Search Results (1,256)

Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60–73) and median two (range 1–4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2–11.8) and 1.5 months (95% CI 0.9–4.4), respectively. Prolonged survival (range 10.2–27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA. Full article

Spodoptera frugiperda is a highly destructive migratory pest of global concern that infests a wide range of crops, particularly maize, as well as rice and sugarcane, causing substantial economic losses in China. Since its invasion of China, S. frugiperda has experienced prolonged insecticide selection pressure, resulting in the accelerated evolution and increasing prevalence of resistance to specific insecticides. This study aimed to elucidate the role of cytochrome P450 monooxygenase (CYP) gene families in mediating resistance to chlorantraniliprole and to evaluate the efficacy of nanoparticle-mediated delivery systems combined with P450-specific synergists for controlling S. frugiperda. Toxicity bioassays conducted on field populations demonstrated that chlorantraniliprole still retained considerable insecticidal activity. Analyses of three detoxification enzyme activities revealed a significant elevation in cytochrome P450 activity, and expression profiling of candidate CYP genes was performed using quantitative real-time PCR (qPCR). Exposure to chlorantraniliprole resulted in a 2.53-fold upregulation of CYP4G75 expression. Furthermore, nano-agrochemical formulation assays showed that the combined application of LDHs-dsCYP4G75 and chlorantraniliprole exerted a significant synergistic effect, increasing mortality by 21.99% compared with either treatment applied alone. Overall, this study provides mechanistic insights into P450-mediated resistance and offers a promising strategy to reduce reliance on chemical insecticides, thereby contributing to the development of sustainable integrated pest management (IPM) programs. Full article

Intracellular transport is essential for cellular organization and function. This process is driven by molecular motors that ferry cargo along microtubules, but is characterized by intermittent motility, where cargoes switch between directed runs and prolonged pauses. The fundamental nature of these pauses has remained a mystery, specifically whether they are periods of motor detachment and passive drifting or states of active motor engagement. By combining single-particle tracking with large-scale motion analysis, we discovered that pauses are not passive. Instead, they are active, motor-driven states. We uncovered a unifying quantitative law: the diffusivity of a vesicle during a pause scales with the square of its velocity during a run. This parabolic relationship, D_eff ∝ v², holds true for both kinesin and dynein motors, different cargo types, and a variety of cellular perturbations. We show that this coupling arises because the number of engaged motors governs motility in both states. When we reduce motor engagement, vesicles move more slowly and become trapped in longer, less mobile pauses, collectively causing them to fail to reach their destination. Our work redefines transport pauses as an essential, motor-driven part of microtubule-based cargo delivery, revealing a quantitative principle that contributes to robust cargo transport through the crowded cellular environment. Full article

Nanoemulgels have emerged as a promising hybrid drug delivery system that integrates the advantages of nanoemulsions and gels, offering enhanced drug penetration, prolonged residence time, and improved patient compliance. This review provides a comprehensive overview of the therapeutic applications of nanoemulgels in wound healing, microbial infections, skin cancer, and various dermatological disorders. The article begins with an overview of skin architecture and its implications for cutaneous drug delivery, followed by a clear distinction between transdermal and topical drug delivery systems. The mechanisms of drug transport into and through the skin are discussed in detail, highlighting the role of nano-sized carriers, particularly nanoemulsions, in overcoming the stratum corneum barrier. Mechanistic insights into nanocarrier-mediated cutaneous drug transport and their versatility as dermal delivery platforms are described. The formulation aspects of nanoemulgels, including their components and both high-energy and low-energy methods for nanoemulsion preparation, are critically discussed to elucidate their impact on formulation performance. An overview of in vitro characterization techniques and biological screening methods employed to evaluate nanoemulgel performance is presented, along with a tabulated compilation of relevant patents to highlight translational progress. Finally, current challenges, regulatory considerations, and future perspectives are discussed, underscoring the potential of nanoemulgels as a versatile and effective platform for advanced topical drug delivery. Full article

Background: The tumor microenvironment (TME) poses significant challenges to effective therapy, with cancer-associated fibroblasts (CAFs) playing a key role in tumor progression and drug resistance in triple-negative breast cancer (TNBC). Herein, a TME responsive nanocapsule, NPC-ABS/FDS, was developed utilizing baicalein, a CAFs modulator, and the cytotoxic drug doxorubicin to selectively target CAFs and tumor cells, respectively, in a stepwise manner. Methods: NPC-ABS/FDS was designed with CD13-mediated primary targeting for tumor accumulation and secondary targeting via σ-receptor binding (ABS nanoparticles) for CAFs and folate modification (FDS nanoparticles) for cancer cells. Physicochemical properties were assessed using TEM, particle size, and ζ-potential analyses. Fluorescence imaging evaluated tumor retention, while cellular uptake and TME modulation were analyzed in vitro and in vivo. Results: The successful preparation of NPC-ABS/FDS was demonstrated by its uniform morphology, stable characteristics, charge reversal, and increased particle size. Fluorescence imaging confirmed prolonged peritumoral retention. Cellular uptake increased 2.5-fold for baicalein in CAFs and 4.3-fold for doxorubicin in cancer cells. NPC-ABS/FDS downregulated α-SMA and FAP, reducing CAFs activation, improving intratumoral drug penetration, and enhancing CD8⁺ and CD4⁺ T cell infiltration while decreasing regulatory T cells. Conclusions: NPC-ABS/FDS effectively modulates multiple TME components, including CAFs and immune cells, and improves drug delivery in TNBC. These findings may support the development of improved therapeutic approaches for TNBC. Full article

Background/Objectives: Poly(lactic-co-glycolic acid) (PLGA) microspheres offer sustained drug delivery but often suffer from broad particle size distribution (PSD), leading to inconsistent release profiles. This study investigates wet sieving as a post-processing strategy to precisely control PSD, quantified by the Span value, and evaluates its impact on the performance of triamcinolone acetonide (TA)-loaded PLGA microspheres. Methods: Triamcinolone acetonide-loaded PLGA microspheres were prepared via emulsification-solvent evaporation. Wet sieving was employed as a post-processing strategy to obtain distinct particle size fractions and groups with defined polydispersity (Span values). The microspheres were characterized for particle size distribution, drug loading, surface morphology, and in vitro release kinetics. To establish the in vivo relevance of polydispersity control, the pharmacokinetic profiles of different Span groups were first determined using LC-MS/MS following intra-articular injection in rats. Subsequently, their therapeutic efficacy was evaluated in a rat model of knee osteoarthritis, with outcomes assessed by joint swelling measurement and histopathological analysis. Results: Microspheres were prepared, fractionated into distinct size groups (0–20, 20–28, 28–40, 40–50, >50 μm) and polydispersity groups (Span = 1.4, 0.8, 0.5). We identified Span as a dominant factor independent of mean particle size. Reducing the Span from 1.4 to 0.5 significantly decreased burst release (24.15% to 14.51%), prolonged mean residence time (MRT 88.52 to 123.53 h), and enhanced anti-inflammatory and cartilage-protective effects in a rat model of knee osteoarthritis. Conclusions: This work establishes Span ≤ 0.5 as a critical quality attribute and presents wet sieving as a simple, effective method to ensure batch-to-batch consistency and predictable in vivo performance for PLGA microsphere products. Full article

Background/Objectives: Peritoneal metastases (PMs) remain difficult to treat because the peritoneum–plasma barrier limits drug penetration from the systemic circulation. Intraperitoneal chemotherapy (IPC), particularly repeated intraperitoneal (IP) administration via implantable ports, can achieve high local drug exposure with prolonged retention. This review summarizes the pharmacological rationale, clinical evidence, and future directions of catheter-based IPC, with emphasis on combined IP and systemic chemotherapy for ovarian, gastric, and pancreatic cancers. Methods: We narratively reviewed prospective clinical trials and key retrospective studies evaluating IPC and compared repeated catheter-based IPC with hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). Efficacy, safety, practice considerations, and opportunities for ascites-based monitoring were examined. Results: In ovarian cancer, several randomized trials demonstrated improved progression-free survival (PFS), and in selected trials, improved overall survival (OS) was demonstrated using IP plus intravenous (IV) therapy, although in the latter trials, toxicity and catheter-related complications limited treatment completion. A phase III Intraperitoneal Therapy for Ovarian Cancer with Carboplatin (iPocc) trial further showed significantly prolonged PFS with IP carboplatin and weekly paclitaxel, with non-catheter-related toxicity comparable to that of IV therapy. In gastric and pancreatic cancer, phase II studies reported symptomatic control, cytologic conversion, and higher rates of conversion surgery in selected patients, although confirmatory phase III data are limited. Device complications, including infection, obstruction, and leakage, occurred, but were manageable. Conclusions: Repeated catheter-based IPC is a feasible approach that enhances intraperitoneal drug delivery and complements IV chemotherapy. Future priorities include randomized trials, pharmacokinetic optimization, and biomarker-guided patient selection, supported by serial ascites assessment to refine indications and improve outcomes. Full article

Conventional gelatin capsules deliver a rapid drug release in the stomach, which is suboptimal for therapies requiring controlled and delayed release, emphasizing the need for customizable drug delivery systems for precision medicine. This study’s objective was to optimize 3D-printed capsule shells formulated with pH-responsive polymer blends—hydroxypropyl methylcellulose acetate succinate (HPMC-AS), PEG-4000, and PVA—to achieve controlled and sustained drug release, comparing profiles against a commercial enteric capsule. Capsule shells were produced via fused filament fabrication (FFF) at two ratios (80:15:5 and 70:20:10), filled with acetaminophen (250 mg), and tested using a two-stage dissolution method (simulated gastric fluid (SGF) for 2 h followed by simulated intestinal fluid (SIF) for 4–5 h). Results showed negligible drug release in SGF (≤5%) for both printed and commercial capsules. However, in SIF, the commercial capsule released its payload rapidly (>80% within 15 min), while the 3D-printed capsules achieved a prolonged, gradual release. The higher HPMC-AS content significantly extended the release duration. All capsules met the pharmacopeial weight uniformity criteria. In conclusion, the 3D-printed shells provided a controllable, sustained drug release profile, underscoring 3D printing’s potential to create tunable, patient-specific dosage forms. Full article

Background/Objectives: Cisplatin (CDDP) is widely used in the treatment of non-small cell lung cancer (NSCLC); however, its clinical efficacy is limited by severe systemic toxicity. Hyaluronic acid (HA) modification enables the targeting of CD44-overexpressing cancer cells, enhances biocompatibility, provides controlled drug release, and prolongs systemic circulation. This study aimed to develop high-molecular-weight hyaluronic acid-modified, cisplatin-loaded mesoporous silica nanoparticles (HA-MSN-CDDP) to selectively target CD44-overexpressing lung adenocarcinoma cells. Methods: HA-MSN-CDDP nanoparticles were synthesized via the sol–gel method and characterized by FTIR, DLS, SEM, and TEM methods. Antitumor efficacy was evaluated using both in vitro and in vivo xenograft lung cancer models in mice. Results: HA modification enabled controlled and sustained release of cisplatin from the HA-MSN-CDDP drug delivery system. Through HA-mediated receptor-dependent endocytosis, the nanoparticles exhibited enhanced cellular uptake and selective cytotoxicity toward CD44-positive cells. HA-MSN-CDDP significantly reduced the cytotoxic, genotoxic, and oxidative stress effects of free cisplatin on healthy cells while markedly enhancing apoptosis in A549-Luc-C8 cells. The system showed excellent hemocompatibility, supporting its potential for intravenous use. In vivo, HA-MSN-CDDP effectively suppressed tumor growth, mitigated lipid peroxidation, and preserved antioxidant enzyme activities (SOD and CAT) in major organs. Histological analyses confirmed reduced cisplatin-induced nephrotoxicity. Conclusions: HA-MSN-CDDP demonstrates strong potential as a targeted chemotherapeutic platform for NSCLC, combining high antitumor efficacy with reduced systemic toxicity. Full article

Lung cancer in never-smokers (LCINS) represents a distinct clinical entity driven by dominant oncogenic alterations and characterized by a low tumor mutational burden. Although tyrosine kinase inhibitors (TKIs) achieve high initial response rates, their long-term efficacy is limited by suboptimal pharmacokinetics, restricted central nervous system (CNS) penetration, tumor microenvironment barriers, and acquired resistance. In this review, we critically assess the current state of nanotechnology-assisted drug delivery systems for LCINS, with a primary focus on how rationally designed nanocarriers can overcome biological barriers, enable molecular subtype-specific therapeutic strategies, and address mechanisms that limit clinical efficacy and durability of response. We conducted a structured literature search using PubMed and Web of Science (January 2022 to November 2025), focusing on primary studies reporting the preparation, physicochemical properties, and therapeutic performance of nanocarriers in in vitro and in vivo models, as well as available pharmacokinetic and clinical data. LCINS is characterized by inefficient vasculature, high extracellular matrix density, active efflux transporters, and immunosuppressive niches, and is frequently complicated by brain metastases. Nanocarrier-based platforms can enhance aqueous solubility, prolong systemic circulation, and improve tumor or CNS targeting. Co-delivery systems combining TKIs with nucleic acid-based therapeutics, together with stimuli-responsive platforms, offer the potential for simultaneous modulation of multiple oncogenic pathways and partial mitigation of resistance mechanisms. In summary, nanotechnology provides a promising strategy to improve both the efficacy and specificity of targeted therapies in LCINS. Successful clinical translation will depend on biologically aligned carrier–payload combinations, scalable and reproducible manufacturing processes, and biomarker-guided patient selection. Full article

More than 90% of bladder cancers are classified as urothelial carcinomas (UC), with approximately 75% of these cases presenting as non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette–Guérin (BCG) is the current standard immunotherapy for NMIBC, yet it suffers from limited efficacy, frequent tumor recurrence, and substantial toxicity. These limitations underscore the need for safer, more effective, and accessible alternatives. We investigated whether uropathogenic Escherichia coli (UPEC), a natural inducer of immune responses in the bladder, could serve as a novel intravesical immunotherapeutic agent. Using orthotopic bladder cancer models in both mice (MB49-luc) and rats (AY-27), we evaluated the efficacy, specificity, immune dependence, and safety of formaldehyde-inactivated UPEC strains, including mutants with altered type 1 fimbriae expression. Intravesical administration of inactivated UPEC significantly reduced tumor burden and prolonged survival, outperforming BCG in murine models and demonstrating equivalent efficacy with markedly reduced toxicity in rats. The antitumor effect was T cell-dependent and partially mediated by type I fimbriae, which facilitated tumor-specific adhesion. Notably, systemic (subcutaneous) administration of UPEC abrogated efficacy and increased mortality, emphasizing the necessity of localized bladder delivery. In conclusion, we identify inactivated UPEC as a potent, tumor-targeting, and T cell-dependent immunotherapeutic agent with a superior safety profile compared to BCG. This approach might represent a promising and practical alternative for bladder cancer treatment. Full article

Glioblastoma multiforme (GBM) is characterized by aggressive growth, extensive vascularization, high metabolic malleability, and a striking capacity for therapy resistance. Current treatments involve surgical resection and concomitant radiation therapy and chemotherapy, prolonging survival times marginally due to the therapy resistance that is built up by the tumor cells. A growing body of research has identified exosomes as critical enablers of therapy resistance. These nanoscale vesicles enable GBM cells to disseminate oncogenic proteins, nucleic acids, and lipids that collectively promote angiogenesis, maintain autophagy under metabolic pressure, and suppress apoptosis. As interest grows in targeting tumor communication networks, exosome-based therapeutic strategies have emerged as promising avenues for improving therapeutic outcomes in GBM. This review integrates current insights into two complementary therapeutic strategies: inhibiting exosome biogenesis and secretion, and engineering exosomes as precision vehicles for the delivery of anti-tumor molecular cargo. Key molecular regulators of exosome formation—including the endosomal sorting complex required for transport (ESCRT) machinery, tumor susceptibility gene 101 (TSG101) protein, ceramide-driven pathways, and Rab GTPases—govern the sorting and release of factors that enhance GBM survival. Targeting these pathways through pharmacological or genetic means has shown promise in suppressing angiogenic signaling, disrupting autophagic flux via modulation of autophagy-related gene (ATG) proteins, and sensitizing tumor cells to apoptosis by destabilizing mitochondria and associated survival networks. In parallel, advances in exosome engineering—encompassing siRNA loading, miRNA enrichment, and small-molecule drug packaging—offer new routes for delivering therapeutic agents across the blood–brain barrier with high cellular specificity. Engineered exosomes carrying anti-angiogenic, autophagy-inhibiting, or pro-apoptotic molecules can reprogram the tumor microenvironment and activate both the intrinsic mitochondrial and extrinsic ligand-mediated apoptotic pathways. Collectively, current evidence underscores the potential of strategically modulating endogenous exosome biogenesis and harnessing exogenous engineered therapeutic exosomes to interrupt the angiogenic and autophagic circuits that underpin therapy resistance, ultimately leading to the induction of apoptotic cell death in GBM. Full article

Background/Objectives: Peri-implantitis is a chronic inflammatory condition affecting tissues surrounding dental implants and is characterized by progressive marginal bone loss that can ultimately lead to implant failure. Reduced vascularization and impaired immune clearance in peri-implant tissues contribute to persistent inflammation and limited therapeutic efficacy. MicroRNAs (miRNAs), particularly miR-21, have emerged as key regulators of inflammatory responses and bone remodeling. The objective of this study was to develop a bioactive dental implant coating capable of locally delivering miR-21 to modulate inflammation and promote peri-implant tissue regeneration, thereby preventing peri-implantitis. Methods: Cationic nanoparticles were synthesized using lecithin and low-molecular-weight polyethylenimine (PEI) as a non-viral delivery system for miR-21. Lecithin was employed to enhance biocompatibility, while PEI functionalization provided a positive surface charge to improve miRNA complexation and cellular uptake. The resulting lecithin–PEI nanoparticles (LEC–PEI NPs) were incorporated into a chitosan-based coating and applied to titanium implant surfaces to obtain a sustained miR-21–releasing system (miR21-implant). Transfection efficiency and biological activity were evaluated in human periodontal ligament fibroblasts (hPDLFs) and compared with a commercial transfection reagent (Lipofectamine). Release kinetics and long-term activity of miR-21 from the coating were also assessed. Results: MiR-21-loaded LEC–PEI nanoparticles demonstrated significantly higher transfection efficiency than Lipofectamine and retained marked biological activity in hPDLFs relevant to peri-implantitis prevention. The chitosan-based nanoparticle coating enabled controlled and sustained miR-21 release over time, supporting prolonged modulation of inflammatory and osteogenic signaling pathways involved in peri-implant tissue homeostasis. Conclusions: The miR21-implant system, based on lecithin–PEI nanoparticles incorporated into a chitosan coating, represents a promising therapeutic strategy for peri-implantitis prevention. By enabling sustained local delivery of miR-21, this approach has the potential to preserve peri-implant bone architecture, modulate chronic inflammation, and enhance the osseointegration of titanium dental implants. Full article

To address the bottlenecks of low water and fertilizer utilization efficiency and limited yield potential inherent in Henan Province’s traditional winter wheat cultivation model of “furrow irrigation + conventional row seeding”, this study delved into the synergistic regulatory mechanisms of drip irrigation combined with wide-row precision seeding. It focused on their effects on the physiological ecology and yield-quality traits of winter wheat. A two-factor experiment, encompassing “sowing method × irrigation method” will be carried out during the 2024–2025 wheat growing season, featuring four treatments: furrow irrigation + conventional row seeding (QT), drip irrigation + conventional row seeding (DT), furrow irrigation + wide-row precision seeding (QK), and drip irrigation + wide-row precision seeding (DK). Results reveal that wide-row precision seeding optimized the canopy structure, raising the leaf area index (LAI) at the heading stage by 20.19% compared to QT, thereby enhancing ventilation and light penetration and reducing plant competition. Drip irrigation, with its precise water delivery, boosted the net photosynthetic rate of the flag leaf 35 days after flowering by 62.99% relative to QT, stabilizing root water uptake and significantly delaying leaf senescence. The combined effect of the two treatments (DK treatment) synergistically improved the canopy structure and photosynthetic performance of winter wheat, prolonging the functional period of green leaves by 29.41%. It established a highly efficient photosynthetic cycle, marked by “high stomatal conductance-low intercellular CO₂ concentration-high net photosynthetic rate”. The peak net photosynthetic rate (P_n) 13 days post-flowering rose by 23.9% compared to QT. Moreover, while reducing total water consumption by 21.4%, it substantially increased water use efficiency (WUE) and irrigation water use efficiency (IWUE) by 43.2% and 14.2%, respectively, compared to the QT control. Ultimately, the DK treatment achieved a synergistic enhancement in both yield and quality: grain yield increased by 14.7% compared to QT, wet gluten content reached 35.5%, and total protein yield per unit area rose by 13.1%. This study demonstrates that coupling drip irrigation with wide-row precision seeding is an effective strategy for achieving water-saving, high-yield, and high-quality winter wheat cultivation in the Huang-Huai-Hai region. This is achieved through the synergistic optimization of canopy structure, enhanced photosynthetic efficiency, and improved WUE. These findings provide a mechanistic basis and a scalable agronomic solution for sustainable intensification of winter wheat production under water-limited conditions in major cereal-producing regions. Full article

Objective: The objective was to evaluate the optimal timing of cervical cerclage insertion for perinatal outcomes, such as birthweight, gestational week, and pregnancy prolongation in women with diagnosed cervical insufficiency (CI). Methods: This retrospective study was conducted at the 1st Department of Obstetrics and Gynaecology of the Medical University of Warsaw, over a 10-year period. Maternal and perinatal outcomes were compared between 75 women divided into three groups based on the gestational week (GW) at cerclage insertion: (1) before 18 GW (n = 31), (2) 18–22 GW (n = 31), (3) after 22 GW (n = 13). Only single pregnancies were included in the final analysis in order to maintain the homogeneity of the population. The primary outcomes included the week of delivery and pregnancy prolongation following cervical cerclage insertion. Numerous secondary outcomes were also evaluated, including neonatal mortality, need for NICU hospitalization, Apgar score, birthweight, maternal white blood cell (WBC) count and C-reactive protein (CRP) levels. Results: Birth week was significantly associated with GW at insertion—35.8 ± 3.8 vs. 34.8 ± 5.2 vs. 32 ± 5.7, respectively, p = 0.016. Moreover, statistical difference was also found regarding birthweight of the analysed groups—2723.8 ± 951.6 g vs. 2518.5 ± 1167.9 g vs. 1886.7 ± 1011.2 g, respectively, p < 0.001, and pregnancy prolongation following cerclage insertion 20.4 ± 4.2 vs. 14.7 ± 5.5 vs. 7.3 ± 5.7 weeks, respectively, p < 0.001. Conclusions: Earlier cerclage placement (<18 weeks) is associated with significantly improved perinatal outcomes. However, this association largely reflects the benefit of prophylactic intervention over emergency ‘rescue’ procedures (common in the >22-week group). The sharp decline in outcomes after 22 weeks highlights the risks of advanced cervical dilation, suggesting that clinical management should prioritize risk assessment within the prophylactic window. Full article