Pharmaceutical Research最新文献

Introduction: The nonpsychoactive cannabinoid cannabidiol (CBD) has shown a wide range of pharmacological effects that are beneficial for wound healing. However, its local delivery is challenged by a very low aqueous solubility.

Methods: In this work, we synthesized hierarchical hydrogels made of the fructan hydrolyzed levan crosslinked with glycerol diglycidyl ether and loaded them with CBD nanoencapsulated within Pluronic^® F127 polymeric micelles (25% w/w payload).

Results: Hydrogels showed the typical porous structure (high resolution-scanning electron microscopy) and water uptake capacity up to ~ 1700%. The CBD release kinetics was studied in water (pH 6.8) and phosphate buffered saline (pH 7.4) under sink conditions, at 37°C. An initial burst release stage within the first 2 h of the assay was followed by a more sustained release stage over 72 h. As expected, hydrogels with a lower crosslinking density exhibited faster CBD release in both media. Release data fit the Korsmeyer-Peppas model with a combined mechanism involving diffusion and polymer chain relaxation together with the release of CBD-loaded polymeric micelles. The good compatibility of the hydrogels was initially confirmed in the monocyte-derived human macrophage cell line THP-1 over 72 h. Then, we showed > 70% viability of primary patient-derived gingival mesenchymal stem cells (GMSCs) exposed to hydrolyzed levan solutions, CBD-loaded polymeric micelle suspensions, and the CBD-loaded hydrogels for 28 days. Finally, we conducted preliminary differentiation studies of GMSCs cultured on non-loaded and CBD-loaded hydrolyzed levan hydrogels. Non-loaded hydrogels promote a transient increase in the secretion of the osteogenic marker alkaline phosphatase secretion that peaked at day 7 and declined thereafter, while CBD-loaded ones promote adipogenic differentiation.

Conclusion: Overall, results demonstrate the potential of levan hydrogels as platforms for local drug delivery applications.

The peritoneal cavity presents both unique challenges and promising opportunities for targeted therapy in malignancies like ovarian, gastric, pancreatic, and colorectal cancers. Intraperitoneal drug delivery offers significant pharmacokinetic advantages over intravenous administration by achieving high local drug concentrations and tumor-specific delivery potential while minimizing systemic toxicity. Despite these theoretical advantages, the clinical implementation of intraperitoneal therapy is limited by several barriers, including restricted tissue penetration, incomplete peritoneal coverage, rapid drug clearance, catheter-related complications, posttreatment peritoneal adhesions, and ascites-induced permeability dysregulation. This review highlights three advanced strategies developed to overcome these obstacles: (1) particulate-based delivery systems, such as nanoparticles to enhance tumor specificity through passive accumulation, active targeting and on-demand drug release in response to internal or external stimuli; (2) Sustained drug release hydrogels and (3) pressurized intraperitoneal aerosol chemotherapy. Despite promising preclinical and clinical advancements, successful translation requires systematic optimization of multiple parameters, such as ascites dynamics, tumor heterogeneity, and multidrug resistance. The integration of advanced delivery technologies with a comprehensive understanding of peritoneal physiology remains crucial for achieving safe and effective clinical applications.

Solid lipid nanoparticles (SLNs) have garnered significant interest for their safety and efficacy, especially following the success of COVID-19 mRNA vaccines. This study presents the synthesis and characterization of a novel stearic acid (SA)-gambogic acid (GA) conjugate, where GA, a xanthonoid, exhibits high affinity for the transferrin receptor (TfR) without competing with endogenous transferrin. The SA-GA conjugate was employed to formulate SLNs using a hot homogenization-ultrasonication-solvent evaporation technique for the peroral delivery of cyclosporine (CsA), paclitaxel (PTX), and urolithin-A (UA). Physicochemical properties, including particle size, zeta potential, drug loading, and entrapment efficiency, were assessed. Among the three tested compounds, UA exhibited the highest encapsulation efficiency at both 5% and 10% w/w loading, with particle sizes remaining under 250 nm. SA-GA SLNs demonstrated excellent stability in simulated gastric fluids, supporting their potential for oral administration. Cellular uptake studies using Coumarin-6 (C6) and drug-loaded SLNs indicated that UA achieved the highest uptake (~ 50%) in both FHS-74 (human small intestine) and HK2 (human kidney) cell lines. Further, in cisplatin-induced HK2 cell damage models, UA-loaded SA-GA SLNs significantly reduced inflammatory markers TLR4, NF-κB, and IL-1β. These results highlight UA-loaded SA-GA SLNs as a promising TfR-targeted oral delivery system for mitigating cisplatin-induced acute kidney injury (AKI) in cancer therapy.

Purpose: siRNA enables highly specific and targeted gene silencing, offering potential treatment for a range of diseases. Cytosolic access of siRNA is essential for efficacy; Current delivery systems generally use endosomal uptake pathways, leading to siRNA degradation due to inefficient escape. Guanidinium functionalized poly(oxanorbornene)imide (PONI) polymers facilitate direct cytosolic siRNA delivery with excellent gene knockdown efficacy in vitro and in vivo. The use of lyophilization to generate stable powders that retain excellent delivery and knockdown activity when reconstituted is demonstrated, providing a key tool for translation.

Methods: PONI-Guan polymers were mixed with siRNA to form PONI-Guan/siRNA polyplexes. The generated polyplexes were lyophilized and stored at varying temperature conditions for a total duration of 4 weeks. After reconstitution and delivery, cytosolic access of siRNA was assessed through confocal laser scanning microscopy. Knockdown efficacy was assessed in GFP expressing reporter deGFP HEK 293 T cell line using flow cytometry. Efficacy of reconstituted PONI-Guan/si_STAT3 in 4T1 breast cancer cells was evaluated by quantifying gene expression levels (qRT-PCR) and cell growth inhibition (Alamar blue assay). Delivery and therapeutic efficiency were compared between lyophilized and freshly made polyplexes.

Results: Lyophilized polyplexes retained critical functional features of freshly made polyplexes. Resuspended polyplexes facilitated effective cytosolic delivery siRNA and showed therapeutic relevance through the delivery of siRNA targeting STAT-3 gene in 4T1 cells with successful cell growth inhibition (~ 70%) and knockdown (~ 80%) of the gene.

Conclusion: Overall, this strategy signifies a highly transferrable and versatile method for effective storage of siRNA.

Background: Transdermal Drug Delivery Systems (TDDS) offer a non-invasive route for sustained systemic or localized drug delivery. By bypassing hepatic first-pass metabolism and improving bioavailability, TDDS enhances patient compliance, especially in the management of chronic diseases. Drug permeation across the skin is mediated through pathways involving the complex skin barrier, predominantly the stratum corneum, with efficacy influenced by both drug properties and skin physiology.

Methods: This review systematically integrates the fundamental mechanisms underlying TDDS, highlights cutting-edge technological advancements developed to overcome the skin barrier, and discusses their expanding clinical applications. The advanced technologies covered include permeation enhancers, vesicular systems (liposomes, transfersomes, ethosomes), microemulsions, microneedles (MNs), responsive systems (pH-, temperature-, enzyme-sensitive), and 3D printing.

Results: These innovative technologies effectively enhance drug flux, enable targeted delivery, and achieve spatiotemporal control of drug release. Clinically, FDA-approved TDDS formulations have been successfully applied to manage various conditions, including chronic pain (fentanyl, buprenorphine), neurological disorders (rotigotine, rivastigmine), cardiovascular diseases (nitroglycerin, clonidine), hormone replacement, and substance dependence (nicotine). Despite significant clinical value, TDDS still faces challenges such as limitations in delivering macromolecules, potential skin irritation, and inter-individual variability.

Conclusion: Future directions in TDDS research focus on integrating nanotechnology, AI-driven optimization, wearable sensors, and closed-loop smart systems. These integrations aim to achieve greater precision, personalization, and efficiency in transdermal drug delivery, providing valuable insights for future research and translational development.

Background: Jatyadi Taila (JT) is an Ayurvedic herbal formulation traditionally used for wound healing. However, its oily nature restricts clinical use due to greasy texture, slower absorption, occlusiveness, and application difficulties, resulting in poor patient compliance.

Objectives: To develop and optimize a JT containing nanoemulsion (JT-NE) and incorporate it into a Carbopol-based hydrogel for enhanced wound healing efficacy.

Methods: JT-NE was developed using a Quality by Design (QbD) approach and incorporated into a Carbopol-based hydrogel. The formulations were characterized for physicochemical properties, rheology, and morphology. In vitro fibroblast proliferation and migration assays, along with in vivo wound healing studies in full-thickness wound-bearing Wistar rats, were performed to evaluate therapeutic efficacy.

Results: The optimized JT-NE formulations exhibited a globule size range of 220-300 nm, polydispersity index (0.245-0.380), and zeta potential values of -25.94 ± 1.01 mV, 18.14 ± 1.20 mV, and -26.10 ± 1.25 mV. Hydrogels containing JT-NE demonstrated thixotropic behavior with an average viscosity of 88748 mPa, pH 4.5-5.5, a porous mesh-like morphology with entrapped JT-NE, and ~70% water loss within 4 h. In vitro, JT-NE significantly promoted fibroblast proliferation and migration. In vivo, the formulation enhanced wound closure, increased collagen biosynthesis, downregulated TNF-α, and upregulated KI-67 expression compared to untreated and JT treated groups.

Conclusion: The JT-NE hydrogel significantly improved the therapeutic efficacy of JT, offering a novel, patient-compliant delivery system for effective wound management.

Nanoparticles (NPs), due to their small size and large surface area, have advanced their use as drug carriers for delivering various therapeutic molecules. When entering biological environments, nanoparticles typically adsorb proteins, forming a surface layer known as a protein corona that significantly affects the biological and therapeutic functions of a delivery system. Understanding and predicting protein adsorption is essential for optimizing nanoparticle design in drug delivery, diagnostics, and therapy. Machine learning and deep learning (ML/DL) offer promising methods for designing nanoparticles with specific properties, particularly given recent advancements in computation and nanoparticle analysis. This review explores ML/DL studies of nanoparticle-protein interactions and emphasizes the popularity of Random Forest (RF) and Deep Learning (DL) models in predicting protein corona compositions. RF models are highly valued for managing high-dimensional data and offering interpretability, which helps identify key NP features influencing protein adsorption. Conversely, DL excels at modeling non-linear relationships and detecting subtle interaction patterns. While most current research focuses on protein coronas, future models may also include other biocorona components. This is particularly relevant for soft materials, such as lipid nanoparticles (LNPs), which are now approved for delivering mRNA and peptide-based vaccines. Our findings underscore the need for advanced modeling techniques and high-quality, diverse experimental data to drive innovations in nanomedicine. Combining RF and DL approaches leverages their complementary strengths to overcome the challenge of limited experimental data and further improve NP designs for biomedical use.

Background: Therapeutic proteins are playing an increasingly important role in marketed drugs and clinical candidates. However, their development still faces major challenges, particularly aggregation.

Objectives: This review explores the recent advancements, current limitations, and future directions of new research methods for therapeutic proteins.

Results: Characterization techniques identify aggregation tendencies and elucidate underlying mechanisms, while computational chemistry provides microscopic insights into the aggregation process. Theoretical modeling and machine learning offer tools for predicting protein stability, enabling high-throughput screening in early formulation development.

Conclusion: Fostering interdisciplinary collaboration will be essential. The integration of diverse approaches offers a more comprehensive understanding of protein aggregation and unlocks new opportunities for innovation in protein formulation development.

The purpose of this review is to provide a concise overview of phytochemicals and their possible effects on gastrointestinal (GI) malignancies via modification of the mitogen-activated protein kinase (MAPK) signaling cascade. Abnormal activation of the MAPK pathway significantly contributes to GI cancer progression and is associated with various facets of cancer, including cellular proliferation, apoptosis, invasion, angiogenesis, and metastasis. Although standard medications are essential for managing GI cancers, their side effects frequently present considerable obstacles to the patient's quality of life. Thus, there is increasing emphasis on phytochemicals that are safe, non-toxic, and multitargeted properties. In recent years, phytochemicals have garnered significant interest in antitumor therapy, leveraging their multifaceted signaling regulatory actions to activate several biological mechanisms, thereby offering substantial benefits in tumor inhibition. These phytochemicals have the ability to reduce tumor development and induce cancer cell death by selectively inhibiting several components of the MAPK pathway in in vitro and in vivo GI cancer models. Thus, this review highlights the current knowledge on phytochemicals that modulate MAPK pathway in GI cancers, their mode of action along with their limitations. In conclusion, phytochemicals offer a promising strategy for addressing dysregulation of the MAPK pathway in gastrointestinal cancer, necessitating further investigation.

Purpose: Mechanical, interfacial, and shear stresses encountered during development, manufacturing and transportation of biologics can compromise monoclonal antibody (mAb) stability. However, most scale-down shaking models often depend solely on orbital agitation and overlook the effect of the solid-liquid interface. To study this gap, stress conditions were applied to simulate early-stage product development and real-world transportation in this work.

Methodology: Accordingly, the aggregation profiles of Cetuximab and Tocilizumab formulations, with and without polysorbate 80 (PS80), were systematically compared after applying horizontal and orbital shaking. Protein aggregation was assessed using orthogonal techniques such as size-exclusion chromatography, dynamic light scattering, flow imaging microscopy, ultraviolet-visible spectroscopy, and visual inspection.

Results: Horizontal shaking more effectively revealed Cetuximab's susceptibility to aggregation under mechanical and interfacial stress whereas orbital shaking conditions were not as discriminative. Furthermore, to explore the effect of vial surface chemistry on subsequent protein aggregation, Cetuximab was subjected to horizontal shaking stress using both untreated and silanized glass vials. Interestingly, hydrophobic silanized vials without surfactant resulted in increased Cetuximab aggregation compared to untreated vials. In contrast, Cetuximab with PS80 showed fewer aggregates in silanized vials than in glass vials.

Conclusion: These results underscore the value of selecting right-for-purpose agitation models and highlight the need to explore the triple interface for improving stress screening in drug product development.