Encapsulation of semiconducting polymers in vault protein cages

We demonstrate that a semiconducting polymer [poly(2-methoxy-5-propyloxy sulfonate phenylene vinylene), MPS-PPV] can be encapsulated inside recombinant, self-assembling protein nanocapsules called "vaults". Polymer incorporation into these nanosized protein cages, found naturally at approximately 10,000 copies per human cell, was confirmed by fluorescence spectroscopy and small-angle X-ray scattering. Although vault cellular functions and gating mechanisms remain unknown, their large internal volume and natural prevalence within the human body suggests they could be used as carriers for therapeutics and medical imaging reagents. This study provides the groundwork for the use of vaults in encapsulation and delivery applications.     

Assessment of the Structural Response of Masonry Cross Vaults

Cross vaults have been used extensively in the roofing of medieval buildings. Knowledge of the behaviour of cross vaults under load is fundamental for the planning of structurally compatible and economic conservation programmes. A method is presented here to assess their safety under various loading conditions. A 1/4‐scale model was built in wood, representing an aisle vault of the partially collapsed Abbey Church of Holyrood in Edinburgh. The structure was loaded with dead weight and deformations and strains were recorded. Subsequently, the abutments were allowed to move progressively to cause the collapse of the vault. Finite element modelling was employed to interpret the experimental pattern, confirming the collapse of the vault was due to the development of hinges along the transverse vertex and the front abutments and membrane cracks at the back groins.     

Liposome nano‐formulation with cationic polar lipid DOTAP and cholesterol as a suitable pH‐responsive carrier for molecular therapeutic drug (all‐trans retinoic acid) delivery to lung cancer cells

The molecular targeted drug ATRA demands a suitable carrier that delivers to the cancer site due to its poor bioavailability and drug resistance. ATRA, being a lipid with carboxylic acid, has been nano‐formulated as a cationic lipo‐ATRA with DOTAP:cholesterol:ATRA (5:4:1) and its pH‐responsive release, intracellular drug accumulation, and anticancer effect on human lung cancer (A549) cell line analysed. The analysis of the physicochemical characteristics of the developed lipo‐ATRA (0.8 µmol) revealed that the size of 231 ± 2.35 d.nm had a zeta potential of 6.4 ± 1.19 and an encapsulation efficiency of 93.7 ± 3.6%. The ATRA release from lipo‐ATRA in vitro was significantly (p ≤ 0.05) higher at acidic pH 6 compared to pH 7.5. The intracellular uptake of ATRA into lipo‐ATRA‐treated A549 cells was seven‐fold higher (0.007 ± 0.001 mg/ml) while only three‐fold uptake was observed in free ATRA treatment (0.003 ± 0.002 mg/ml). The lipo‐ATRA treatment caused a highly significant (p ≤ 0.001) decrease in percent cell viability at 48 h when compared with the free ATRA treatment. Overall, the results proved that the developed lipo‐ATRA has suitable physicochemical properties with enhanced ATRA release at acidic pH, while maintaining stability at physiologic pH and temperature. This resulted in an increased ATRA uptake by lung cancer cells with enhanced treatment efficiency. Hence, it is concluded that DOTAP lipo‐ATRA is a suitable carrier for ATRA delivery to solid cancer cells.     

A review on parenteral delivery of peptides and proteins

The recent advances in pharmaceutical industry in the area of drug delivery and development have resulted into wide variety of biomolecules, particularly peptides and proteins, to palliate the treatment for severe diseases. The rampant development of peptides and proteins in industry mandate the understanding of their characteristic nature and developability. Despite their therapeutic potential, peptides and proteins pose complex challenges in drug delivery and require scientist to contemplate to achieve suitable delivery system. As most of the commercial products for proteins and peptides are available as a parenteral delivery and freeze drying process is one commonly used technique, it is imperative to understand the complex steps of development for better and faster product development. This review provides an overview of the stability and formulation development for peptides and proteins. The most common route for protein delivery, parenteral, has been focused on parenteral solution and lyophilization as formulation strategy. Additionally, new drug delivery and half-life extension approaches will further the reach of this unique class of molecules. Efforts are underway to explore the area with new technologies and development.     

An approach to the positioning of FRP provisions in vaulted masonry structures

In the paper, one starts from a theoretical formulation aimed at analysing masonry vaults by selecting, in an inverted approach, families of load shapes that may be equilibrated by sets of admissible solutions, in order to develop an operative method for the positioning of FRP reinforcements in masonry vaulted constructions. On the basis of this premise a strategy is outlined for identifying the areas of the vault to be selected for introducing the FRP provisions. As shown in the numerical investigation, higher intensities of the stress state are then allowed by the introduction of the reinforcement and the local relaxation of some of the constraints of the problem is possible.     

Reversible pH lability of cross-linked vault nanocapsules

Vaults are ubiquitous, self-assembled protein nanocapsules with dimension in the sub-100 nm range that are conserved across diverse phyla from worms to humans. Their normal presence in humans at a copy number of over 10,000/cell makes them attractive as potential drug delivery vehicles. Toward this goal, bifunctional amine-reactive reagents are shown to be useful for the reversible cross-linking of recombinant vaults such that they may be closed and opened in a controllable manner.     

Cellulose acetate microspheres as floating depot systems to increase gastric retention of antidiabetic drug: formulation, characterization and in vitro-in vivo evaluation

Gastric emptying is a complex process that is highly variable and makes the in vivo performance of drug delivery systems uncertain. In order to avoid this variability, efforts have been made to increase the retention time of the drug delivery systems for more than 12 hours utilizing floating or hydrodynamically controlled drug delivery systems. The objective of this investigation was to develop a floating, depot-forming drug delivery system for an antidiabetic drug based on microparticulate technology to maintain constant plasma drug concentrations over a prolonged period of time for effective control of blood sugar levels. Formulations were optimized using cellulose acetate as the polymer and evaluated in vitro for physicochemical characteristics and drug release in phosphate buffered saline (pH 7.4), and evaluated in vivo in healthy male albino mice. The shape and the surface morphology of the prepared microspheres were characterized by optical microscopy and scanning electron microscopy. In vitro drug release studies were performed and drug release kinetics were calculated using the linear regression method. Effects of stirring rate during preparation and polymer concentration on the size of microspheres and drug release were observed. The prepared microspheres exhibited prolonged drug release (more than 10 hours) and remained buoyant for over 10 hours. Spherical and smooth-surfaced microspheres with encapsulation efficiency ranging from 73% to 98% were obtained. The release rate decreased and the mean particle size increased at higher polymer concentrations. Stirring speed affected the morphology of the microspheres. This investigation revealed that upon administration, the biocompatible depot-forming polymeric microspheres controlled the drug release and plasma sugar levels more efficiently than plain orally given drug. These formulations, with their reduced frequency of administration and better control over drug disposition, may provide an economic benefit to the user compared with products currently available for diabetes control.     

Determining the ultimate load of historic masonry arches by using eccentricity charts

The eccentricity charts presented in this paper have been developed on the basis of experimental investigations in order to enable a realistic calculation method of the ultimate load of flat brickwork vaulted floors with standard structural software. The vault is modelled as a three‐hinged arch with eccentric hinges in order to thus represent the non‐linear behaviour of the load‐bearing structure. Furthermore the hinge configuration, which is adapted with the eccentricity charts, takes into account the degree of plastification of historic masonry, existing load‐induced damage, any displacement of the abutments and the location of the thrust line. Two examples are described to explain the applicability of this method, and the results are compared with results from other modelling approaches. This makes clear that the eccentricity charts enable realistic structural analysis of flat brickwork vaults with various geometries and with highly efficient use of time.     

System analysis of Neo‐Gothic vaults / Systemanalyse neugotischer Gewölbe

From the middle of the 19th century until the beginning of World War I, many buildings were built in the Neo‐Gothic style. In this period, Gothic elements were built regarding the former needs to save material. These lightweight and thin vaults are often relatively fragile support systems. They tend to show systemic damages in the form of significant crack patterns in the vault caps and arches. In the research project Preservation of Neo‐Gothic vault structures, typical damages of Neo‐Gothic vaulted structures are analyzed with the objective to find sustainable and rehabilitative measures. In this context, since 2011, numerical and experimental studies have been carried out on a reference structure. Measured values of a 3D laser scanning, including all the imperfections of the structure, provide the basis of the geometry model, created for the finite element simulation. The system behavior was studied experimentally in the non‐critical load range with a load test for the calibration of this numerical model. In this paper, the project framework as well as the implementation and the evaluation of the load test are presented. In further papers, the transfer of the geodetic measurement data to the numerical model and the consideration of the load test results within a realistically finite element simulation will be addressed.     

Tumor-Activated Size-Enlargeable Bioinspired Lipoproteins Access Cancer Cells in Tumor to Elicit Anti-Tumor Immune Responses

The limited lymphocytes infiltration and immunosuppression in tumor are the major challenges of cancer immunotherapy. The use of immunogenic cell death (ICD)-inducing agents has potential to potentiate antitumor immune responses, but is tremendously hampered by the poor delivery efficiency. Herein, a tumor-activated size-enlargeable bioinspired lipoprotein of oxaliplatin (TA-OBL) is designed to access cancer cells and boost the ICD-induced antitumor immunity for synergizing immune-checkpoint blockades (ICBs)-mediated immunotherapy. TA-OBL is constructed by integrating a legumain-sensitive melittin conjugate for improving intratumoral permeation and cancer cell accessibility, a pH-sensitive phospholipid for triggering size-enlargement and drug release in intracellular acidic environments, a nitroreductase-sensitive hydrophobic oxaliplatin prodrug (N-OXP) for eliciting antitumor immunity into the bioinspired nano-sized lipoprotein system. TA-OBL treatment produced robust antitumor immune responses and its combination with ICBs demonstrates strong therapeutic benefits with delayed tumor growth and extended survival rate, making it a promising delivery nanoplatform to elicit antitumor immunity for cancer immunotherapy.     

Overcoming blood–brain barrier transport: Advances in nanoparticle-based drug delivery strategies

The blood–brain barrier (BBB), a unique structure in the central nervous system (CNS), protects the brain from bloodborne pathogens by its excellent barrier properties. Nevertheless, this barrier limits therapeutic efficacy and becomes one of the biggest challenges in new drug development for neurodegenerative disease and brain cancer. Recent breakthroughs in nanotechnology have resulted in various nanoparticles (NPs) as drug carriers to cross the BBB by different methods. This review presents the current understanding of advanced NP-mediated non-invasive drug delivery for the treatment of neurological disorders. Herein, the complex compositions and special characteristics of BBB are elucidated exhaustively. Moreover, versatile drug nanocarriers with their recent applications and their pathways on different drug delivery strategies to overcome the formidable BBB obstacle are briefly discussed. In terms of significance, this paper provides a general understanding of how various properties of nanoparticles aid in drug delivery through BBB and usher the development of novel nanotechnology-based nanomaterials for cerebral disease therapies.     

Standardization Approaches for Extracellular Vesicle Loading with Oligonucleotides and Biologics

Extracellular vesicles (EVs) are widely recognized for their potential as drug delivery systems. EVs are membranous nanoparticles shed from cells. Among their natural features are their ability to shield cargo molecules against degradation and enable their functional internalization into target cells. Especially biological or bio-inspired large molecules (LMs), like nucleic acids, proteins, peptides, and others, may profit from encapsulation in EVs for drug delivery purposes. In the last years, a variety of loading protocols are explored for different LMs. The lack of standardization in the EV drug delivery field has impeded their comparability so far. Currently, the first reporting frameworks and workflows for EV drug loading are proposed. The aim of this review is to summarize these evolving standardization approaches and set recently developed methods into context. This will allow for enhanced comparability of future work on EV drug loading with LMs.     

Development and characterization of liposomal disodium ascorbyl phytostanyl phosphates (FM-VP4)

The specific objectives of this project were (1) to develop liposomal disodium ascorbyl phytostanyl phosphate (FM-VP4) formulations, (2) to develop a liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) assay for quantification of FM-VP4 in liposomal formulations and plasma sample, and (3) to characterize liposomal FM-VP4 formulations by finding optimal drug-to-lipid ratios and determining the degradation of FM-VP4 in liposomes. Section 2 describes an LC/MS/MS assay developed for the identification and quantification of FM-VP4 in liposomal formulations to provide estimates of drug concentrations and encapsulation efficiency. The extra step of removing plasma proteins prior to LC/MS/MS assay yields an analysis of FM-VP4 in plasma samples. Section 3 describes experiments designed to find the optimal drug-to-lipid ratio for liposomal FM-VP4 formulations by comparing encapsulation efficiencies and varying the lipid compositions. Additionally, this section details our degradation studies to determine if liposomes have any protective effects on FM-VP4; these studies tested various lipid compositions at 37°C in rabbit plasma. The mechanism of how FM-VP4 lowers low-density lipoprotein (LDL) cholesterol and total cholesterol levels in various animal models is presently unknown. However, before the mechanism of action could be studied, FM-VP4 first had to be delivered efficiently into plasma or cultured cell. The low systemic bioavailability and cellular uptake of FM-VP4 further suggested the importance of finding an efficient delivery vehicle for this drug. This project proposed a framework for such delivery and paves the way for further investigation into how FM-VP4 works in vivo and in vitro.     

Development and in vitro evaluation of diltiazem hydrochloride transdermal patches based on povidone-ethylcellulose matrices

To select a suitable formulation for the development of transdermal drug-delivery system of diltiazem hydrochloride. Transdermal patches of the drug, employing different ratios of polymers, ethylcellulose (EC), and povidone (PVP) were developed and evaluated for the potential drug delivery using depilated freshly excised abdominal mouse skin. The influence of different film compositions on in vitro drug permeation into receptor fluid were studied using a modified Franz diffusion cell. The cumulative amount of drug was found to be proportional to the square root of time, i.e., Higuchi kinetics. From this study, it was concluded that the films composed of povidone:ethylcellulose (1:2) should be selected for the development of transdermal drug-delivery system of diltiazem hydrochloride, using a suitable adhesive layer and backing membrane, for potential therapeutic use.     

Synthesis of biomolecule-modified mesoporous silica nanoparticles for targeted hydrophobic drug delivery to cancer cells

Synthetic methodologies integrating hydrophobic drug delivery and biomolecular targeting with mesoporous silica nanoparticles are described. Transferrin and cyclic-RGD peptides are covalently attached to the nanoparticles utilizing different techniques and provide selectivity between primary and metastatic cancer cells. The increase in cellular uptake of the targeted particles is examined using fluorescence microscopy and flow cytometry. Transferrin-modified silica nanoparticles display enhancement in particle uptake by Panc-1 cancer cells over that of normal HFF cells. The endocytotic pathway for these particles is further investigated through plasmid transfection of the transferrin receptor into the normal HFF cell line, which results in an increase in particle endocytosis as compared to unmodified HFF cells. By designing and attaching a synthetic cyclic-RGD, selectivity between primary cancer cells (BT-549) and metastatic cancer cells (MDA-MB 435) is achieved with enhanced particle uptake by the metastatic cancer cell line. Incorporation of the hydrophobic drug Camptothecin into these two types of biomolecular-targeted nanoparticles causes an increase in mortality of the targeted cancer cells compared to that caused by both the free drug and nontargeted particles. These results demonstrate successful biomolecular-targeted hydrophobic drug delivery carriers that selectively target specific cancer cells and result in enhanced drug delivery and cell mortality.     

Microemulsions as transdermal drug delivery systems for nonsteroidal anti-inflammatory drugs (NSAIDs): a literature review

Abstract

Pain is a global crisis and significant efforts have gone into the development of drugs that can be used to treat pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of analgesics that act to selectively relieve pain and inflammation without significantly altering consciousness. Although there have been many advancements with NSAIDs drug development; these drugs still present with severe adverse effects and toxicities, which often limits their use in many patients. Moreover, others are inadequate in relieving specific types of pain such as localized or nerve pain because of poor systemic absorption with conventional delivery systems. The topical route of drug delivery has been used to avoid many of these effects, but not without challenges of its own. The skin acts as an impermeable barrier to most polar drug candidate and absorption across the dermal membranes is often too slow and incomplete to produce meaningful therapeutic benefit. Nevertheless, the use of microemulsions as topical delivery systems for small molecule drug candidates like NSAIDs has been posited as a solution to this problem for years. This review focuses on the recent use of microemulsions as a probable solution to the challenges of transdermal drug delivery of NSAIDs and how microemulsions may be used to enhance the development of more effective but safer analgesic drug products for patients.     

BioMEMS for drug delivery

Recent research into methods of using microelectromechanical systems (MEMS) technology for medical and biological applications has developed several interesting devices. This paper reviews various approaches to the use of MEMS for drug therapy, including devices based on microporous silicon, microneedles, micropumps, and microreservoirs. Microdevices can improve drug therapy because they allow precise and complex dosing, induce less pain, or increase compliance. Microneedles have been tested on humans, and the other drug delivery MEMS have shown promise in vitro and in vivo. Investigations into the use of microelectromechanical systems (MEMS) technology to produce microdevices for drug delivery have expanded recently. We present several different approaches to the use of microdevices for drug therapy and the current state of the field.     

ROS‐Responsive Polyprodrug Nanoparticles for Triggered Drug Delivery and Effective Cancer Therapy

The application of nanoparticles (NPs) to drug delivery has led to the development of novel nanotherapeutics for the treatment of various diseases including cancer. However, clinical use of NP‐mediated drug delivery has not always translated into improved survival of cancer patients, in part due to the suboptimal properties of NP platforms, such as premature drug leakage during preparation, storage, or blood circulation, lack of active targeting to tumor tissue and cells, and poor tissue penetration. Herein, an innovative reactive oxygen species (ROS)‐responsive polyprodrug is reported that can self‐assemble into stable NPs with high drug loading. This new NP platform is composed of the following key components: (i) polyprodrug inner core that can respond to ROS for triggered release of intact therapeutic molecules, (ii) polyethylene glycol (PEG) outer shell to prolong blood circulation; and (iii) surface‐encoded internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration. These targeted ROS‐responsive polyprodrug NPs show significant inhibition of tumor cell growth both in vitro and in vivo.     

Preparation of All-Trans Retinoic Acid nanosuspensions using a modified precipitation method

All-Trans Retinoic Acid (ATRA) nanosuspensions were prepared with a modified precipitation method. The ATRA solution in acetone was injected into pure water by an air compressor under the action of ultrasonication. Photon correlation spectroscopy results showed that the mean particle size of ATRA nanoparticles in nanosuspensions reduced from 337 nm to 155 nm as the injection velocity increased and the polydispersity index was 0.45-0.50. The morphology of ATRA nanoparticles varied with the different concentration of ATRA solution in acetone. ATRA nanoparticles showed an amorphous state and stable in 6 months. It could be concluded that this modified precipitation method could produce stable and controllable ATRA nanosuspension to a certain extent, thus benefit for higher saturation solubility.