and Hydrolytic Degradation Behaviors of a Drug-Delivery System Based on the Blend of PEG and PLA Copolymers.

This paper presents the and degradation of BEPO, a marketed forming depot technology used for the formulation of long-acting injectables. BEPO is composed of a solution of a blend of poly(ethylene glycol)--poly(lactic acid) (PEG-PLA) triblock and diblock in an organic solvent, where a therapeutic agent may be dissolved or suspended. Upon contact with an aqueous environment, the solvent diffuses and the polymers precipitate, entrapping the drug and forming a reservoir.

A two-tiered system for selective receptor and transporter protein degradation.

Diverse physiology relies on receptor and transporter protein down-regulation and degradation mediated by ESCRTs. Loss-of-function mutations in human ESCRT genes linked to cancers and neurological disorders are thought to block this process. However, when homologous mutations are introduced into model organisms, cells thrive and degradation persists, suggesting other mechanisms compensate.

Long-acting injectable formulation technologies: challenges and opportunities for the delivery of fragile molecules.

Introduction: The development of long-acting injectables (LAIs) for protein and peptide therapeutics has been a key challenge over the last 20 years. If these molecules offer advantages due to their high specificity and selectivity, their controlled release may confer several additional benefits in terms of extended half-life, local delivery, and patient compliance.

Area Covered: This manuscript aims to give an overview of peptide and protein-based LAIs from an industrial perspective, describing both approved and promising technologies (with exceptions of protein engineering strategies and devices), their advantages and potential improvements to aid their access to the market.

Reconstitution of the dTDP-l-Daunosamine Biosynthetic Pathway Provides Insights into Anthracycline Glycosylation.

Many small molecule natural products are decorated with sugar moieties that are essential for their biological activity. A considerable number of natural product glycosides and their derivatives are clinically important therapeutics. Anthracyclines like daunorubicin and doxorubicin are examples of valuable glycosylated natural products used in medicine as potent anticancer agents.

Evaluation of Loco-Regional Skin Toxicity Induced by an In Situ Forming Depot after a Single Subcutaneous Injection at Different Volumes and Flow Rates in Göttingen Minipigs.

The present study aims to investigate the loco-regional tolerability and injection parameters (i.e., flow rate and administration volume) of an in situ forming depot (ISFD) in Göttingen minipigs, to secure both the therapeutic procedure and compliance in chronic medical prescriptions.

Impact of octreotide counterion nature on the long-term stability and release kinetics from an in situ forming depot technology.

The generation of acylated impurities has represented an important hurdle in the development of long acting injectables for therapeutic peptides using biocompatible polymers with a polyester moiety. We investigated here an in situ forming depot (ISFD) technology that uses polyethylene glycol - polyester copolymers and a solvent exchange mechanism to promote depot formation. This technology has shown promise in formulating small molecules as well as therapeutic proteins.

Challenges and opportunities in the delivery of cancer therapeutics: update on recent progress.

Global cancer prevalence has continuously increased in the last decades despite substantial progress achieved for patient care. Cancer is no longer recognized as a singular disease but as a plurality of different ones, leading to the important choice of the drug administration route and promoting the development of novel drug-delivery systems (DDS). Due to their structural diversity, therapeutic cancer drugs present specific challenges in physicochemical properties that can adversely affect their efficacy and toxicity profile.

BEPO®: Bioresorbable diblock mPEG-PDLLA and triblock PDLLA-PEG-PDLLA based in situ forming depots with flexible drug delivery kinetics modulation.

This article presents BEPO®, an in situ forming depot (ISFD) technology mediated by a solvent-exchange mechanism. The matrix of the in situ formed drug delivery depot is composed of the combination of a diblock (DB) and a triblock (TB) polyethylene glycol-polyester copolymer. This combination offers a broad capability to tune the release of a wide variety of drugs to the desired pharmacokinetics.

Organic Nanoscrolls from Electrostatic Interactions between Peptides and Lipids: Assembly Steps and Structure.

An important aspect of cells is their shape flexibility that gives them motion but also a high adaptation versatility to their environment. This shape versatility is mediated by different types of protein-membrane interactions among which electrostatic plays an important role. In the present work we examined the interaction between a small dicationic peptide, that possesses self-assembly properties, and lipid model membranes.

A Genome-Wide Screen Identifies Genes in Rhizosphere-Associated Required to Evade Plant Defenses.

and related plant root ("rhizosphere")-associated species contribute to plant health by modulating defenses and facilitating nutrient uptake. To identify bacterial fitness determinants in the rhizosphere of the model plant , we performed a high-throughput transposon sequencing (Tn-Seq) screen using the biocontrol and growth-promoting strain sp. WCS365.

Readability of advance directive documentation in Canada: a cross-sectional study.

Background: In the Canadian context, health literacy has been shown to depend on place of birth, education level, socioeconomic status, language spoken and geographic location. This study seeks to determine whether currently available advance directive documentation in Canada is written in accordance with the average reading level of the population and to assess whether recommendations for health literacy are currently being met.

Methods: A cross-sectional study design was used.

Challenges in oral peptide delivery: lessons learnt from the clinic and future prospects.

Therapeutic peptides have become very successful drugs due to their specificity, potency and low toxicity, but they show challenges for their delivery, due to their short half-life and rapid plasma clearance. For these reasons, peptides are usually administered using injectable sustained-release formulations. Oral peptide route is highly compelling from a patient and commercial point of view.

Lanreotide Depot: An Antineoplastic Treatment of Carcinoid or Neuroendocrine Tumors.

Purpose: Peptide drugs for antineoplastic therapies usually have low oral bioavailability and short in vivo half-lives, requiring less preferred delivery methods. Lanreotide depot is a sustained-release somatostatin analog (SSA) formulation produced via an innovative peptide self-assembly method. Lanreotide is approved in the USA and Europe to improve progression-free survival (PFS) in patients with unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and also approved in Europe for symptom control in carcinoid syndrome associated with GEP-NETs.

Unlocking Index Animalium: From paper slips to bytes and bits.

In 1996 Smithsonian Libraries (SIL) embarked on the digitization of its collections. By 1999, a full-scale digitization center was in place and rare volumes from the natural history collections, often of high illustrative value, were the focus for the first years of the program. The resulting beautiful books made available for online display were successful to a certain extent, but it soon became clear that the data locked within the texts needed to be converted to more usable and re-purposable form via digitization methods that went beyond simple page imaging and included text conversion elements.

Evaluation of Three Sensor Types for Particle Motion Measurement.

All fish sense acoustic particle motion; some species also sense pressure. Concern over the effects of anthropogenic sounds is increasing the need to monitor acoustic particle motion. Particle motion can be measured directly using vector sensors or calculated from pressure gradients.

Challenges in the delivery of peptide drugs: an industry perspective.

Due mainly to their poor stability and short plasma half-life, peptides are usually administered by injection, often several times daily. Injectable sustained-release formulations of peptides based on biodegradable polymer microparticles or implants early demonstrated the power of drug delivery technologies to enhance patient adherence and convenience, and increase safety and efficacy. Injectable sustained-release formulations are likely to remain a significant part of new peptide products.

Challenges and opportunities in the delivery of cancer therapeutics.

The idea that cancer is not one but many diseases has completely changed the oncology landscape and promoted the development of personalized cancer therapy. Based on a better understanding of the mechanisms of cancer cell proliferation and tumor growth, novel therapies have emerged to address unmet medical needs and effectively treat pre-identified, responsive patients. These novel therapies require specific drug-delivery strategies that depend on the type and location of cancer, as well as the type of drugs administered, that is, a small molecule, a peptide, a therapeutic protein or a monoclonal antibody.

The formulation and immunogenicity of therapeutic proteins: Product quality as a key factor.

The formation of anti-drug antibodies represents a risk that should be assessed carefully during biopharmaceutical drug product (DP) development, as such antibodies compromise safety and efficacy and may alter the pharmacokinetic properties of a compound. This feature review discusses immunogenicity issues in biopharmaceutical DP development, with a focus on product quality. Excipient-induced and aggregate-induced immunogenicity are reviewed based on the concepts of 'aggregation-competent' species and 'provocative' aggregates.

Conformational modifications of alpha gliadin and globulin proteins upon complex coacervates formation with gum Arabic as studied by Raman microspectroscopy.

As a molecular model of gelatin-free coacervates, complexes of pea globulin and alpha gliadin proteins with gum arabic prepared at different acidic pH values are studied using Raman microspectrometry. Raman spectra confirm higher content of beta-sheets and random coils in pea globulin and dominating alpha-helical structures in alpha gliadin. For protein-gum arabic complexes, Raman data support the existence of specific pH conditions for optimal complex coacervation (pH 2.

Busulfan loading into poly(alkyl cyanoacrylate) nanoparticles: physico-chemistry and molecular modeling.

The busulfan is an alkylating agent widely used for the treatment of haematological malignancies and nonmalignant disorders. For a long time, it has been available only in an oral form. This treatment leads to a wide variability in bioavailability and side effects such as the veino-occlusive disease.

Baclofen-loaded microspheres in gel suspensions for intrathecal drug delivery: in vitro and in vivo evaluation.

Severe spasticity is a very disabling disorder treated by continuous baclofen intrathecal infusion which unfortunately remains an expensive and uncomfortable treatment. In order to address these issues, new sustained release formulations designed for intrathecal baclofen delivery were sought with the aim of minimising the burst effect of baclofen which can lead to toxicity. Baclofen was encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres which were then dispersed in chitosan thermosensitive gels, Pluronic PF-127 gels, carboxymethylcellulose solutions or Ringer lactate solution.

Nanoencapsulation of a crystalline drug.

The aim of this work was to assess the influence of various formulation parameters on the incorporation of a poorly water-soluble crystalline drug into nanoparticles. For this purpose, the influence of the polymer (polylactic acid, polysebacic acid terminated with lithocholic acid, and polysebacic acid-co-lithocholic acid) as well as the effect of the dispersion medium (aqueous phases at different temperatures, saline medium and ethanol) on the encapsulation was investigated. 3H-labelled drug was used in order to determine the loading efficiency by liquid scintillation counting.

Baclofen-loaded microspheres: preparation and efficacy testing in a new rabbit model.

Intrathecal baclofen is the reference treatment for severe spasticity. This drug has to be injected chronically in the intrathecal space by implanted pumps which are very expensive, uncomfortable and sometimes lead to side effects. Previous work has been performed by our group to assess the feasibility of encapsulating baclofen into poly(lactide-co-glycolide) (PLGA) microspheres and injecting these preparations in the intrathecal space of rabbits.