Optimised Electroporation for Loading of Extracellular Vesicles with Doxorubicin

The clinical use of chemotherapeutics is limited by several factors, including low cellular uptake, short circulation time, and severe adverse effects. Extracellular vesicles (EVs) have been suggested as a drug delivery platform with the potential to overcome these limitations. EVs are cell-derived, lipid bilayer nanoparticles, important for intercellular communication. They can transport bioactive cargo throughout the body, surmount biological barriers, and target a variety of tissues. Several small molecule drugs have been successfully incorporated into the lumen of EVs, permitting efficient transport to tumour tissue, increasing therapeutic potency, and reducing adverse effects. However, the cargo loading is often inadequate and refined methods are a prerequisite for successful utilisation of the platform. By systematically evaluating the effect of altered loading parameters for electroporation, such as total number of EVs, drug to EV ratio, buffers, pulse capacitance, and field strength, we were able to distinguish tendencies and correlations. This allowed us to design an optimised electroporation protocol for loading EVs with the chemotherapeutic drug doxorubicin. The loading technique demonstrated improved cargo loading and EV recovery, as well as drug potency, with a 190-fold increased response compared to naked doxorubicin.

Antimicrobial Resistance and Inorganic Nanoparticles

Antibiotics are being less effective, which leads to high mortality in patients with infections and a high cost for the recovery of health, and the projections that are had for the future are not very encouraging which has led to consider antimicrobial resistance as a global health problem and to be the object of study by researchers. Although resistance to antibiotics occurs naturally, its appearance and spread have been increasing rapidly due to the inappropriate use of antibiotics in recent decades. A bacterium becomes resistant due to the transfer of genes encoding antibiotic resistance. Bacteria constantly mutate; therefore, their defense mechanisms mutate, as well. Nanotechnology plays a key role in antimicrobial resistance due to materials modified at the nanometer scale, allowing large numbers of molecules to assemble to have a dynamic interface. These nanomaterials act as carriers, and their design is mainly focused on introducing the temporal and spatial release of the payload of antibiotics. In addition, they generate new antimicrobial modalities for the bacteria, which are not capable of protecting themselves. So, nanoparticles are an adjunct mechanism to improve drug potency by reducing overall antibiotic exposure. These nanostructures can overcome cell barriers and deliver antibiotics to the cytoplasm to inhibit bacteria. This work aims to give a general vision between the antibiotics, the nanoparticles used as carriers, bacteria resistance, and the possible mechanisms that occur between them.

Blend Segregation in Tablets Manufacturing and Its Effect on Drug Content Uniformity—A Review

Content uniformity (CU) of the active pharmaceutical ingredient is a critical quality attribute of tablets as a dosage form, ensuring reproducible drug potency. Failure to meet the accepted uniformity in the final product may be caused either by suboptimal mixing and insufficient initial blend homogeneity, or may result from further particle segregation during storage, transfer or the compression process itself. This review presents the most relevant powder segregation mechanisms in tablet manufacturing and summarizes the currently available, up-to-date research on segregation and uniformity loss at the various stages of production process—the blend transfer from the bulk container to the tablet press, filling and discharge from the feeding hopper, as well as die filling. Formulation and processing factors affecting the occurrence of segregation and tablets’ CU are reviewed and recommendations for minimizing the risk of content uniformity failure in tablets are considered herein, including the perspective of continuous manufacturing.

Benefits and risks of antiplatelet medication in hemodynamically stable adult moyamoya disease

Revascularization surgery is considered a standard treatment for preventing additional stroke in symptomatic moyamoya disease (MMD). In hemodynamically stable, and asymptomatic or mildly symptomatic patients, however, the treatment strategy is controversial because of the obscure natural course of them. The authors analyzed the benefits and risks of antiplatelet medication in those patients. Medical data were retrospectively reviewed in 439 hemispheres of 243 patients with stable hemodynamic status. Overall, 121 patients (49.8%) with 222 studied hemispheres (50.6%) took antiplatelet medication. Symptomatic cerebral infarction and hemorrhage occurred in 10 (2.3%) and 30 (6.8%) hemispheres, over a mean follow-up of 62.0 ± 43.4 months (range 6–218 months). The use of antiplatelet agents was statistically insignificant in terms of symptomatic infarction, hemorrhage and improvement of ischemic symptoms. In subgroup analyses within the antiplatelet group according to drug potency and duration of medication, a longer duration of antiplatelet medication significantly improved ischemic symptoms (adjusted OR 1.02; 95% CI 1.01–1.03; p = 0.006). Antiplatelet medication failed to prevent symptomatic cerebral infarction or improve ischemic symptoms. However, antiplatelet therapy did not increase the risk of cerebral hemorrhage.

Establishing a protocol for the compatibilities of closed-system transfer devices with multiple chemotherapy drugs under simulated clinical conditions

Closed-system drug transfer devices (CSTDs) are used to prevent occupational exposure to hazardous drugs in health care providers. They are considered Class II medical devices by the US FDA and are cleared but not approved before marketing. While compatibility tests are conducted by CSTD manufacturers, the procuring institution needs to consider performing its own studies before buying these devices. Herein we tested the compatibility of the components of the Needleless® DualGuard CSTD system (vial access clips, vial access spikes, and administration adaptors) with 10 antineoplastic drugs, under simulated clinical conditions, including compounding and administration, and examined drug potency maintenance, plasticizer migration, and device functionality. All drugs maintained potency within 5%. Diisononyl phthalate leakage was observed from the administration adaptors for paclitaxel and concentrated etoposide solution. In addition, white particles were discovered in CSTDs storing busulfan solution and small cracks were observed on devices which stored melphalan. Thus, it was concluded that even in simulated clinical conditions, instead of extreme conditions, there are still concerns regarding the efficacy and safety of CSTD components. The methodology may be used to implement and detect possible interactions between antineoplastic agents and CSTD components before procurement.

Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target

HDAC drugs have entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a chemical proteomics assay using three promiscuous chemotypes and quantitative mass spectrometry that we deployed to establish the target landscape of 53 drugs. The results highlight 14 direct targets, including 9 out of the 11 human zinc-dependent HDACs, question the reported selectivity of widely-used molecules, notably for HDAC6, and delineate how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-beta-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent target of hydroxamate drugs. This ill-annotated palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nM potency. Both enzymatic inhibition and knocking down the protein led to the accumulation of extracellular vesicles. Given the importance of exosome biology in neurological diseases or cancer, this HDAC-independent drug effect creates the incentive for considering MBLAC2 as a target for drug discovery.

Targeting activated macrophages intracellular milieu to augment anti-inflammatory drug potency

We present pH-responsive phosphorylcholine polymersomes ability to target activated macrophages via scavenger receptors, enter them via endocytosis, and escape from early endosomes enabling the intracellular drug delivery. Using an arthritis experimental model and the gold standard disease-modifying anti-rheumatic drug, methotrexate, we prove that polymersomes augment therapeutic efficacy while minimizing the off-target effect. First, we demonstrate the selective accumulation of polymersomes within the inflamed synovial tissues and cells, including macrophages. Second, we show the beneficial therapeutic effect of methotrexate loaded polymersomes in preventing both joint inflammation and further damage. Hence, we prove the therapeutic potential of polymersomes in enhancing the complete prevention of arthritis progression, which makes it a promising nano therapy for arthritis treatment as well as other inflammatory disorders.