics in Human Food.

Microplastics are increasingly reported, not only in the environment but also in a wide range of food commodities. While studies on microplastics in food abound, the current state of science is limited in its application to regulatory risk assessment by a continued lack of standardized definitions, reference materials, sample collection and preparation procedures, fit-for purpose analytical methods for real-world and environmentally relevant plastic mixtures, and appropriate quality controls. This is particularly the case for nanoplastics. These methodological challenges hinder robust, quantitative exposure assessments of microplastic and nanoplastic mixtures from food consumption. Furthermore, limited toxicological studies on whether microplastics and nanoplastics adversely impact human health are also impeded by methodology challenges. Food safety regulatory agencies must consider both the exposure and the risk of contaminants of emerging concern to ascertain potential harm. Foundational to this effort is access to and application of analytical methods with the capability to quantify and characterize micro- and nanoscale sized polymers in complex food matrices. However, the early stages of method development and application of early stage methods to study the distribution and potential health effects of microplastics and nanoplastics in food have largely been done without consideration of the stringent requirements of methods to inform regulatory activities. We provide regulatory science perspectives on the state of knowledge regarding the occurrence of microplastics and nanoplastics in food and present our general approach for developing, validating, and implementing analytical methods for regulatory purposes.

Comprehensive analysis of common polymers using hyphenated TGA-FTIR-GC/MS and Raman spectroscopy towards a database for micro- and nanoplastics identification, characterization, and quantitation.

Environmental contamination by micro- and nanoplastics (MNPs) is well documented with potential for their increased accumulation globally. Growing public concern over environmental, ecological, and human exposure to MNPs has led to exponential increase in publications, news articles, and reports (Casillas et al., 2023). Significant knowledge gap exists in standardized analytical methods for the identification and quantification of MNPs from real world environmental samples. Here, we report comprehensive datasets utilizing thermogravimetric analyzer (TGA) coupled to a Fourier transformed infrared spectrometer (FTIR) and a gas chromatography/mass spectrometer (GC/MS) with corresponding Raman spectral data for the most common polymers documented to be present in the environment (35 plastics of 12 polymer types), to serve as a base line reference for the identification and quantitation of MNPs. Various parameters for TGA-FTIR-GC/MS data acquisition were optimized. Commercial consumer plastic product compositions were identified using this analytical database. Case studies to showcase the utility of the method for polymer mixtures analysis is included. This dataset would serve towards the development of a collaborative, global, comprehensive, and curated public database for the identification of various MNPs and mixtures.

Radiation impacts on toxicity of cobalt-chromium (CoCr) implant debris.

Particulate and soluble debris are generated by mechanical and non-mechanical degradation of implanted medical devices. Debris containing cobalt and chromium (CoCr) is known to cause adverse biological reactions. Implant-related complications are often diagnosed using radiography, which results in more frequent patient exposure to ionizing radiation. The aim of this study was to evaluate the potential for increased toxicity due to combined radiation and CoCr exposure. This was investigated using a controlled in vitro model consisting of commercially available CoCr debris that was generated from components of hip replacements and human cell lines relevant to the joint environment: endothelial HMEC-1 and synovial SW982. Particle sizes and shapes were heterogenous. Cells tended to internalize smaller particles, as observed by electron microscopy. Indicators of toxicity were measured after short (24 h after radiation) or extended (12-14 d after radiation) exposure timelines. In the short-term, CoCr reduced cell viability, increased apoptosis, and increased oxidative stress. The effects of radiation were not apparent until the timeline was extended. CoCr and radiation reduced cell survival, with both additive and synergistic effects. Mechanisms for reduced survival included rapid cell death caused by CoCr and senescence caused by radiation. In conclusion, results showed combined toxicological effects of CoCr and radiation at the doses and timelines used for this in vitro model. These observations warrant further investigation using other experimental models to determine translational impact.

Optimization of Detection of Gadodiamide Brain Retention in Rats Using Quantitative T2 Mapping and Intraperitoneal Administration.

BACKGROUND: Currently, the gadolinium retention in the brain after the use of contrast agents is studied by T1 -weighted magnetic resonance imaging (MRI) (T1 w) and T1 mapping. The former does not provide easily quantifiable data and the latter requires prolonged scanning and is sensitive to motion. T2 mapping may provide an alternative approach. Animal studies of gadolinium retention are complicated by repeated intravenous (IV) dosing, whereas intraperitoneal (IP) injections might be sufficient. HYPOTHESIS: T2 mapping will detect the changes in the rat brain due to gadolinium retention, and IP administration is equivalent to IV for long-term studies. STUDY TYPE: Prospective longitudinal. ANIMAL MODEL: A total of 31 Sprague-Dawley rats administered gadodiamide IV (N = 8) or IP (N = 8), or saline IV (N = 6) or IP (N = 9) 4 days per week for 5 weeks. FIELD STRENGTH/SEQUENCES: A 7 T, T1 w, and T2 mapping. ASSESSMENT: T2 relaxation and image intensities in the deep cerebellar nuclei were measured pre-treatment and weekly for 5 weeks. Then brains were assessed for neuropathology (N = 4) or gadolinium content using inductively coupled plasma mass spectrometry (ICP-MS, N = 12). STATISTICAL TESTS: Repeated measures analysis of variance with post hoc Student-Newman-Keuls tests and Hedges' effect size. RESULTS: Gadolinium was detected by both approaches; however, T2 mapping was more sensitive (effect size 2.32 for T2 vs. 0.95 for T1 w), and earlier detection (week 3 for T2 vs. week 4 for T1 w). ICP-MS confirmed the presence of gadolinium (3.076 ± 0.909 nmol/g in the IV group and 3.948 ± 0.806 nmol/g in the IP group). There was no significant difference between IP and IV groups (ICP-MS, P = 0.109; MRI, P = 0.696). No histopathological abnormalities were detected in any studied animal. CONCLUSION: T2 relaxometry detects gadolinium retention in the rat brain after multiple doses of gadodiamide irrespective of the route of administration. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Emerging technologies and their impact on regulatory science.

There is an evolution and increasing need for the utilization of emerging cellular, molecular and in silico technologies and novel approaches for safety assessment of food, drugs, and personal care products. Convergence of these emerging technologies is also enabling rapid advances and approaches that may impact regulatory decisions and approvals. Although the development of emerging technologies may allow rapid advances in regulatory decision making, there is concern that these new technologies have not been thoroughly evaluated to determine if they are ready for regulatory application, singularly or in combinations. The magnitude of these combined technical advances may outpace the ability to assess fit for purpose and to allow routine application of these new methods for regulatory purposes. There is a need to develop strategies to evaluate the new technologies to determine which ones are ready for regulatory use. The opportunity to apply these potentially faster, more accurate, and cost-effective approaches remains an important goal to facilitate their incorporation into regulatory use. However, without a clear strategy to evaluate emerging technologies rapidly and appropriately, the value of these efforts may go unrecognized or may take longer. It is important for the regulatory science field to keep up with the research in these technically advanced areas and to understand the science behind these new approaches. The regulatory field must understand the critical quality attributes of these novel approaches and learn from each other's experience so that workforces can be trained to prepare for emerging global regulatory challenges. Moreover, it is essential that the regulatory community must work with the technology developers to harness collective capabilities towards developing a strategy for evaluation of these new and novel assessment tools.

U.S. Federal Agency interests and key considerations for new approach methodologies for nanomaterials.

Engineered nanomaterials (ENMs) come in a wide array of shapes, sizes, surface coatings, and compositions, and often possess novel or enhanced properties compared to larger sized particles of the same elemental composition. To ensure the safe commercialization of products containing ENMs, it is important to thoroughly understand their potential risks. Given that ENMs can be created in an almost infinite number of variations, it is not feasible to conduct in vivo testing on each type of ENM. Instead, new approach methodologies (NAMs) such as in vitro or in chemico test methods may be needed, given their capacity for higher throughput testing, lower cost, and ability to provide information on toxicological mechanisms. However, the different behaviors of ENMs compared to dissolved chemicals may challenge safety testing of ENMs using NAMs. In this study, member agencies within the Interagency Coordinating Committee on the Validation of Alternative Methods were queried about what types of ENMs are of agency interest and whether there is agency-specific guidance for ENM toxicity testing. To support the ability of NAMs to provide robust results in ENM testing, two key issues in the usage of NAMs, namely dosimetry and interference/bias controls, are thoroughly discussed.

Regulatory landscape of nanotechnology and nanoplastics from a global perspective.

Nanotechnology and more particularly nanotechnology-based products and materials have provided a huge potential for novel solutions to many of the current challenges society is facing. However, nanotechnology is also an area of product innovation that is sometimes developing faster than regulatory frameworks. This is due to the high complexity of some nanomaterials, the lack of a globally harmonised regulatory definition and the different scopes of regulation at a global level. Research organisations and regulatory bodies have spent many efforts in the last two decades to cope with these challenges. Although there has been a significant advancement related to analytical approaches for labelling purposes as well as to the development of suitable test guidelines for nanomaterials and their safety assessment, there is a still a need for greater global collaboration and consensus in the regulatory field. Furthermore, with growing societal concerns on plastic litter and tiny debris produced by degradation of littered plastic objects, the impact of micro- and nanoplastics on humans and the environment is an emerging issue. Despite increasing research and initial regulatory discussions on micro- and nanoplastics, there are still knowledge gaps and thus an urgent need for action. As nanoplastics can be classified as a specific type of incidental nanomaterials, current and future scientific investigations should take into account the existing profound knowledge on nanotechnology/nanomaterials when discussing issues around nanoplastics. This review was conceived at the 2019 Global Summit on Regulatory Sciences that took place in Stresa, Italy, on 24-26 September 2019 (GSRS 2019) and which was co-organised by the Global Coalition for Regulatory Science Research (GCRSR) and the European Commission's (EC) Joint Research Centre (JRC). The GCRSR consists of regulatory bodies from various countries around the globe including EU bodies. The 2019 Global Summit provided an excellent platform to exchange the latest information on activities carried out by regulatory bodies with a focus on the application of nanotechnology in the agriculture/food sector, on nanoplastics and on nanomedicines, including taking stock and promoting further collaboration. Recently, the topic of micro- and nanoplastics has become a new focus of the GCRSR. Besides discussing the challenges and needs, some future directions on how new tools and methodologies can improve the regulatory science were elaborated by summarising a significant portion of discussions during the summit. It has been revealed that there are still some uncertainties and knowledge gaps with regard to physicochemical properties, environmental behaviour and toxicological effects, especially as testing described in the dossiers is often done early in the product development process, and the material in the final product may behave differently. The harmonisation of methodologies for quantification and risk assessment of nanomaterials and micro/nanoplastics, the documentation of regulatory science studies and the need for sharing databases were highlighted as important aspects to look at.

Sierpinski Pyramids by Molecular Entanglement.

Planar, terpyridine-based metal complexes with the Sierpinski triangular motif and alkylated corners undergo a second self-assembly event to give megastructural Sierpinski pyramids; assembly is driven by the facile lipophilic-lipophilic association of the alkyl moieties and complementary perfect fit of the triangular building blocks. Confirmation of the 3D, pyramidal structures was verified and supported by a combination of TEM, AFM, and multiscale simulation techniques.

Effect of titanium dioxide nanoparticles on DNA methylation in multiple human cell lines.

Nanoscale titanium dioxide (TiO2) is manufactured in wide scale, with a range of applications in consumer products. Significant toxicity of TiO2 nanoparticles has, however, been recognized, suggesting considerable risk to human health. To evaluate fully their toxicity, assessment of the epigenetic action of these nanoparticles is critical. However, only few studies are available examining capability of nanoparticles to alter epigenetic integrity. In the present study, the effect of TiO2 nanoparticles exposure on DNA methylation, a major epigenetic mechanism, was investigated in in vitro cellular model systems. A panel of cells relevant to portals of human exposure (Caco-2 (colorectal), HepG2 (liver), NL20 (lung), and A-431 (skin)) was exposed to TiO2 nanoparticles to assess effects on global methylation, gene-specific methylation, and expression levels of DNA methyltransferases, MBD2, and UHRF1. Global methylation was determined by enzyme-linked immunosorbent assay-based immunochemical analysis. Degree of promoter methylation across a defined panel of genes was evaluated using EpiTect Methyl II Signature PCR System Array technology. Expression of DNMT1, DNMT3a, DNMT3b, MBD2, and URHF1 was quantified by qRT-PCR. Decrease in global DNA methylation in cell lines Caco-2, HepG2, and A-431 exposed to TiO2 nanoparticles was shown. Across four cell lines, eight genes (CDKN1A, DNAJC15, GADD45A, GDF15, INSIG1, SCARA3, TP53, and BNIP3) were identified in which promotors were methylated after exposure. Altered expression of these genes is associated with disease etiology. The results also revealed aberrant expression of epigenetic regulatory genes involved in DNA methylation (DNMT1, DNMT3a, DNMT3b, MBD2, and UHRF1) in TiO2 exposed cells, which was cell type dependent. Findings from this study clearly demonstrate the impact of TiO2 nanoparticles exposure on DNA methylation in multiple cell types, supporting potential involvement of this epigenetic mechanism in the toxicity of TiO2 nanoparticles. Hence for complete assessment of potential risk from nanoparticle exposure, epigenetic studies are critical.

Bridging communities in the field of nanomedicine.

An early dialogue between nanomedicine developers and regulatory authorities are of utmost importance to anticipate quality and safety requirements for these innovative health products. In order to stimulate interactions between the various communities involved in a translation of nanomedicines to clinical applications, the European Commission's Joint Research Centre hosted a workshop titled "Bridging communities in the field of Nanomedicine" in Ispra/Italy on the 27th -28th September 2017. Experts from regulatory bodies, research institutions and industry came together to discuss the next generation of nanomedicines and their needs to obtain regulatory approval. The workshop participants came up with recommendations highlighting methodological gaps that should be addressed in ongoing projects addressing the regulatory science of nanomedicines. In addition, individual opinions of experts relevant to progress of the regulatory science in the field of nanomedicine were summarised in the format of a survey.

Emerging technologies for food and drug safety.

Emerging technologies are playing a major role in the generation of new approaches to assess the safety of both foods and drugs. However, the integration of emerging technologies in the regulatory decision-making process requires rigorous assessment and consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) in partnership with the Brazilian Health Surveillance Agency (ANVISA) hosted the seventh Global Summit on Regulatory Science (GSRS17) in Brasilia, Brazil on September 18-20, 2017 to discuss the role of new approaches in regulatory science with a specific emphasis on applications in food and medical product safety. The global regulatory landscape concerning the application of new technologies was assessed in several countries worldwide. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the development, application and review of emerging technologies. The need for advanced approaches to allow for faster, less expensive and more predictive methodologies was elaborated. In addition, the strengths and weaknesses of each new approach was discussed. And finally, the need for standards and reproducible approaches was reviewed to enhance the application of the emerging technologies to improve food and drug safety. The overarching goal of GSRS17 was to provide a venue where regulators and researchers meet to develop collaborations addressing the most pressing scientific challenges and facilitate the adoption of novel technical innovations to advance the field of regulatory science.

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Physicochemical Characterization.

The objective of this study was to evaluate physicochemical equivalence between brand (i.e., Ferrlecit) and generic sodium ferric gluconate (SFG) in sucrose injection by conducting a series of comparative in vitro characterizations using advanced analytical techniques. The elemental iron and carbon content, thermal properties, viscosity, particle size, zeta potential, sedimentation coefficient, and molecular weight were determined. There was no noticeable difference between brand and generic SFG in sucrose injection for the above physical parameters evaluated, except for the sedimentation coefficient determined by sedimentation velocity analytical ultracentrifugation (SV-AUC) and molecular weight by asymmetric field flow fractionation-multi-angle light scattering (AFFF-MALS). In addition, brand and generic SFG complex products showed comparable molecular weight distributions when determined by gel permeation chromatography (GPC). The observed minor differences between brand and generic SFG, such as sedimentation coefficient, do not impact their biological activities in separate studies of in vitro cellular uptake and rat biodistribution. Coupled with the ongoing clinical study comparing the labile iron level in healthy volunteers, the FDA-funded post-market studies intended to illustrate comprehensive surveillance efforts ensuring safety and efficacy profiles of generic SFG complex in sucrose injection, and also to shed new light on the approval standards on generic parenteral iron colloidal products.

Investigating the susceptibility of mice to a bacterial challenge after intravenous exposure to durable nanoparticles.

AIM: The goal of this study was to determine whether bacterial clearance in a rodent model would be impaired upon exposure to gold, silver or silica nanoparticles (NPs). MATERIALS & METHODS: Mice received weekly injections of NPs followed by a challenge of Listeria monocytogenes (LM). On days 3 and 10 after LM injections, the animals were sacrificed and their tissues were collected for elemental analysis, electron microscopy and LM count determination. RESULTS: The untreated and NP-treated animals cleared LM at the same rate suggesting that bioaccumulation of NPs did not increase the animals' susceptibility to bacterial infection. CONCLUSION: The data from this study indicate that the bioaccumulation of NPs does not significantly affect the ability to react to a bacterial challenge.

Protein corona composition does not accurately predict hematocompatibility of colloidal gold nanoparticles.

Proteins bound to nanoparticle surfaces are known to affect particle clearance by influencing immune cell uptake and distribution to the organs of the mononuclear phagocytic system. The composition of the protein corona has been described for several types of nanomaterials, but the role of the corona in nanoparticle biocompatibility is not well established. In this study we investigate the role of nanoparticle surface properties (PEGylation) and incubation times on the protein coronas of colloidal gold nanoparticles. While neither incubation time nor PEG molecular weight affected the specific proteins in the protein corona, the total amount of protein binding was governed by the molecular weight of PEG coating. Furthermore, the composition of the protein corona did not correlate with nanoparticle hematocompatibility. Specialized hematological tests should be used to deduce nanoparticle hematotoxicity. From the clinical editor: It is overall unclear how the protein corona associated with colloidal gold nanoparticles may influence hematotoxicity. This study warns that PEGylation itself may be insufficient, because composition of the protein corona does not directly correlate with nanoparticle hematocompatibility. The authors suggest that specialized hematological tests must be used to deduce nanoparticle hematotoxicity.

Inhibition of phosphoinositol 3 kinase contributes to nanoparticle-mediated exaggeration of endotoxin-induced leukocyte procoagulant activity.

AIM: Disseminated intravascular coagulation is an increasing concern for certain types of engineered nanomaterials. Recent studies have shed some light on the nanoparticle physicochemical properties contributing to this toxicity; however, the mechanisms are poorly understood. Leukocyte procoagulant activity (PCA) is a key factor contributing to the initiation of this toxicity. We have previously reported on the exaggeration of endotoxin-induced PCA by cationic dendrimers. Herein, we report an effort to discern the mechanism. MATERIALS & METHODS: Poly(amidoamine) dendrimers with various sizes and surface functionalities were studied in vitro by the recalcification test, flow cytometry and other relevant assays. RESULTS & CONCLUSION: Cationic dendrimers exaggerated endotoxin-induced PCA, but their anionic or neutral counterparts did not; the cationic charge prompts this phenomenon, but different cationic surface chemistries do not influence it. Cationic dendrimers and endotoxin differentially affect the PCA complex. The inhibition of phosphoinositol 3 kinase by dendrimers contributes to the exaggeration of the endotoxin-induced PCA.

Assessing the barriers to image-guided drug delivery.

Imaging has become a cornerstone for medical diagnosis and the guidance of patient management. A new field called image-guided drug delivery (IGDD) now combines the vast potential of the radiological sciences with the delivery of treatment and promises to fulfill the vision of personalized medicine. Whether imaging is used to deliver focused energy to drug-laden particles for enhanced, local drug release around tumors, or it is invoked in the context of nanoparticle-based agents to quantify distinctive biomarkers that could risk stratify patients for improved targeted drug delivery efficiency, the overarching goal of IGDD is to use imaging to maximize effective therapy in diseased tissues and to minimize systemic drug exposure in order to reduce toxicities. Over the last several years, innumerable reports and reviews covering the gamut of IGDD technologies have been published, but inadequate attention has been directed toward identifying and addressing the barriers limiting clinical translation. In this consensus opinion, the opportunities and challenges impacting the clinical realization of IGDD-based personalized medicine were discussed as a panel and recommendations were proffered to accelerate the field forward.

Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment.

The gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer, but it remains unclear whether commensal bacteria affect inflammation in the sterile tumor microenvironment. Here, we show that disruption of the microbiota impairs the response of subcutaneous tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy. In antibiotics-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment and deficient production of reactive oxygen species and cytotoxicity after chemotherapy. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.

A novel gadolinium-based trimetasphere metallofullerene for application as a magnetic resonance imaging contrast agent.

OBJECTIVE: Macromolecular contrast agents for magnetic resonance imaging (MRI) are useful blood-pool agents because of their long systemic half-life and have found applications in monitoring tumor vasculature and angiogenesis. Macromolecular contrast agents have been able to overcome some of the disadvantages of the conventional small-molecule contrast agent Magnevist (gadolinium-diethylenetriaminepentaacetic acid), such as rapid extravasation and quick renal clearance, which limits the viable MRI time. There is an urgent need for new MRI contrast agents that increase the sensitivity of detection with a higher relaxivity, longer blood half-life, and reduced toxicity from free Gd3+ ions. Here, we report on the characterization of a novel water-soluble, derivatized, gadolinium-enclosed metallofullerene nanoparticle (Hydrochalarone-1) in development as an MRI contrast agent. MATERIALS AND METHODS: The physicochemical properties of Hydrochalarone-1 were characterized by dynamic light scattering (hydrodynamic diameter), atomic force microscopy (particle height), ζ potential analysis (surface charge), and inductively coupled plasma-mass spectrometry (gadolinium concentration). The blood compatibility of Hydrochalarone-1 was also assessed in vitro through analysis of hemolysis, platelet aggregation, and complement activation of human blood. In vitro relaxivities, in vivo pharmacokinetics, and a pilot in vivo acute toxicity study were also performed. RESULTS: An extensive in vitro and in vivo characterization of Hydrochalarone-1 is described here. The hydrodynamic size of Hydrochalarone-1 was 5 to 7 nm depending on the dispersing media, and it was negatively charged at physiological pH. Hydrochalarone-1 showed compatibility with blood cells in vitro, and no significant hemolysis, platelet aggregation, or complement activation was observed in vitro. In addition, Hydrochalarone-1 had significantly higher r1 and r2 in vitro relaxivities in human plasma in comparison with Magnevist and was not toxic at the doses administered in an in vivo pilot acute-dose toxicity study in mice.In vivo MRI pharmacokinetic analysis after a single intravenous injection of Hydrochalarone-1 (0.2 mmol Gd/kg) showed that the volume of distribution at steady state was approximately 100 mL/kg, suggesting prolonged systemic circulation. Hydrochalarone-1 also had a long blood half-life (88 minutes) and increased relaxivity, suggesting application as a promising blood-pool MRI contrast agent. CONCLUSIONS: The evidence suggests that Hydrochalarone-1, with its long systemic half-life, may have significant utility as a blood-pool MRI contrast agent.

Biotargeted nanomedicines for cancer: six tenets before you begin.

Biotargeted nanomedicines have captured the attention of academic and industrial scientists who have been motivated by the theoretical possibilities of the 'magic bullet' that was first conceptualized by Paul Ehrlich at the beginning of the 20th century. The Biotargeting Working Group, consisting of more than 50 pharmaceutical scientists, engineers, biologists and clinicians, has been formed as part of the National Cancer Institute's Alliance for Nanotechnology in Cancer to harness collective wisdom in order to tackle conceptual and practical challenges in developing biotargeted nanomedicines for cancer. In modern science and medicine, it is impossible for any individual to be an expert in every aspect of biology, chemistry, materials science, pharmaceutics, toxicology, chemical engineering, imaging, physiology, oncology and regulatory affairs. Drawing on the expertise of leaders from each of these disciplines, this commentary highlights six tenets of biotargeted cancer nanomedicines in order to enable the translation of basic science into clinical practice.