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Achieving efficacious systemic levels of orally administered peptides is incredibly challenging due to the significant barriers to their bioavailability—their stability in the gastrointestinal tract and challenge of transepithelial transit, and variable pharmacokinetics. Even so, as the generally preferred route of administration, significant research effort in academic and industrial settings has focused on enabling the systemic absorption of orally delivered peptides. Despite several decades of research, few have ever reached the market. The recent approval of Rybelsus® (oral semaglutide) by the FDA [1], the EMA [2], and the Pmda [3] represents a significant landmark in the delivery of therapeutic peptides and is the culmination of more than 30 years research and development of the drug delivery technology enabling the product—Emisphere’s Eligen™ technology—and an outstanding commitment to scientific, technical, and clinical innovation by Novo Nordisk. Following years of fundamental and applied research, an innovative clinical strategy led to the aptly named PIONEER clinical programme. This included ten Phase 3 clinical trials that demonstrated the tablet formulation to be as effective as the already approved injectable form of the drug, and more effective than competitor products in terms of its blood glucose lowering effects and weight loss. Not only is this a potentially life changing medicine for diabetic patients, it holds tremendous commercial potential for Novo Nordisk, with some analysts predicting the product to reach $5 billion in peak revenues [3]. In this “Inspirational Note,” we summarize some of the public domain work that led to the achievement of this significant milestone and provide commentary on its potential future impact.

Supplemental Digital Content is available in the text.Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), in the context of hepatocellular carcinoma (HCC) treatment. We studied the effect of vandetanib on proliferation, cell cycle and apoptosis of HCC cells, in hypoxic conditions, as well as the direct effects of the beads on 3D HCC spheroids. Vandetanib suppressed proliferation and induced apoptosis of HCC cells in vitroand was equipotent in hypoxic and normoxic conditions. High degrees of apoptosis were observed among cell lines in which vandetanib suppressed ERK1/2 phosphorylation and upregulated the proapoptotic protein Bim, but this did not appear essential for vandetanib-induced cell death in all cell lines. Vandetanib also suppressed the hypoxia-induced secretion of VEGF from HCC cells and inhibited proliferation of endothelial cells. Incubation of tumour spheroids with VERB led to sustained growth inhibition equivalent to the effect of free drug. We conclude that vandetanib has both antiangiogenic and direct anticancer activity against HCC cells even in hypoxic conditions, warranting the further evaluation of VERB as novel anticancer agents.

ABSTRACTIntroductionDrug-eluting embolic (DEE) microspheres, or drug-eluting beads (DEB), delivered by transarterial chemoembolization (TACE) serve as a therapeutic embolic to stop blood flow to tumors and a drug delivery vehicle. New combinations of drugs and DEE microspheres may exploit the potential synergy between mechanisms of drug activity and local tissue responses generated by TACE to enhance the efficacy of this mainstay therapy.Areas coveredThis review provides an overview of key drug delivery concepts related to DEE microspheres with a focus on recent technological developments and promising emerging clinical applications as well as speculation into the future.Expert opinionTACE has been performed for nearly four decades by injecting chemotherapy drugs into the arterial supply of tumors while simultaneously cutting off their blood supply, trying to starve and kill cancer cells, with varying degrees of success. The practice has evolved over the decades but has yet to fulfill the promise of truly personalized therapies envisioned through rational selection of drugs and real-time multi-parametric image guidance to target tumor clonality or heterogeneity. Recent technologic and pharmacologic developments have opened the door for potentially groundbreaking advances in how TACE with DEE microspheres is performed with the goal of achieving advancements that benefit patients.

Vandetanib-eluting radiopaque beads are well tolerated and show strong antitumor effects in a preclinical model of liver cancer; both the embolic effect and the antiangiogenic drug play roles in the antitumor effects.

Radiopaque drug-eluting beads may be used to estimate drug dose in the liver based on CT images, possibly enabling spatial drug dosimetry and providing insight into the effects of transarterial chemoembolization with drug-eluting beads.

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths worldwide. The standard of care for intermediate HCC is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxia-adapted cancer cells. The transcription factor that orchestrates responses to hypoxia is hypoxia-inducible factor 1 (HIF-1). The aim of this work is to show that targeting HIF-1 with combined drug therapy presents an opportunity for improving outcomes for HCC treatment. HepG2 cells were cultured under normoxic and hypoxic conditions exposed to doxorubicin, rapamycin and combinations thereof, and analyzed for viability and the expression of hypoxia-induced HIF-1α in response to these treatments. A pilot study was carried out to evaluate the antitumour effects of these drug combinations delivered from drug-eluting beads in vivousing an ectopic xenograft murine model of HCC. A therapeutic doxorubicin concentration that inhibits the viability of normoxic and hypoxic HepG2 cells and above which hypoxic cells are chemoresistant was identified, together with the lowest effective dose of rapamycin against normoxic and hypoxic HepG2 cells. It was shown that combinations of rapamycin and doxorubicin are more effective than doxorubicin alone. Western Blotting indicated that both doxorubicin and rapamycin inhibit hypoxia-induced accumulation of HIF-1α. Combination treatments were more effective in vivothan either treatment alone. mTOR inhibition can improve outcomes of doxorubicin treatment in HCC.

Radiopaque microspheres were visible with multiple radiologic imaging modalities during transarterial embolization in the VX2 rabbit liver tumor model and increased conspicuity of tumor location and its feeding arteries.

Context:The development of an improved, efficacious human GH (hGH) product administered by a noninjectable route of delivery such as the nasal route is highly desirable. We have developed a novel nasal hGH product (CP024) that showed excellent nasal absorption in animal models; however, the translation of these results into the clinical setting is essential because past attempts to develop such formulations by other groups have been unable to induce IGF-1 in man.Objective:The objective of the study was to assess the pharmacokinetics, pharmacodynamics, and tolerability of CP024 compared with a sc hGH injection.Design:This was a single-center, nonrandomized placebo-controlled, open-label, five-way crossover study in eight healthy volunteers.Setting:The study was carried out at a contract research organization, Quotient Bioresearch.Volunteers:Eight healthy male volunteers, given an iv infusion of octreotide to suppress the endogenous GH secretion during the study period, participated in the study. No volunteers were withdrawn due to side effects.Main Outcome Measures:Measurement of hGH and IGF-1 levels and tolerability of the drug product was performed.Results:No serious adverse events were reported and no subjects withdrawn from study due to the treatment. After the nasal administration of CP024, 3-fold higher hGH blood levels were obtained as compared with hGH nasal control. The relative bioavailability was about 3%. CP024 (given twice daily) induced a significant increase in IGF-1 levels up to 19 hours after administration, with no significant difference to those obtained after the sc injection of hGH.Conclusions:The study indicates that CP024 is a promising candidate for an efficacious nasal product for the treatment of GH deficiency due to induction of IGF-1 similar to that after a sc injection, despite the lower plasma hGH concentration obtained. A dose-response study is needed to evaluate the optimal nasal dose.

Cell therapy is a field of growing interest in the prevention of post acute myocardial infarction (AMI) heart failure. Stem cell retention upon local delivery to the heart, however, is still unsatisfactory. CellBeads were recently developed as a potential solution to this problem. CellBeads are 170-μm alginate microspheres that contain mesenchymal stem cells (MSCs) genetically modified to express glucagon-like peptide-1 (GLP-1) supplementary to inherent paracrine factors. GLP-1 is an incretin hormone that has both antiapoptotic and cardioprotective effects. Transplanting CellBeads in the post-AMI heart might induce cardiomyocyte salvage and ultimately abrogate adverse cardiac remodeling. We aimed to investigate the feasibility of intracoronary infusion of CellBeads in a large animal model of AMI. Four pigs were used in a pilot study to assess the maximal safe dose of CellBeads. In the remaining 21 animals, an AMI was induced by balloon occlusion of the left circumflex coronary artery for 90 min. During reperfusion, 60,000 CellBeads (n= 11), control beads (n= 4), or lactated Ringers' (n= 6) were infused. Animals were sacrificed after 2 or 7 days, and the hearts were excised for histological analyses. Intracoronary infusion did not permanently affect coronary flow in any of the groups. Histological analysis revealed CellBeads containing viable MSCs up to 7 days. Viability and activity of the MSCs was confirmed by qPCR analysis that showed expression of recombinant GLP-1 and human genes after 2 and 7 days. CellBeads reduced inflammatory infiltration by 29% (p= 0.001). In addition, they decreased the extent of apoptosis by 25% (p= 0.001) after 2 days. We show that intracoronary infusion of 5 million encapsulated MSCs is safe and feasible. Also, several parameters indicate that the cells have paracrine effects, suggesting a potential therapeutic benefit of this new approach.

Drug-eluting beads (DEBs) are becoming a mainstay locoregional therapy for hepatic malignancies but are currently loaded with single drugs alone. Here, we wished to prepare DEB containing different drug combinations, to screen their efficacy using an in-vitro cell culture assay and to include any promising combinations that demonstrate additive efficacy in an in-vivo model of locoregional tumour treatment. A modified in-vitro assay was used based upon the use of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) with either HepG2 liver cancer or PSN1 pancreatic cancer cell lines. The comparative cytotoxicity of DEB combinations prepared containing doxorubicin, irinotecan, topotecan and rapamycin was evaluated. Those combinations that demonstrated an additive cytotoxicity effect were investigated in vivousing a nude mouse xenograft model of pancreatic cancer. Although many of the DEB combinations showed either no effect or a slight antagonistic effect, the combination of doxorubicin and rapamycin DEBs demonstrated synergistic activity. On the basis of these findings, a method was developed to prepare a doxorubicinrapamycin dual-loaded DEB, which was shown to possess the same drug-loading capacities, drug elution properties and HepG2 cell cytotoxicity synergy as the single drug-loaded DEB combination. Evaluation of this dual-loaded combination DEB versus the respective single drug-loaded DEBs in a mouse xenograft model of pancreatic cancer showed an equivalent tumour volume reduction as the doxorubicin DEB, but with less toxicity than the rapamycin DEB. The doxorubicinrapamycin combination DEB offers great potential for enhanced efficacy in the locoregional treatment of malignant tumours.

Introduction:As an essential complement to chemically crosslinked hydrogels, drug delivery systems based on physical hydrogels with self-assembled nanostructures are gaining increasing attention, owing to potential advantages of reduced toxicity, convenience of in situgel formation, stimuli-responsiveness, reversible sol-gel transition, and improved drug loading and delivery profiles.Areas covered:In this review, drug delivery systems based on physical hydrogels are discussed according to their self-assembled nanostructures, such as micelles, layer-by-layer constructs, supramolecular inclusion complexes, polyelectrolyte complexes and crystalline structures. The driving forces of the self-assembly include hydrophobic interaction, hydrogen bonding, electrostatic interaction, π–π stacking and weak van der Waals forces. Stimuli-responsive properties of physical hydrogels, including thermo- and pH-sensitivity, are considered with particular focus on self-assembled nanostructures.Expert opinion:Fabricating self-assembled nanostructures in drug delivery hydrogels, via physical interactions between polymer–polymer and polymer–drug, requires accurately controlled macro- or small molecular architecture and a comprehensive knowledge of the physicochemical properties of the therapeutics. A variety of nanostructures within hydrogels, with which payloads may interact, provide useful means to stabilize the drug form and control its release kinetics.

Nature has the exquisite ability to design specific surface patterns and topologies on both the macro- and nanolength scales that relate to precise functions. Following a biomimetic approach, we have engineered fully synthetic nanoparticles that are able to self-organize their surface into controlled domains. We focused on polymeric vesicles or “polymersomes”; enclosed membranes formed viaself-assembly of amphiphilic block copolymers in water. Exploiting the intrinsic thermodynamic tendency of dissimilar polymers to undergo phase separation, we mixed different vesicle-forming block copolymers in various proportions in order to obtain a wide range of polymersomes with differing surface domains. Using a combination of confocal laser scanning microscopy studies of micrometer-sized polymersomes, and electron microscopy, atomic force microscopy, and fluorescence spectroscopy on nanometer-sized polymersomes, we find that the domains exhibit similar shapes on both the micro- and nanolength scales, with dimensions that are linearly proportional to the vesicle diameter. Finally, we demonstrate that such control over the surface “patchiness” of these polymersomes determines their cell internalization kinetics for live cells.

Introduction:DC Bead is an embolic drug-eluting bead designed to be loaded with chemotherapeutic agents (such as doxorubicin and irinotecan), delivered intra-arterially into tumor blood vessels to block nutrient flow and then to deliver the drug locally in a sustained fashion. This product is finding increasing use in the treatment of patients with both primary and secondary liver cancers.Areas covered:This review positions DC Bead in the field of targeted embolic drug delivery and with respect to other competitive technologies in the treatment of liver cancer. An overview of the studies that demonstrate the product's performance, safety and efficacy is presented. The clinical application of the doxorubicin loaded DC Bead is firstly reviewed, in the context of treatment of patients with various stages of hepatocellular carcinoma. Its combination with other therapies is also discussed, together with consideration of the treatment of other liver tumors. Secondly, the use of irinotecan loaded DC Bead, primarily for the treatment of colorectal cancer metastases to the liver, but also some additional rare metastases, is summarized.Expert Opinion:An opinion is proffered as to how this technology and its application is evolving, illustrating a move towards synergistic combination therapies and into other cancer indications.

Shell shock: The one‐pot synthesis of shell cross‐linked (SCL) micelles was achieved using an ABC triblock copolymer in a 9:1 alcohol/water mixture. These SCL micelles were dialyzed against water, leading to solvation of the core‐forming PMPC chains. If the cross‐linking is not too high, these chains migrate through the inner shell to join the coronal PEO chains, hence forming nanocages.

Antisense therapy has been investigated extensively over the past two decades, either experimentally for gene functional research or clinically as therapeutic agents owing to the conceptual simplicity, ease of design and low cost. The concept of this therapeutic approach is promising because short antisense oligonucleotides (ASOs) can be delivered into target cells for specific hybridisation with target mRNA, resulting in the inhibition of the expression of pathogenic genes. However, the efficient delivery of the ASO molecules into target cells remains challenging; this bottleneck together with several other technical hurdles need to be overcome before this approach becomes effective and widely adopted. A variety of vectors such as lipids, polymers, peptides and nanoparticles have been explored. This review outlines the recent advances of the non-viral ASO delivery strategies. Several recent scientific studies, including authors' contributions, have been selected to highlight the technical aspects of ASO delivery.

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Hydrogel polymers incorporating phosphorylcholine have found widespread use in the manufacture of medical devices with improved haemo- and biocompatibility. Examples include soft contact lenses or coatings for devices, such as coronary stents and extracorporeal circuits. The advent of drug-device combinations has prompted the application of PC Technology™ (Biocompatibles UK Ltd) as a bioinert drug delivery vehicle, particularly in the form of coatings, for targeted delivery from a device surface. The flexible polymer chemistry employed in the synthesis of these materials offers a range of molecular architectures that could find applicability in a wide variety of drug delivery applications, including micellar, vesicular and gel systems, and even drug conjugation.

Corn (Zea maysL.) hybrids may show different silage quality responses to harvest date and cutting height because hybrids differ in neutral detergent fiber (NDF) digestibility. A brown midrib, leafy, and dual‐purpose hybrid were harvested at early [≈280 g kg−1dry matter (DM) content], medium (≈350 g kg−1), and late (≈420 g kg−1) harvest dates at 15‐, 30‐, and 46‐cm cutting heights in 2001 and 2002 to determine optimum harvest management for each hybrid type. Most forage quality characteristics had hybrid × harvest date interactions as indicated by the 73 g kg−1decrease in NDF digestibility of the brown midrib compared with 20 g kg−1decreases of the other hybrids between the early and late harvest date. Milk per megagram, a forage quality index, declined (1523, 1487, and 1417 kg Mg−1), but DM yields increased (13.2, 13.6, and 14.1 Mg ha−1), so calculated milk yields were similar (20333, 20200, and 20233 kg ha−1) at early, medium, and late harvest dates, respectively, suggesting a broad optimum DM content for harvest. The sharp decline in NDF digestibility, however, raises concern about harvesting the brown midrib hybrid above 350 g kg−1DM content. Calculated milk yield had a hybrid × cutting height interaction, as indicated by no change in the leafy hybrid and a 13% decrease in the brown midrib hybrid as cutting height increased from 15 to 46 cm. This suggests that an increase in cutting height may be a good management practice for the leafy hybrid but not for the brown midrib hybrid.

A major limitation in the construction of a functional engineered liver is the short-term survival and rapid de-differentiation of hepatocytes in culture. Heterotypic cell-cell interactions may have a role to play in modulating long-term hepatocyte behavior in engineered tissues. We describe the potential of 3T3 fibroblast cells in a co-culture system to modulate function and viability of primary isolated rat hepatocytes. Over an 18-day period after isolation, hepatocytes in pure culture rapidly declined in viability, displayed sparse bile canaliculi, and lost two function markers, the secretion of albumin and ethoxyresorufin O-dealkylase (EROD) activity. In comparison, the hepatocytes within the co-cultures maintained viability, possessed well-formed canalicular systems, and displayed both functional markers. Fixed 3T3 cells or 3T3 cell conditioned medium did not substitute for the viable 3T3 cell co-culture system in preserving hepatocyte viability and functionality.

Discusses a historical overview of naval aviation in the United States. Legislative foundation of the national defense system; Highlights of the legislative investigations of October 1949; Scope of power and duties of the military services; Debate over the importance of the various services; Rivalry between the Navy and Air Force departments.

Therapeutic embolotherapy is the deliberate occlusion of a blood vessel within the body, which can be for the prevention of internal bleeding, stemming of flow through an arteriovenous malformation, or occlusion of blood vessels feeding a tumor. This is achieved using a wide selection of embolic devices such as balloons, coils, gels, glues, and particles. Particulate embolization is often favored for blocking smaller vessels, particularly within hypervascularized tumors, as they are available in calibrated sizes and can be delivered distally via microcatheters for precise occlusion with associated locoregional drug delivery. Embolic performance has been traditionally evaluated using animal models, but with increasing interest in the 3R's (replacement, reduction, refinement), manufacturers, regulators, and clinicians have shown interest in the development of more sophisticated in vitro methods for evaluation and prediction of in vivo performance. Herein the current progress in developing bespoke techniques incorporating physical handling, fluid dynamics, occlusive behavior, and sustained drug elution kinetics within vascular systems is reviewed. While it is necessary to continue to validate the safety of such devices in vivo, great strides have been made in the development of bench tests that better predict the behavior of these products aligned with the principles of the 3R's. Particulate embolizationis used to block blood vessels, particularly within hypervascularized tumors, as they are available in calibrated sizes and can be delivered distally via microcatheters for precise occlusion with optional locoregional drug delivery. The current progress in development of bespoke techniques incorporating physical handling, fluid dynamics, occlusive behavior, and sustained drug elution kinetics within vascular systems is reviewed.

We report the synthesis of novel biomimetic gelators with star diblock copolymer architectures by sequential monomer addition viaalcoholic ATRP at 20 °C; free-standing gels can be formed from 5 aqueous copolymer solutions at 37 °C.

N,N′-Substituted amines (as illustrated using TMEDA) will react with a short chain 2-alkoxy-2-oxo-1,3,2-dioxaphospholane, to form a stabilised phospholane salt and not the corresponding phosphobetaine as anticipated.