We updated affiliation 5 from "Dotquant LLC, CoMotion Labs at University of Washington, Seattle, WA 98195, USA" to "Dotquant LLC, Seattle, WA 98195, USA", as CoMotion Labs at University of Washington is a start-up incubator [...].
We updated affiliation 5 from "Dotquant LLC, CoMotion Labs at University of Washington, Seattle, WA 98195, USA" to "Dotquant LLC, Seattle, WA 98195, USA", as CoMotion Labs at University of Washington is a start-up incubator [...].
Background/Objectives: Cytokine release during organ transplantation contributes to primary graft dysfunction and requires careful immunomodulation. CytoSorb, a hemoadsorption device developed to reduce circulating cytokine levels, is increasingly used in critically ill patients. However, its impact on concurrent immunosuppressive therapy remains unclear. Methods: In this ex vivo study, we investigated the adsorption of five immunosuppressants-cyclosporine A, tacrolimus, methylprednisolone, mycophenolic acid, and 6-mercaptopurine-using a scaled-down CytoSorb hemoadsorption circuit and compared results to chronic and acute dialysis. Additionally, a whole blood model was used to assess the functional impact of CytoSorb treatment on leukocyte activation, using LPS and anti-CD3 stimulation and subsequent cytokine measurement (TNF-α, IL-1β, IL-6, IL-8). Results: CytoSorb significantly reduced serum levels of methylprednisolone (92 ± 3%), mycophenolate (80 ± 2%), 6-mercaptopurine (65 ± 32%), and cyclosporine A (61 ± 16%), but had no significant effect on tacrolimus. Dialysis effectively removed methylprednisolone and 6-mercaptopurine, while strongly protein-bound drugs such as cyclosporine A and tacrolimus remained largely unaffected. In the whole blood model, CytoSorb treatment did not significantly alter cytokine release after immunostimulation, suggesting preserved immunosuppressive efficacy. Conclusions: CytoSorb treatment reduces the plasma concentration of selected immunosuppressants. However, short-term treatment appears to have minimal impact on immunosuppressive function. These findings support the cautious use of CytoSorb in transplant settings but highlight the need for in vivo confirmation.
Background/Objectives: Conventional solidification methods for liquid self-nanoemulsifying drug delivery systems face significant limitations. This includes complex manufacturing processes, high costs, and environmental concerns. This study aimed to develop and optimize a thermoresponsive self-nanoemulsifying drug delivery system (T-SNEDDS) for dapagliflozin as a sustainable alternative solidification technique. Methods: Oil and surfactant were selected based on solubility and emulsification studies. The Box-Behnken approach was used to examine the impacts of three independent variables (pluronic F127, propylene glycol, and dapagliflozin concentrations) on liquefying temperature and time. Optimized T-SNEDDS was characterized in terms of particle size, zeta potential, and dissolution performance. Stability assessment included centrifugation testing and a six-month storage evaluation. The green pharmaceutical performance was comparatively evaluated against five conventional solidification methods using ten adapted parameters. Results: Imwitor 308 and Cremophor EL were selected as optimal excipients for SNEDDS formulation. In addition, Pluronic F127 and propylene glycol were used to induce solidification during storage. The optimized formulation (8.60% w/w Pluronic F127, 10% w/w propylene glycol, and 5% w/w dapagliflozin) exhibited a liquefying temperature of 33.5 °C with a liquefying time of 100.3 s and a particle size of 96.64 nm. T-SNEDDS significantly enhanced dissolution efficiency of dapagliflozin (95.7%) compared to raw drug (42.4%) and marketed formulation (91.3%). Green pharmaceutical evaluation revealed that T-SNEDDS achieved the highest score compared to conventional approaches. Conclusions: T-SNEDDS represents a superior sustainable approach for SNEDDS solidification that offers enhancement in drug dissolution while addressing manufacturing, environmental, and economic challenges through its solvent-free and single-step preparation process with excellent scalability potential.
Tuberculosis (TB) remains a significant worldwide health challenge due to the limitations of conventional treatments and the rising incidence of drug-resistant Mycobacterium tuberculosis strains. This review consolidates the advancements in nanotechnology-based therapeutics, inhalable formulations, CRISPR-Cas tools, host-directed therapies (HDTs), and nanoparticle-based vaccine development aimed at enhancing TB management. Novel nanocarriers such as liposomes, solid-lipid nanoparticles (SLNs), dendrimers, and polymeric nanoparticles (NPs) offer enhanced bioavailability of drugs, sustained release, as well as targeted delivery to infected macrophages, thereby reducing systemic toxicity and dosing frequency. Inhalable nanomedicines provide localized delivery to the pulmonary site, enhancing the concentration of the drug at the primary site of infection. CRISPR-Cas technology is emerging as a transformative approach to disabling drug-resistant genes and enhancing diagnostic precision. HDTs, including agents like vitamin D and metformin, show potential in modulating host immune responses and enhancing pathogen clearance. Nanoparticle-based vaccines, including mRNA and antigen-conjugated platforms, aim to overcome the limitations of the BCG vaccine by enhancing antigen presentation and eliciting stronger, longer-lasting immunity. Collectively, these modalities mark a shift toward more personalized, effective, and less toxic TB therapies. However, challenges such as regulatory approval, safety, scalability, and accessibility remain. This review highlights the integrated potential of nanomedicine, gene editing, and immunomodulation to transform TB care and combat drug resistance, paving the way for more robust and durable treatment strategies.
Background/Objectives: The widespread use of sulfamethoxazole (SMX) has led to increasing antibiotic resistance, and there is a need for improved formulations to enhance its therapeutic effectiveness. In this study, we investigated the biocidal potential of SMX composite crystals incorporated with functionalized poly(lactic-co-glycolic acid) (nfPLGA) and nano-graphene oxide (nGO). Methods: The composites, namely SMX-nfPLGA and SMX-nGO, were synthesized via antisolvent precipitation and evaluated using Kirby-Bauer disk diffusion assays. Results: Incorporation of nfPLGA and nGO significantly improved SMX solubility, increasing it from 0.029 mg/mL to 0.058 mg/mL and 0.063 mg/mL, respectively. Additionally, the log partition coefficient (log P or Kw) also improved from 1.4 to 0.86 for nGO and 0.92 for nfPLGA composites. Both formulations exhibited improved antibacterial activity with distinct time-dependent bactericidal effects. Compared to pure SMX, the SMX-nfPLGA showed 60% and 53% greater bacterial inhibition at concentrations of 50 mg/mL and 100 mg/mL, respectively. Although SMX-nGO was slightly less potent, it still surpassed pure SMX, with 50% and 33% higher inhibition at the same concentrations. Conclusions: Importantly, neither nfPLGA nor nGO showed any biocidal effects, confirming that the observed enhancement was due to improved SMX solubility caused by their incorporation. These findings suggest that embedding solubility-enhancing nanoparticles into the existing crystal structure of the antibiotic is a promising strategy for enhancing the effectiveness.
Background: The potential of injectable hydrogels as drug depots lies in their ability to achieve local and sustained co-delivery of chemotherapeutic drugs and immunostimulants for combined tumor therapy. Method: In this study, we devised a localized chemo-immunotherapeutic strategy by co-loading the chemotherapeutic drug, oxaliplatin (OXA), and the immune-checkpoint blockade (ICB) antibody, anti-programmed cell death protein ligand 1 (anti-PD-L1), into a matrix metalloproteinase (MMP)-responsive injectable poly(L-glutamic acid) hydrogel (MMP-gel). Results: The in situ gelation of hydrogels enables local retention of OXA and model antibody IgG, as well as MMP-triggered sustained release. Meanwhile, the OXA-loaded MMP-gel caused the immunogenic cell death (ICD) of tumor cells. When administered intratumorally in mice carrying B16F10 melanoma, the MMP-gel co-loaded with OXA and anti-PD-L1 (OXA&anti-PD-L1@MMP-gel) demonstrated superior tumor suppression efficacy and prolonged the survival time of the animals with low systemic toxicity. Meanwhile, the OXA&anti-PD-L1@MMP-gel induced an increase in CD8+ T cells and M1 macrophages within tumors, and a decrease in Treg cells and M2 macrophages, demonstrating that the drug-loaded system enhanced the antitumor immune response. Moreover, the OXA&anti-PD-L1@MMP-gel effectively inhibited the growth of distal tumors in a bilateral-tumor experiment. Conclusions: Consequently, the responsive hydrogel-based chemo-immunotherapy holds potential in tumor treatment.
Fracture nonunion remains an unresolved complication after extremity fracture, with notable costs to patient quality of life and health systems. Nonunion is defined by the inability of fracture ends to unite without evidence of progressive healing over time. Approximately 2 to 10% of all fractures go onto nonunion, with increased rates observed in specific fracture locations and patient populations. Despite advances in fixation techniques and bone grafting, current treatments remain limited and frequently fail to restore durable bone healing. In this review, the current state of emerging biologic and bioengineering therapies for nonunion will be summarized, with a focus on how these advances may shift treatment from palliative reconstruction toward durable healing. Biological therapies such as growth factors, stem cells, and gene-modified constructs show promise but face challenges of short half-life, inconsistent efficacy, and safety concerns. Emerging approaches, including controlled-release scaffolds, immunomodulatory materials, stem cell-derived exosomes, and gene therapy platforms, offer opportunities to more precisely restore the osteogenic, angiogenic, and immunologic environment required for union.
Background/Objectives: Predicting whether a compound is subject to active transport is crucial in drug development. We propose a simple threshold for passive membrane permeability (Pm), derived from the cell's energy limitation, to identify compounds unlikely to be actively effluxed. Results: By considering fundamental cellular energy constraints, our approach provides a mechanistic rationale for why compounds with very high passive permeability in combination with low applied concentration will not undergo active efflux. This moves beyond the empirical observation (such as in previous systems that associate fast-permeating, poorly soluble compounds with low transporter activity) by grounding the prediction in the cell's energetic limitations. For MDCK (Madin-Darby canine kidney) cells, this threshold-normalized to the applied compound concentration (Cext)-was determined to be Pm×Cext = 10-1.7 cm/s×µM. Methods: To derive this threshold, we conducted an extensive analysis of literature-reported efflux ratios (ERs) in MDCKII cells overexpressing efflux transporters (MDR1, BCRP, MRP2; 294 datapoints across 136 unique compounds). Concentration-dependent measurements for Amprenavir, Eletriptan, Loperamide, and Quinidine-chosen because these borderline compounds exhibited the highest Pm×Cext while still being actively effluxed-enabled the most accurate determination of the threshold. Literature ER values were re-evaluated through the experimental determination of reliable Pm values, as well as newly measured ER values with MDCK efflux assays. Conclusions: The results of these assays and the re-evaluation allowed us to reclassify all but three outliers (compounds with ER > 2.5 and log(Pm×Cext) > -1.7). In contrast, more than 60% of the compounds analyzed without significant ER values (123 compounds) fell above the threshold, in strong agreement with our theory of an energy limitation to active transport. This permeability threshold thus provides a simple and broadly applicable criterion to identify compounds for which active efflux is energetically not feasible and may serve as a practical tool for early drug discovery and optimization, pending further validation in practical applications.
Background/Objectives: Sublingual vaccination offers a non-invasive route for inducing both systemic and mucosal immunity, yet the formulation properties that govern its success remain poorly defined. This study investigated the relationships among key formulation parameters for sublingual vaccines, such as viscosity, mucoadhesion, and mucosal residence, to understand their impact on in vivo immune responses in the sublingual delivery context. Methods: Ovalbumin (OVA)-based vaccine formulations containing cholera toxin B (CTB) adjuvant and mucoadhesive excipients such as hydroxypropyl methylcellulose (HPMC) or methylglycol chitosan (MGC), were evaluated for: (1) their respective rheological properties-characterized by viscosity and mucoadhesion parameters, as well as (2) in situ mucosal retention (assessed using Cy7-labeled formulations tracked by IVIS in vivo imaging system) and (3) in vivo immunogenicity via systemic (IgG) and mucosal (IgA) responses measured by ELISA, following sublingual administration to mice. Correlations between rheology, in situ/ex situ mucosal residence, and in vivo immune outcomes were determined. Results: Sublingual vaccine formulations containing HPMC exhibited the highest viscosity, mucoadhesion, and mucosal retention profiles, but paradoxically elicited the weakest systemic and mucosal antibody responses. In contrast, chitosan-based formulations enhanced immune responses even at reduced antigen and adjuvant doses, likely due to its permeation-enhancing and adjuvant effects. Correlation analyses revealed that while formulation viscosity and mucoadhesive strength were positively associated with mucosal retention, both rheological and retentive properties showed a significant inverse relationship with immunogenicity in the context of sublingual vaccine delivery. Conclusions: While viscosity and mucoadhesion are essential for in situ retention of sublingual vaccines, prolonged residence driven by excipient's excessive rheological strength was found to reduce vaccine immunogenicity-likely due to restricted antigen release and mucosal uptake. Accordingly, HPMC appears suboptimal as a sublingual vaccine excipient, while chitosan shows promise for sublingual delivery as a permeation-enhancing adjuvant. These findings may shift the design paradigm for sublingual vaccine formulations, highlighting the need to balance mucosal retention with efficient antigen absorption for maximizing immune responses.
Vitamin C, a water-soluble micronutrient, is one of the most widely used dietary supplements pertaining to its vital role in maintaining overall human health, particularly through its potent antioxidant and immune-supportive functions. This mini review summarizes key pharmacokinetic constraints of vitamin C and evaluates formulation strategies aimed at improving its systemic availability. Achieving sustained optimal plasma levels of vitamin C remains challenging due to its dose-dependent absorption, tissue saturation, rapid renal clearance, and short half-life. These pharmacokinetic limitations restrict systemic retention, with high oral doses providing only marginal increases in plasma concentrations and necessitating multiple daily administrations. Conventional vitamin C supplements show efficient absorption only at low to moderate doses, while higher intakes are restricted by transporter saturation and increased renal excretion. Alternative delivery systems such as liposomal encapsulation, esterified derivatives, nano-emulsions, and co-formulations with bioenhancers have been examined; however, evidence for prolonged systemic retention remains inconsistent. The sustained-release formulation of vitamin C shows more reliable outcomes, demonstrating prolonged plasma exposure, higher steady-state concentrations, and potential for improved compliance through reduced dosing frequency. While further robust comparative studies are needed, current evidence suggest that advanced formulation approaches, particularly sustained-release delivery, may help overcome these pharmacokinetic limitations, thereby supporting improved clinical utility of vitamin C supplementation.
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