1,720,958 research outputs found
Rational development of intra-articular drug delivery systems for the treatment of osteoarthritis
No full textOsteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degradation and calcification, synovitis, and subchondral bone sclerosis, resulting in pain and functional impairment. OA pathogenesis is multifactorial with mechanical (wear and tear) and biochemical components that converge on the progressive cartilage destruction mainly orchestrated by inflammatory cytokines and catabolic enzymes. Current therapies provide only temporary relief from symptoms, and no disease-modifying OA drugs (DMOADs) are clinically available. Clinically approved intra-articular OA therapies include corticosteroids to manage pain and inflammation and hyaluronic acid (HA) to restore cartilage lubrication. However, several clinical trials revealed that this approach is associated with several limitations, including rapid clearance from the joint space. Therefore, there is an unmet clinical need for precision medicines capable of both extending the retention of drugs within the osteoarthritic joint and addressing the underlying causes of cartilage degradation. An optimal approach in precision medicine for OA involves the synergistic combination of a drug delivery system (DDS) with a disease-modifying osteoarthritis drug. In the present research project, various strategies were employed to develop intra-articular DDS containing potential DMOADs. Three therapeutic approaches were investigated to target distinct aspects of OA pathology: cartilage lubrication failure, pathological cartilage calcification, and the accumulation of senescent cells in osteoarthritic joints. Reduced cartilage lubrication is a key factor in OA, which causes increased friction between cartilage interfaces, triggering further cartilage degradation and local inflammation. Thus, early-stage restoration of cartilage lubrication could ameliorate, and potentially reverse, OA. Within this context, the first study presents a methodology for producing injectable cross-linked HA hydrogel microparticles (uHP) tailored for localized OA treatment. Leveraging the crucial lubricant role of HA in the cartilage and synovial fluid, HA-μHP were designed to function not only as a bioinspired lubricant but also as a platform for drug delivery. HA-methacrylate (10 or 50 kDa) precursors with different degrees of methacrylation were employed to generate these hydrogel microparticles, combining a template strategy and multi-step photo-polymerization. This process yielded HA-μHP with a square base measuring 20 μm on each side and a height of 5 μm. The developed method enabled the fine-tuning of particle properties and the loading of diverse payloads, including small molecules, macromolecules, and nanoparticles. Using a linear two-axis tribometer (designed and constructed in the Tribology Laboratory at the Azrieli College of Engineering in Jerusalem), we assessed the static and dynamic friction coefficients of the μHP-enriched simulated synovial fluid. Notably, both friction coefficients exhibited a consistent decrease in the presence of HA-μHP, underscoring the lubricating efficacy of HA, even in the form of microparticles. Under conditions simulating OA oxidative stress (0.3 mM H2O2), these particles exhibited no degradation, emphasizing the advantages of the HA formulation in hydrogel microparticles over bulk hydrogels. Also, the biocompatibility of HA μHP with various cell types, including chondrocytes and fibroblasts – key components of the joint capsule was confirmed, further supporting the potential of this approach for OA treatment. Cartilage calcification is another hallmark of OA because calcium crystals released by chondrocytes promote cartilage degradation via different pathways. Consequently, the inhibition of calcification and prevention of subsequent events can potentially block cartilage deterioration. In the second study, Fetuin, a hepatically synthesized glycoprotein known for its endogenous calcification inhibition and anti-inflammatory properties, was chosen as a therapeutic agent. Two distinct delivery strategies for Fetuin were proposed, either for combinatorial therapy or enhanced drug retention. Fetuin has been effectively nanoformulated with the natural anti-inflammatory fatty acid methyl palmitate, resulting in stable 200 nm nanoparticles (MPN), creating a dual-anti-inflammatory system. Also, Fetuin was incorporated into HA-μHP through a charge-based (ionic) interaction. This platform enabled a sustained delivery of the protein over 30 days in a biologically relevant volume. In vitro studies conducted on human chondrocytes demonstrated that both formulations significantly reduced H2O2-calcium crystals-mediated inflammation, with a more pronounced beneficial effect compared to Fetuin alone. This highlighted the advantageous nature of our strategy, which exploits the benefits of combinatorial therapy with MPN and drug depot with HA-μHP. The final part of this research work, conducted at Vanderbilt University, was focused on a therapeutic target that has drawn significant attention in recent years—namely, the accumulation of senescent cells in OA joints. Targeting senescence through the application of senolytic and senomorphic drugs has emerged as a promising strategy for modifying the disease and addressing OA causes. In the latest research activity, senescence-modulating drugs were effectively encapsulated with high drug-loading capacities within ROS-responsive polysulfide nanoparticles. Two separate in vitro models were utilized to evaluate their effectiveness. Among the senolytic drugs investigated, NVP-CMG097 (MDM2 inhibitor) demonstrated moderate selectivity in eliminating senescent fibroblast-like synoviocytes. Concurrently, senomorphic drugs 114810 and GSK343 exhibited promise in reducing inflammation and cartilage degradation within a 3D model of OA. These results underscore the potential of utilizing this class of drugs as innovative therapeutic agents, thereby paving the way to explore the co-delivery of these drugs using advanced drug delivery systems
Folate-targeted gold nanoparticles for doxorubicin delivery in tumor spheroids
No full textTargeted drug delivery systems represent a promising strategy for enhancing the efficacy and specificity of cancer therapy. In this study, 35 nm folate-targeted gold nanoparticles are presented as nanoparticle-drug conjugates obtained by anchoring on their surface lipoyl terminating doxorubicin prodrug (proDoxo) releasable at the endolysosomal acidic pH to prevent off-site toxic effects. Colloidal stable nanoparticles with a density of proDoxo up to 1000 molecules/particle and 2 kDa mPEG-SH coating were obtained. At pH 5, Doxo was completely released from the nanoparticles in 5 days while only 13% was released over the same period at pH 7.4. The nanoparticle decoration with folic acid as a targeting agent bestowed nanosystems with selective drug delivery to folate receptor (FR)-overexpressing cancer cells and controlled intracellular release. This led to enhanced cancer cell killing by folated nanoparticles compared to their nontargeted counterparts. Moreover, folated nanoparticles were found to distribute more homogeneously inside KBFR+ cancer cell spheroids than non-targeted nanoparticles, resulting in higher spheroid volume reduction
Localized treatment of glioblastoma: a review of clinical strategies and advances in drug delivery systems.
No full textThe prognosis for glioblastoma patients remains poor despite recent advances in neurosurgery, chemotherapy, and radiotherapy. One promising treatment strategy lies in the localized delivery of therapeutics through drug delivery systems designed to enhance existing clinical treatments by directly targeting the tumor site or surrounding area. This review explores the latest advancements in localized therapies for glioblastoma, highlighting recent preclinical and clinical studies and examining how we can integrate these approaches - including stereotactic techniques such as convection-enhanced delivery and therapies targeting the post-surgical resection cavity - with drug delivery systems. We describe the features that the drug delivery system should possess for the efficient transport of drugs for both inoperable and resectable glioblastoma local treatment. Finally, this review discusses future directions that may facilitate the clinical translation of localized treatment strategies for glioblastoma
Unlocking the potential of microfluidic assisted formulation of exenatide-loaded solid lipid nanoparticles
No full textExenatide, a first-in-class GLP-1 receptor agonist, is used to control glycaemic levels in type 2 diabetes. There are two approved injectable formulations: one solution for immediate action and one dispersion for prolonged action. Oral exenatide has low bioavailability due to poor gastrointestinal stability and absorption. To address these obstacles, we designed Solid Lipid Nanoparticles (SLN) including DOTAP in the formulation to yield high exenatide encapsulation by hydrophobic ion pairing and DSPE-PEG2kDa to convey colloidal stability and mucus diffusivity. The microfluidic production of SLN yielded 9.7 % exenatide encapsulation and 94.2 % loading efficiency. SLN exhibited solid cored-spherical morphology with sizes of about 120 nm and zeta potential of + 53 mV. The SLN surface charge was modulated by DSPE-PEG2kDa coating; 10 and 30 w/w% DSPE-PEG2kDa /lipid ratios yielded slightly positive and neutral zeta potentials, respectively. All SLN formulations provided exenatide protection from proteolytic enzymes. The non-PEGylated SLN resulted in a twofold increase of exenatide delivery across Caco-2 cell monolayers compared to the peptide solution. The 10 w/w% SLN PEGylation reduced the exenatide delivery compared to non-PEGylated SLN through Caco-2 cell monolayers. However, the exenatide delivery with 10 w/w% PEGylated SLN across mucus-producing Caco-2/HT29-MTX coculture layer was 2-fold higher compared to the unformulated peptide, and 1.5 higher than non-PEGylated SLN. The 30 w/w% SLN PEGylation did not improve the peptide transport neither through Caco-2 cell monolayers nor through Caco-2/HT29-MTX coculture layer
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Co-delivering of Docetaxel and Curcumin using polymeric nanoconstructs for the treatment of Neuroblastoma
No full textVariations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Squared PLGA microPlates as injectable depot for the management of Post-Traumatic Osteoarthritis
No full textAppropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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