The recalcitrance of tumors to photodynamic therapy (PDT) has been linked to PDT-induced activation of survival pathways in sublethally afflicted cancer cells that modulate cellular responses to oxidative stress and damage. Survival signaling manifests in regions of the tumor where the tumor cells are insufficiently photosensitized or subjected to inadequate fluence rates. The survival signaling in these tumor regions is believed to account for tumor recurrence. Accordingly, PDT efficacy can be...
CRISPR-Cas9 gene editing technology offers the potential to permanently repair genes containing pathological mutations. However, efficient intracellular delivery of the Cas9 ribonucleoprotein complex remains a major hurdle in its therapeutic application. Extracellular vesicles (EVs) are biological nanosized membrane vesicles that play an important role in intercellular communication, and have an innate capability of intercellular transfer of biological cargos, including proteins and RNA. Here,...
Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US-enhanced drug delivery. While the majority of studies utilize commercial MB formulations, increasing experimental evidence indicates that distinct MB features critically determine their diagnostic and therapeutic performance. Here, it is shown that shell stiffness engineering of poly(alkyl cyanoacrylate) (PACA) MB, via introducing monomers with varying alkyl chain lengths and glass transition temperatures,...
Current control strategies for leishmaniases - a group of diseases caused by protozoan parasites of the genus Leishmania - rely on chemotherapy, which is often associated with significant drawbacks, including severe side effects and limited drug efficacy. The public health impact of leishmaniases underscores the urgent need for new therapeutic approaches. Quinoline-(1H)-imines have emerged as promising lead compounds for antileishmanial drug development, however, their poor aqueous solubility...
In biology, ligand-mediated transitions (LMT), where the binding of a molecular ligand onto the binding site of a receptor molecule leads to a well-defined change in the conformation of the receptor, are often referred to as "the second secret of life." Sharp, cooperative transitions arise in many biological cases, while examples of synthetic cooperative systems are rare. This is because well-defined conformational states are hard to "program" into a molecular design. Here, we impose an external...
Therapeutic cargo, such as small molecule drugs, proteins and nucleic acids, can only fulfill their function in an effective way if they reach their biological target site intact and at sufficiently high concentrations. To facilitate and steer this transport process after administration and mitigate limited solubility and/or stability, the therapeutic cargo can be encapsulated into nanocarriers. These nanocarriers need to function in highly complex and crowded biological media and the journey...
Corticosteroids, such as dexamethasone, are clinically used in intravitreal injections for the treatment of inflammatory and age-related ocular diseases; however, frequent injections can cause complications. To prolong the retention of dexamethasone in the eye after intravitreal administration, sustained-release drug delivery systems have previously been investigated. The aim of this study was to evaluate the in vivo release of dexamethasone from a self-healing thermosensitive hydrogel...
Quality attributes (QAs) of monoclonal antibody (mAb) therapeutics can be jeopardized when exposed to stress factors during administration, potentially leading to patient safety risks. Therefore, strict product handling instructions are provided by the manufacturer. However, because of variations in available supplies and local guidelines, there is a need for broadened handling options in clinical setting, to improve logistics and reduce costs and shortages. Therefore 3^(rd) parties (parties...
Increasing evidence implicates ceramides in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). However, the therapeutic potential of liver-targeted ceramide lowering remains unclear. In this study, we demonstrate that elevated ceramide levels in MASH patients and mouse models are closely associated with the activation of hepatic de novo ceramide synthesis. The analysis of human hepatic single-nucleus RNA sequencing (snRNA-seq) data revealed predominant up-regulation of...
CRISPR gene therapy holds the potential to cure a variety of genetic diseases by causing a targeted DNA break, which is repaired by host DNA damage responses. One option to introduce precise gene corrections is via the homology-directed repair (HDR) pathway. The problem in utilizing this pathway is that CRISPR-induced double stranded DNA breaks are more likely to be erroneously repaired by the non-homologous end joining (NHEJ) pathway, which may introduce random insertions or deletions at the...
