Future Delivery Systems Research Articles

Chinese nuclear weapons, 2024

ABSTRACT The modernization of China’s nuclear arsenal has both accelerated and expanded in recent years. In this issue of the Nuclear Notebook, we estimate that China now possesses roughly 500 nuclear warheads, with more in production to arm future delivery systems. China is now believed to have one of the fastest-growing nuclear arsenals among the nine nuclear-armed states. The Nuclear Notebook is researched and written by the staff of the Federation of American Scientists’ Nuclear Information Project: director Hans M. Kristensen, senior research fellow Matt Korda, research associate Eliana Johns, and Herbert Scoville Jr. peace fellow Mackenzie Knight. To see all previous Nuclear Notebook columns in the Bulletin of the Atomic Scientists dating back to 1987, go to https://thebulletin.org/nuclear-notebook/.

Electrochemical DNA-Sensor Based on Macrocyclic Dendrimers with Terminal Amino Groups and Carbon Nanomaterials.

The assembling of thiacalix[4]arene-based dendrimers in cone, partial cone, and 1,3-alternate configuration on the surface of a glassy carbon electrode coated with carbon black or multiwalled carbon nanotubes has been characterized using cyclic voltammetry, electrochemical impedance spectroscopy, and scanning electron microscopy. Native and damaged DNA were electrostatically accumulated on the modifier layer. The influence of the charge of the redox indicator and of the macrocycle/DNA ratio was quantified and the roles of the electrostatic interactions and of the diffusional transfer of the redox indicator to the electrode interface indicator access were established. The developed DNA sensors were tested on discrimination of native, thermally denatured, and chemically damaged DNA and on the determination of doxorubicin as the model intercalator. The limit of detection of doxorubicin established for the biosensor based on multi-walled carbon nanotubes was equal to 1.0 pM with recovery from spiked human serum of 105-120%. After further optimization of the assembling directed towards the stabilization of the signal, the developed DNA sensors can find application in the preliminary screening of antitumor drugs and thermal damage of DNA. They can also be applied for testing potential drug/DNA nanocontainers as future delivery systems.

Encapsulating melittin from animal venom by finely tuned charge compensation with polymer carriers

Due to their wide availability, polypeptide/protein venoms produced by certain insects are of high interest as potential active pharmacological ingredients; however, the number of clinical studies on these venoms remains poor. In this paper, we describe an extremely efficient platform to form polyplexes from cationic amphiphilic animal venoms, such as the hemolytic poison melittin. The idea is based on supramolecular melittin cationic charge compensation with nanoparticles (micelles composed of hydrophobic glassy polystyrene core and hydrophilic poly(meth)acrylic acid corona, PMA and PAA acid homopolymers) with high anion charge density at physiological pH. An instant “mix and go” process and efficient melittin complexation with nanoparticles at concentrations down to micrograms per milliliter of PBS solution was achieved and proven by inhibition of melittin-induced hemolysis. We studied in detail how the structural features of the nanoparticles influence their potency; we found that the most important parameter is the number of carboxylates in the polyanion chain (proportional to the molecular weight and length of the anionic poly(meth)acrylic acid block). The poly(meth)acrylic acid-based polymer nanoparticles may be useful as melittin (and possibly other cationic amphiphilic animal venoms) antidotes but also as models for constructing future delivery systems to apply the venoms therapeutically.

The impacts of automated urban delivery and consolidation

Automation in urban freight transport is an important milestone for city logistics, but it is challenging due to the complex traffic situations. While the parcel volume is soaring due to the popularity of e-commerce – and especially accelerated by COVID, cities are thinking about the future delivery system. Automation and consolidation are expected to bring disruptive changes to the system we know today. The aim of the present paper is to provide an insight in the impact assessment method used and the results related to parcel delivery in Vienna. By applying analytical methods, we show which impacts at what magnitude we may expect from the changes brought by automation in freight transport. We consider the direct impacts consisting of fleet size, freight mileage and fleet operation costs, as well as the wider impacts consisting of parking space, public health and road safety.

Solid Self-Nano Emulsifying Nanoplatform Loaded with Tamoxifen and Resveratrol for Treatment of Breast Cancer.

The solid self-nanoemulsifying drug delivery system (s-SNEDDS) is a growing platform for the delivery of drugs via oral route. In the present work, tamoxifen (TAM) was loaded in SNEDDS with resveratrol (RES), which is a potent chemotherapeutic, antioxidant, anti-inflammatory and P-gp inhibitor for enhancing bioavailability and to obtain synergistic anti-cancer effect against breast cancer. SNEDDS were developed using capmul MCM as oil, Tween 80 as surfactant and transcutol-HP as co-surfactant and optimized by central composite rotatable design. Neusilin US2 concentration was optimized for adsorption of liquid SNEDDS to prepare s-SNEDDS. The developed formulation was characterized and investigated for various in vitro and cell line comparative studies. Optimized TAM-RES-s-SNEDDS showed spherical droplets of a size less than 200 nm. In all in vitro studies, TAM-RES-s-SNEDDS showed significantly improved (p ˂ 0.05) release and permeation across the dialysis membrane and intestinal lumen. Moreover, TAM-RES-s-SNEDDS possessed significantly greater therapeutic efficacy (p < 0.05) and better internalization on the MCF-7 cell line as compared to the conventional formulation. Additionally, oral bioavailability of TAM from SNEDDS was 1.63 folds significantly higher (p < 0.05) than that of combination suspension and 4.16 folds significantly higher (p < 0.05) than TAM suspension. Thus, findings suggest that TAM- RES-s-SNEDDS can be the future delivery system that potentially delivers both drugs to cancer cells for better treatment.

A Detailed Microscopic Insight into the Aggregation Behaviors of Doxorubicin Hydrochloride in Different Microheterogeneous Media

In recent time periods, a large portion of research interests include the study of aggregation properties of different amphiphilic molecules and the resulting morphological architectures due to their significant applications in diverse research fields. The aggregation behaviors of different biomolecules are also very much important and thus recently become the cup of tea to a large number of research communities. In this respect, the aggregation result of potentially important chemotherapeutic molecule, doxorubicin hydrochloride (Dox) in a conventional imidazolium based surface active ionic liquid (SAIL), 1-octyl-3-methylimidazolium chloride (C8mimCl) was studied in details. The complete characterizations using dynamic light scattering (DLS), different microscopic techniques like fluorescence lifetime imaging microscopy (FLIM), transmission electron microscopy (HR-TEM and analytical TEM), field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) with fourier-transform infrared spectroscopy (FTIR) measurements revealed the formation of large spherical vesicular Dox/C8mimCl aggregates. The guiding forces behind such SAIL induced aggregation of Dox were also explored. Finally a common bile salt, sodium cholate (NaCh) was observed to transform Dox/C8mimCl spherical aggregates to rod like fibrillar aggregates. In summary, the aggregation of Dox in microheterogeneous medium of C8mimCl SAIL to spherical vesicular aggregates and also the bile salt induced disruption into rod like fibrillar aggregates were studied in detail. The formation and disruption of Dox forming vesicular aggregates can be modeled as a new generation future delivery system for biologically important molecules with smart loading and release phenomena where the biomolecule itself aggregates to form the delivery system.

BioTM buzz.

This special issue of Bioengineering & Translational Medicine focuses on the development of bioengineered therapeutics; specifically, design and discovery approaches, delivery platforms, and synthesis and manufacturing technologies. These three areas are essential in ensuring the successful clinical translation of new biotechnologies. As such, this first BioTM Buzz will highlight an article in each of these important areas—two articles from this special issue and another from the recent literature. Design and discovery approaches are essential in isolating and selecting lead candidates that hold promise as robust therapeutics. In this issue of Bioengineering & Translational Medicine, engineers from the Jennifer Cochran lab at Stanford University describe an approach to engineer vascular endothelial growth factor (VEGF) for increased binding affinity to vascular endothelial growth factor receptor 2 (VEGFR2), which inhibits VEGF-mediated signaling and thereby reduces angiogenesis. The authors had previously reported the design of VEGF-proteins that enhance VEGF's natural antiangiogenesis properties. In the current study, high-throughput yeast surface display was used to generate highly-potent VEGF-proteins that exhibit enhanced binding affinity to VEGFR2. Enhanced binding of VEGF-variants was confirmed in mammalian cells, which also led to inhibition of VEGF-mediated cell signaling and angiogenic processes in mice. The versatile approach will find utility in the design of new therapeutics to optimize ligand–receptor interactions or to improve binding interactions for already-approved or currently investigated protein-based therapeutics in the clinic. DOI: 10.1002/btm2.10051 Biological barriers and other physiological challenges often limit the ability of therapeutics to interact optimally, or at all, with diseased tissues. Chemical engineer Julie Champion and coworkers from the Georgia Institute of Technology describe methods to systematically investigate how the physical properties of particle-based drug delivery systems influence their fate and function. The particle-based drug delivery systems that have been clinically approved or investigated each possess unique physicochemical properties; as such, defining particle properties that exhibit enhanced biological performance in humans is a significant challenge that if addressed could aid in the design of future delivery systems. In the current study, a layer-by-layer templating approach that enabled control over particle size, shape, and stiffness, while maintaining identical surface chemistry, was used to investigate the individual and combined contributions these modifications have on particle internalization by macrophages. Complex relationships between size, shape, and stiffness were revealed—for example, spherical particles of increased size exhibited reduced internalization by macrophages, while modifications to stiffness exhibited no differences in internalization. The implications described in this paper highlight how current efforts in particle-delivery must consider all physicochemical properties of particles in tandem, since the interplay between these properties and their biological performance is a complex relationship. DOI: 10.1002/btm2.10052 Synthesis and manufacturing technologies that enable the scaled-synthesis of both therapeutics and delivery platforms are a prerequisite for clinical impact. Often times, complex approaches at the lab-scale face difficulties in translation towards industrial and commercial processes. An approach developed by Eric Appel at Stanford University and collaborators including Robert Langer at the Massachusetts Institute of Technology enables the scalable manufacturing of hydrogel materials with complex viscoelastic properties. Hydrogels are widely used as a vehicle to enable the controlled release of drugs in a variety of delivery applications. However, cost issues and scalability related to consistency of the synthesized hydrogels have limited their clinical translation. In this study, hydrogels are formed by mixing polymers and hard nanoparticles (the authors report the linear scaled-synthesis of up to 15 L using this self-assembly process); since polymer adsorption to nanoparticles is transient and reversible the resulting hydrogels exhibit both shear-thinning and self-healing properties. These shear-thinning hydrogels have great potential for biotechnology applications since they can be readily injected and capable of flowing under high stress, but then form a gel when relaxed. The approach described represents a strategy that could be readily translated to enable the large-scale synthesis of hydrogels for biomedical applications, such as combination therapies relying on the delivery of drugs of distinct physical properties. Yu et al., Proc Natl Acad Sci USA. 2016; doi: 10.1073/pnas.1618156113

Advanced drug delivery via self-assembled monolayer-coated nanoparticles

Nanotechnology has greatly enhanced the field of medicine over the last decade. Within this field, advances in nanoparticle research have rendered them attractive candidates for drug delivery. Consequently, controlling the chemistry that occurs at the nanoparticle interface influences the efficiency of the drug-delivery system. In this review, we explore the role of coating materials, in the form of self-assembled monolayers (SAMs), in enhancing the interfacial properties of nanoparticles. We discuss how SAMs enhance the properties of particles, such as stability and dispersibility, as well as provide a platform for delivering biomolecules and other therapeutic agents. In addition, we describe recent methods for generating nanoparticles with targeted surface functionality using custom-designed SAMs. These functionalities offer marked advances to the three stages of a drug-delivery system: loading, delivery, and release of therapeutic molecules. A suitable functionalization strategy can provide a means for covalent or non-covalent immobilization of drug molecules. Moreover, a robust coating layer can aid the encapsulation of drug molecules and inhibit molecular degradation during the delivery process. A stimuli-responsive SAM layer can also provide an efficient release mechanism. Thus, we also review how stimuli-responsive coatings allow for the controlled release of therapeutic agents. In addition, we discuss the merits and limitations of stimuli-responsive SAMs as well as possible strategies for future delivery systems. Overall, advances in this research area allow for developing novel drug delivery methodologies with high efficiency and minimal toxicity.

High-Velocity Impact of Encased Al/PTFE Projectiles on Structural Aluminum Armor

In support of the U.S. Army's science and advanced technology objective in hypervelocity penetration mechanics, the Army Research Laboratory has been studying the terminal ballistics of conventional and non-conventional high-velocity kinetic energy projectiles against urban, light-armor and heavy-armor targets. The purpose is to identify and analyze both mechanisms and concepts to effectively defeat a range of targets with inert payloads using the elevated impact velocities available from future delivery systems. To this end, a series of experiments has been performed launching low-aspect-ratio aluminum and steel cylindrical projectiles, aluminum conical projectiles, and encased reactive material projectiles, with nominal masses between 200 and 240-gm, striking finite aluminum armor at nominal velocities of 2100 m/s to observe crater and spall formation and to determine the damage capacity of the debris.

Cells as delivery vehicles for cancer therapeutics.

Cell-based therapeutics have advanced significantly over the past decade and are poised to become a major pillar of modern medicine. Three cell types in particular have been studied in detail for their ability to home to tumors and to deliver a variety of different payloads. Neural stem cells, mesenchymal stem cells and monocytes have each been shown to have great potential as future delivery systems for cancer therapy. A variety of other cell types have also been studied. These results demonstrate that the field of cell-based therapeutics will only continue to grow.

Anesthesiologists and the Transformation of the Healthcare System

Anesthesiologists and the Transformation of the Healthcare System

Why is the nanoscale special (or not)? Fundamental properties and how it relates to the design of nano-enabled drug delivery systems

AbstractNanoscience studies describe natural phenomena at the submicron scale. Below a critical nanoscale limit, the physical, chemical, and biological properties of materials show a marked departure in their behavior compared to the bulk. At the nanoscale, energy conversion is dominated by phonons, whereas at larger scales, electrons determine the process. The surface-to-volume ratio at the nanoscale is immense, and interfacial interactions are markedly more important than at the macroscopic level, where the majority of the material is shielded from the surface. These properties render the nanoparticles to be significantly different from their larger counterparts. Nano-enabled drug delivery systems have resulted from multidisciplinary cooperation aimed at improving drug delivery. Significant improvements in the thermodynamic and delivery properties are seen due to nanotechnology. Hybrid nanodelivery systems, i.e., membranes with nanopores that can gate stimuli-responsive drug release could be a future development. Nanotechnology will improve current drug delivery and create novel future delivery systems. The fundamental properties and challenges of nanodelivery systems are discussed in this review.

Development of siRNA-probes for studying intracellular trafficking of siRNA nanoparticles.

One important barrier facing the delivery of short interfering RNAs (siRNAs) via synthetic nanoparticles is the rate of nanoparticle disassembly. However, our ability to optimize the release kinetics of siRNAs from nanoparticles for maximum efficacy is limited by the lack of methods to track their intracellular disassembly. Towards this end, we describe the design of two different siRNA-based fluorescent probes whose fluorescence emission changes in response to the assembly state of the nanoparticle. The first probe design involves a redox-sensitive fluorescence-quenched probe that fluoresces only when the nanoparticle is disassembled in a reductive environment. The second probe design is based on a FRET-labeled siRNA pair that fluoresces due to the proximity of the siRNA pair when the nanoparticle is intact. In both approaches, the delivery vehicle need not be labeled. The utility of these probes was investigated with a lipidoid nanoparticle (LNP) as proof-of-concept in both extracellular and intracellular environments. Fluorescence kinetic data from both probes were fit to a two-phase release and decay curve and subsequently quantified to give intracellular disassembly rate constants. Quantitative analysis revealed that the rate constant of siRNA release measured via the fluorescence-quenched probe was almost identical to the rate constant for nanoparticle disassembly measured via the FRET-labeled probes. Furthermore, these probes were utilized to determine subcellular localization of LNPs with the use of automated high-resolution microscopy as they undergo dissociation. Interestingly, this work shows that large amounts of siRNA remain inside vesicular compartments. Altogether, we have developed new siRNA probes that can be utilized with multiple nanocarriers for quantitative and qualitative analysis of nanoparticle dissociation that may serve as a design tool for future delivery systems.

Inclusion of Engineering Economy Concepts and Techniques in B.S. Engineering Curricula

This article presents a summary of an audience-panel member open discussion session conducted at the 2010 ASEE Annual Conference in Louisville, Kentucky. The discussion centered around three topics: concepts and techniques to include in all undergraduate engineering economy courses; current and future delivery systems most helpful in discipline-specific and service courses; and, some action items to move forward. After the conference, each panel member developed a brief statement on a related topic of his or her choice. Included in the article following the discussion summary, the statements focus on several current engineering economy topics: how we teach and should teach engineering economy; use of spreadsheets and web-based materials in teaching; and, ABET guidelines concerning coverage of economic principles.

Vorst AV, Rosen A, Kotsuka Y: RF/Microwave Interaction with Biological Tissues

Vorst AV, Rosen A, Kotsuka Y: RF/Microwave Interaction with Biological Tissues

By gum – a buccal delivery system: Private prescription: A thought-provoking tonic on the lighter side

Rayomd C. Rowe on the history of chewing gum and its potential as a current and future delivery system for active ingredients that provide healthcare benefits.

Direct compressible polymethacrylic acid–starch compositions for site-specific drug delivery

The purpose of this study was to generate and characterize a direct compressible pH-sensitive excipient composition for controlled drug delivery. In acidic aqueous solutions, polymethacrylic acid (PMAA) forms complexes and precipitates with starch. As the extent of the interaction between PMAA and starch reaches a maximum at a weight ratio of 1:1.38 (PMAA/starch), this composition was used for the direct compression of tablets. These tablets (30 mg) showed no disintegration even after 2 days in a disintegration test apparatus according to the USP XXIII, in simulated gastric fluid at pH 1.2. In contrast, in 100 mM phosphate buffer pH 7.0 they disintegrated within 40.25±8.42 min (mean±S.D., n=3). Control tablets of starch disintegrated within the first minute at both pH values. Dissolution studies with the model peptide peroxidase demonstrated no release within 120 min at pH 1.2, whereas at pH 7.0, 100% of the peptide was released within 330 min. Similar release profiles were obtained with the model drugs amoxicillin and rifampicin. In addition, the use of a PMAA–starch composition as a carrier matrix for peroxidase and amoxicillin provided a protective effect towards pepsin and hydrolytic degradation at pH 1.2, respectively. According to these results, the PMAA–starch composition may be a useful tool to overcome the very harsh environment of the stomach for future delivery systems.

FEATURE: From Product to Behavior

Most traditional construction contracts document the purchase of a product in the form of a constructed facility, but construction is about service as well as products. More and more, project delivery systems are recognizing the dual aspects of a construction project and specifying behaviors as well as an end project. Changes to project delivery systems are essentially the recognition of the behavior aspects of the contracts that tie contractors together. Typical project roles include the investment management team, the project management team, contractor management teams, work managers, and work management teams. Program managers must be more broadly based and knowledgeable about specific technologies, as well as about finance, design, construction, and operations. Managers need experience in both the public and the private sector and must be professionals who can work for the project, instead of a specific partner's interests. Perhaps future contracts will be more like employment agreements. The contracting parties will not be directly responsible for the end product but rather will have responsibility for supplying the key managers to lead the various teams. Future delivery systems will concentrate more on teaming and behavior and less on buying a final product.

LASERS FOR THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA

In our experience, efficacy favors the TURP and safety the laser. Unlike balloon dilatation of the prostate, there are likely to be technologic advancements that will allow more efficient tissue ablation, which will presumably result in more TURP-like efficacy. In addition, each of the many side-firing fibers has different physical properties that require fiber specific dosimetry studies. It is not clear how this will impact clinical efficacy; however, it is presumed that this will optimize efficacy while maintaining safety and minimizing catheterization time and postoperative irritative symptoms. VLAP is the surgical procedure of choice in high-risk patients and is an effective alternative for the treatment of symptomatic BPH. In high-risk patients, other devices such as stents may play an important role. From our assessment, TURP seems to provide greater symptomatic relief and probably is more durable than the VLAP procedure. Patients will often choose VLAP over TURP because of the lower risks of major complications and the perceived advantages of laser therapy over more conventional surgery. Other ablation techniques that are less invasive, more efficient, or do not require anesthesia but have equivalent efficacy could challenge the role of laser devices. Similarly, the continued development of more effective medical therapy will continue to challenge the role of all surgical interventions for BPH. Future investigations will focus on issues of dosimetry, tissue coagulation versus vaporization as well as fiber design and durability. The continued efforts to define the optimal technique reflect the general perception of the urologic community to improve the clinical outcome so that efficacy is more TURP-like. New delivery systems are being investigated as part of the effort to improve outcome. This includes the use of the holmium and diode lasers. The efficacy of these future delivery systems awaits proper study.

The health care professional's workstation: a call to action

The environment of health care delivery is changing dramatically, matched by design trends in the organizations that are responsible for care delivery, whether at the hospital or the national level. However, the emerging goals of these organizations have a certain amount of uniformity independent of background, cultural assumptions or organizational size: they are all committed to the delivery of services that maximize satisfaction of system beneficiaries at a minimum of expense. Achievement of these goals will in part require the development of a management and delivery coordination infrastructure that links the key resource utilizers and administrative operators at the point of production. Merged computer and telecommunications systems connecting at user interface nodes called workstations represent a critical enabling technology for meeting the organizational goals described above. Future delivery systems will need to provide compassionate care, retaining the most highly regarded traditions of medical practice without ignoring considerations of cost, clinical outcome and financial sustainability. This paper describes some of the limitations of the current delivery system, and attempts to identify key design concepts and paradigms that might serve to guide future system development.