A boswellic-acid-integrated, pH-responsive hybrid nanogel platform in which boswellic acid serves as a bioactive network modifier and hydrophobic domain-forming component within chitosan matrices offers a scalable alternative to conventional chitosan nanogels for tumor-responsive drug delivery applications.
Abstract
Stimuli-responsive chitosan-based nanogels have attracted significant interest for drug delivery; however, many reported systems rely on synthetic crosslinkers and function primarily as passive carriers with limited control over network architecture and molecular transport. Here, we report a boswellic-acid-integrated, pH-responsive hybrid nanogel platform in which boswellic acid serves as a bioactive network modifier and hydrophobic domain-forming component within chitosan matrices. Chitosan-boswellic acid (CS-g-BOS) hydrogel precursors were first formed via formaldehyde-assisted network formation and subsequently converted into CS-g-BOS nanogels via STPP-mediated ionic condensation, yielding a shear-thinning porous hydrogel precursor and pH-responsive nanogels relevant to injectable formulation development. The triterpenoid constituents of BOS contribute to the formation of a heterogeneous network, introducing hydrophobic domains that regulate mesh size and diffusion pathways. Comprehensive physicochemical characterization (1H NMR, FTIR, SEM, AFM, DLS, zeta potential, thermal stability, and rheological analyses) showed that BOS incorporation altered nanogel morphology, swelling behavior, rheological response, and release kinetics. The nanogels exhibited high sunitinib encapsulation efficiency (95.52%) and sustained, pH-dependent drug release over 18 days, with accelerated release under acidic tumor-mimicking conditions. Among the tested kinetic models, the Korsmeyer–Peppas model provided the best fit, suggesting that sunitinib malate (SUN) release is diffusion-dominated and modulated by pH-dependent swelling of the CS-g-BOS network. In vitro studies demonstrated cytotoxic and apoptosis-inducing activity against A549 human lung cancer cells, while hemolysis assays indicated favorable blood compatibility. Mouse xenograft studies showed tumor growth suppression, and the chick CAM assay demonstrated antiangiogenic activity; however, histological alterations in the liver, lungs, and kidneys indicated that systemic safety requires further optimization. Overall, this work presents a bio-derived hybrid-network strategy that integrates nanogel network engineering, transport control, and therapeutic functionality, offering a scalable alternative to conventional chitosan nanogels for tumor-responsive drug delivery applications.
Curcumin is a bioactive compound with significant therapeutic potential, yet its clinical application is limited by poor aqueous solubility and low gastrointestinal bioavailability. In this study, a fully polysaccharide-based delivery system was rationally designed using alginate and ι-carrageenan as complementary polyanionic matrices, combined with chitosan microparticles (~1.7 μm) as discrete cationic domains. Hierarchical beads were formed via ionotropic crosslinking with Ca2+ and structurally characterized by spectroscopic, morphological, and interfacial analyses, revealing a compositionally heterogeneous architecture with chitosan microparticles preferentially localized near the bead periphery. This organization directly influenced the system's physicochemical behavior, leading to limited curcumin release under simulated gastric conditions (<20%) and pronounced swelling in simulated intestinal fluid, reaching up to 4755% at 37 °C. In intestinal medium, the beads exhibited a sustained and complete release profile within ~30 h, governed by combined diffusion and polymer relaxation mechanisms. Kinetic modeling confirmed a transition from predominantly Fickian diffusion in acidic conditions to anomalous transport in intestinal environments. These findings demonstrate that hierarchical organization and electrostatic interactions can be strategically engineered to modulate structure-property relationships in multicomponent polysaccharide systems. This work provides insights into the rational design of fully biopolymeric platforms for the controlled oral delivery of hydrophobic bioactive compounds.
L. G. Schlüter, H. C. Grahl, L. N. Carli et al.· International Journal of Bio...· 0 citations
Cisplatin-loaded biopolymeric nanogels are promising carriers for sustained anticancer drug delivery; however, establishing physically interpretable links between formulation structure, transport behavior, and temperature-dependent release remains challenging. Here, mucilage-alginate-coated chitosan (MACC) nanogels were developed and evaluated using an integrated framework combining empirical kinetic analysis, mechanistic thermo-diffusive modeling, and complementary interfacial characterization. Basil seed mucilage was incorporated as a hydrophilic shell modifier to tune nanogel physicochemical behavior and release performance. The optimized MACC₂ formulation showed stable core-shell morphology, an average particle size of 75 ± 12 nm, and an encapsulation efficiency of 46.85%. In vitro assays demonstrated high compatibility with normal fibroblast cells and dose-dependent inhibition of MCF-7 breast cancer cells, supporting controlled cisplatin delivery. Drug release in PBS (pH 7.4) followed a biphasic profile with an initial burst stage and a sustained diffusion-dominated regime. Temperature-dependent studies at 35-39 °C showed accelerated release, with effective diffusion coefficients increasing from 2.0 × 10-21 to 3.6 × 10-21 m2 s-1, while Arrhenius analysis supported thermally activated transport within the hydrated polymeric matrix. Empirical kinetic modeling further indicated predominantly diffusion-controlled release with secondary polymer-relaxation contributions. Air-water interfacial tensiometry showed reduced interfacial activity for mucilage-containing nanogels, consistent with increased aqueous affinity and formulation-dependent physicochemical behavior. These measurements were interpreted as complementary descriptors rather than direct evidence of hydration or bulk diffusion. Overall, this integrated empirical-mechanistic-interfacial framework provides a physically interpretable approach for analyzing thermo-diffusive cisplatin transport in hydrated biopolymeric nanogels.
M. Lotfi, Mojtaba Shafiee, A. Sharipova et al.· Colloids and Surfaces B: Bio...· 0 citations
Overall, the Eu-S100@TCh/CS microbead system represents a rationally designed colon-targeted delivery platform with potential to improve local therapeutic efficacy and reduce systemic toxicity.
Huma Hameed, Syed Muhammad Ahmad, Shazia Akram Ghumman et al.· RSC Advances· 0 citations
Methotrexate (MTX) is an effective disease-modifying antirheumatic drug for the treatment of chronic inflammatory disorders; however, its clinical application is limited by poor bioavailability, rapid systemic clearance, and dose-dependent adverse effects. In this study, a pH-responsive methotrexate-loaded chitosan/poly(lactic-co-glycolic acid) ((Chit/PLGA)/MTX) nanogel was developed to improve drug delivery and therapeutic performance. The nanogel was fabricated by ionic gelation followed by gamma radiation-induced in situ free-radical polymerization (20 kGy) and subsequently loaded with methotrexate using a pH-triggered swelling-shrinking encapsulation strategy. Physicochemical characterization by TEM, DLS, FTIR, UV-Vis spectroscopy, and zeta potential analysis confirmed the successful formation of spherical nanogel particles with an average hydrodynamic diameter of 125 nm, a polydispersity index of 0.18 ± 0.03, and a zeta potential of -2.5 mV. The nanogel exhibited a high encapsulation efficiency (89.3 ± 2.1%) and drug-loading capacity (15.1 ± 0.8%). In vitro release studies demonstrated pronounced pH-responsive behavior, with cumulative methotrexate release reaching approximately 60% at pH 5.5 compared with 40% at pH 7.4 after 300 s, indicating preferential drug release under acidic inflammatory conditions. Cytotoxicity evaluation showed that the nanogel formulation exhibited improved biocompatibility (IC₅₀ = 422.5 μg/mL) compared with free methotrexate (IC₅₀ = 311.7 μg/mL). The (Chit/PLGA)/MTX nanogel significantly enhanced antioxidant activity, exhibiting 79.1% DPPH radical scavenging, 81.8% membrane stabilization, and 83.3% inhibition of protein denaturation. Furthermore, the formulation effectively suppressed the expression of major inflammatory mediators, including COX-2 (37.2%), iNOS (47.2%), TNF-α (40.3%), and NF-κB (40.9%), while reducing IL-1β (33.5%) and IL-6 (45.0%) production. Collectively, these findings demonstrate that the pH-responsive Chitosan-PLGA nanogel provides efficient methotrexate encapsulation, controlled drug release, enhanced antioxidant activity, and potent anti-inflammatory effects, highlighting its promise as a nanocarrier platform for the treatment of chronic inflammatory diseases.
R. Darwesh, Sarah Alharthi, N. H. Al-Shaalan et al.· Bioorganic chemistry (Print)· 0 citations
Stable hydrogel formation with favorable porous architecture, swelling behavior, thermal stability, and homogeneous distribution of nanovesicles was well established and exhibited excellent biocompatibility, hemocompatibility, and enhanced cell-material interactions.
Rizos Evangelos Bikiaris, Ioanna Koumentakou, A. Niti et al.· ACS Applied Bio Materials· 0 citations
Ulcerative colitis (UC) is a chronic inflammatory bowel disease for which effective oral colon-targeted therapies remain limited. Sinapic acid (Sin), a dietary polyphenol, has demonstrated therapeutic potential in UC due to its antioxidant and anti-inflammatory properties; however, its clinical application is hindered by poor stability and low water solubility. To address these limitations, we designed a smart macromolecular double-network hydrogel based on quaternized chitosan (QCTS) derivatives and glycyrrhizic acid (GA) self-assembled hydrogel to enhance targeted Sin delivery for UC treatment. Specifically, Sin was conjugated to QCTS via reduction-cleavable disulfide linkages and dynamically crosslinked with aldehyde-functionalized GA through Schiff-base reactions, yielding the double-network hydrogel, QSAG. QSAG demonstrated structural robustness, colon-targeting capability, and reduction-responsive drug release under inflammatory conditions, which was evidenced by swelling equilibrium within 120 min, 94.23% degradation in simulated colonic fluid within 24 h, and a cumulative Sin release of 83.66% under 10 mM GSH. In vivo imaging confirmed prolonged colonic retention of QSAG in the inflamed colon for at least 24 h and localized drug accumulation. Therapeutic efficacy was evaluated in a 3% DSS-induced UC mouse model following 5 days of treatment. Both in vitro and in vivo studies revealed that QSAG effectively alleviated colitis by suppressing oxidative stress and inflammation while promoting intestinal barrier repair. Collectively, this dual-crosslinked QSAG hydrogel, with its structural stability and inflammation-responsive drug release, represents a promising oral platform for targeted and enhanced UC therapy.
Mengqi Shen, Shuai Sun, Huilin Zhu et al.· International Journal of Bio...· 0 citations
