DELOS Nanovesicles-Based Hydrogels: An Advanced Formulation for Topical Use

Topical delivery has received great attention due to its localized drug delivery, its patient compliance, and its low risk for side effects. Recent developments have focused on studying new drug delivery systems as a strategy for addressing the challenges of current topical treatments. Here we describe the advances on an innovative drug delivery platform called DELOS nanovesicles for topical drug delivery. Previously, the production of DELOS nanovesicles demonstrated potentiality for the topical treatment of complex wounds, achieving well-tolerated liquid dispersions by this route. Here, research efforts have been focused on designing these nanocarriers with the best skin tolerability to be applied even to damaged skin, and on exploring the feasibility of adapting the colloidal dispersions to a more suitable dosage form for topical application. Accordingly, these drug delivery systems have been efficiently evolved to a hydrogel using MethocelTM K4M, presenting proper stability and rheological properties. Further, the integrity of these nanocarriers when being gellified has been confirmed by cryo-transmission electron microscopy and by Förster resonance energy transfer analysis with fluorescent-labeled DELOS nanovesicles, which is a crucial characterization not widely reported in the literature. Additionally, in vitro experiments have shown that recombinant human Epidermal Growth Factor (rhEGF) protein integrated into gellified DELOS nanovesicles exhibits an enhanced bioactivity compared to the liquid form. Therefore, these studies suggest that such a drug delivery system is maintained unaltered when hydrogellified, becoming the DELOS nanovesicles-based hydrogels, an advanced formulation for topical use.

Bridging Insights From Lymph Node and Synovium Studies in Early Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology characterized by inflammation of the peripheral synovial joints leading to pannus formation and bone destruction. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) are present years before clinical manifestations and are indicative of a break in tolerance that precedes chronic inflammation. The majority of studies investigating disease pathogenesis focus on the synovial joint as target site of inflammation while few studies explore the initial break in peripheral tolerance which occurs within secondary lymphoid organs such as lymph nodes. If explored during the earliest phases of RA, lymph node research may provide innovative drug targets for disease modulation or prevention. RA research largely centers on the role and origin of lymphocytes, such as pro-inflammatory T cells and macrophages that infiltrate the joint, as well as growing efforts to determine the role of stromal cells within the synovium. It is therefore important to explore these cell types also within the lymph node as a number of mouse studies suggest a prominent immunomodulatory role for lymph node stromal cells. Synovium and proximal peripheral lymph nodes should be investigated in conjunction with one another to gain understanding of the immunological processes driving RA progression from systemic autoimmunity toward synovial inflammation. This perspective seeks to provide an overview of current literature concerning the immunological changes present within lymph nodes and synovium during early RA. It will also propose areas that warrant further exploration with the aim to uncover novel targets to prevent disease progression.

Development of an Innovative Drug Information Evidence-Based Medicine Advanced Pharmacy Practice Experience

Aim: To describe the development, implementation, and structure of an innovative evidence-based medicine (EBM) advanced pharmacy practice experience (APPE) rotation and evaluate student pharmacists’ perceptions of the course. Methods: A five-week, EBM APPE rotation was designed by seven faculty. Students worked remotely in teams and individually to complete pre- and post-assessments, journal clubs, journal scans, drug information questions, and clinical debates, as well as self- and peer-assessments. Students were asked to rate their perceptions of the course on a 5-point Likert scale. Results: A total of eighteen students, precepted by seven faculty members, completed the rotation. Students completed three group journal clubs, three individual journal scans, one individual journal club, one drug information question, and one clinical debate. Students survey data indicated that confidence in EBM skills was high following the rotation. Conclusion: This EBM APPE rotation was successful. The structure of this rotation may be transferable to a variety of settings.

Polymerized Porin as a Novel Delivery Platform for Coronavirus Vaccine

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), seriously threatens human life and health. The correct folding and polymerization of the receptor-binding domain (RBD) protein of coronavirus in Escherichia coli may reduce the cost of SARS-CoV-2 vaccines. Here, we designed this nanopore by using the principle of ClyA porin polymerization triggered by the cell membrane. We use surfactants to "pick" the ClyA-RBD nanopore from the bacterial outer membrane in this study. More importantly, the polymerized RBD displayed on ClyA-RBD polymerized porin (RBD-PP) already has some correct spatial structures of virus spikes. The nanostructures of RBD-PP can target lymph nodes and promote antigen uptake and processing by dendritic cells, thereby effectively eliciting the production of anti-SARS-CoV-2 neutralizing antibodies and systemic cellular immune responses and immune memory. We applied ofthis PP-based vaccine platform to make an RBD-based subunit vaccine against SARS-CoV-2, which will provide a foundation for the development of inexpensive coronavirus vaccines. The development of novel vaccine delivery system is an important part of innovative drug research. This novel PP-based vaccine platform is likely to be applied to more fields, including other viral vaccines, bacterial vaccines, tumor vaccines, drug delivery, and disease diagnosis.

Mitochondrial Targeting Therapeutics: Promising Role of Natural Products in Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide, and its prevalence is still growing rapidly. However, the efficient therapies for this liver disease are still limited. Mitochondrial dysfunction has been proven to be closely associated with NAFLD. The mitochondrial injury caused reactive oxygen species (ROS) production, and oxidative stress can aggravate the hepatic lipid accumulation, inflammation, and fibrosis. which contribute to the pathogenesis and progression of NAFLD. Therefore, pharmacological therapies that target mitochondria could be a promising way for the NAFLD intervention. Recently, natural products targeting mitochondria have been extensively studied and have shown promising pharmacological activity. In this review, the recent research progress on therapeutic effects of natural-product-derived compounds that target mitochondria and combat NAFLD was summarized, aiming to provide new potential therapeutic lead compounds and reference for the innovative drug development and clinical treatment of NAFLD.

Peptide Functionalised Nanocarriers for Bone Specific Delivery of PTH (1-34) in Osteoporosis

: Osteoporosis represents a major public health burden especially considering the aging population worldwide. Treatment modalities for osteoporosis are classified into two categories based on the effect on bone remodelling: anabolic drugs and antiresorptive drugs. Anabolic drugs are preferred as it stimulates new bone formation. Currently, PTH (1-34) is the only peptide-based drug approved as an anabolic agent for the treatment of osteoporosis by both USFDA as well as EMA. However, its non-specific delivery results in prolonged kidney exposure, causing hypercalcemia. Nanotechnology-based drug delivery systems functionalized by conjugating it with homing moieties, such as peptides, offer an advantage of targeted delivery with reduced off-target effects. Here, we propose an innovative and targeted nanovesicle approach to efficiently deliver PTH (1-34) to the bone surface using peptides as a homing moiety. The proposed innovative delivery approach will augment the specific interaction between the drug and bone surface without producing side effects. This will reduce the off-target effects of PTH (1-34), and at the same time, it will also improve the outcome of anabolic therapy. Therefore, we postulate that the proposed innovative drug delivery approach for PTH (1-34) will establish as a promising therapy for osteoporotic patients, specifically in postmenopausal women who are at greater risk of bone fracture.

Acidic microenvironment responsive polymeric MOF-based nanoparticles induce immunogenic cell death for combined cancer therapy

Background The complex tumor microenvironment and non-targeting drugs limit the efficacy of clinical tumor therapy. For ensuring the accurate delivery and maximal effects of anticancer drugs, it is important to develop innovative drug delivery system based on nano-strategies. Result In this study, an intracellular acidity-responsive polymeric metal organic framework nanoparticle (denoted as DIMP) has been constructed, which can co-deliver the chemotherapy agent of doxorubicin (DOX) and phototherapy agent of indocyanine green (ICG) for breast carcinoma theranostics. Specifically, DIMP possesses a suitable and stable nanometer size and can respond to the acidic microenvironment in cells, thus precisely delivering drugs into target tumor sites and igniting the biological reactions towards cell apoptosis. Following in vivo and in vitro results showed that DIMP could be effectively accumulated in tumor sites and induced powerful immunogenic cell death (ICD) effect. Conclusion The designed DIMP displayed its effectiveness in combined photo-chemotherapy with auxiliary of ICD effect under a multimodal imaging monitor. Thus, the present MOF-based strategy may offer a potential paradigm for designing drug-delivery system for image-guided synergistic tumor therapy. Graphical Abstract

Aptamer-Aptamer Chimera for Targeted Delivery and ATP-Responsive Release of Doxorubicin into Cancer Cells

Aptamers offer a great opportunity to develop innovative drug delivery systems that can deliver cargos specifically into targeted cells. In this study, a chimera consisting of two aptamers was developed to deliver doxorubicin into cancer cells and release the drug in cytoplasm in response to adenosine-5′-triphosphate (ATP) binding. The chimera was composed of the AS1411 anti-nucleolin aptamer for cancer cell targeting and the ATP aptamer for loading and triggering the release of doxorubicin in cells. The chimera was first produced by hybridizing the ATP aptamer with its complementary DNA sequence, which is linked with the AS1411 aptamer via a poly-thymine linker. Doxorubicin was then loaded inside the hybridized DNA region of the chimera. Our results show that the AS1411–ATP aptamer chimera was able to release loaded doxorubicin in cells in response to ATP. In addition, selective uptake of the chimera into cancer cells was demonstrated using flow cytometry. Furthermore, confocal laser scanning microscopy showed the successful delivery of the doxorubicin loaded in chimeras to the nuclei of targeted cells. Moreover, the doxorubicin-loaded chimeras effectively inhibited the growth of cancer cell lines and reduced the cytotoxic effect on the normal cells. Overall, the results of this study show that the AS1411–ATP aptamer chimera could be used as an innovative approach for the selective delivery of doxorubicin to cancer cells, which may improve the therapeutic potency and decrease the off-target cytotoxicity of doxorubicin.

Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,

PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.

Can repurposing drugs play a role in malaria control?

Innovative drug treatments for malaria, optimally with novel targets, are needed to combat the threat of parasite drug resistance. As drug development efforts continue, there may be a role for a host-targeting, repurposed cancer drug administered together with an artemisinin combination therapy that was shown to improve the speed of recovery from a malaria infection.