The study reports a bio-derived hybrid nanogel in which boswellic acid (BOS) is chemically integrated into chitosan to form chitosan-boswellic acid (CS-g-BOS) hydrogel precursors. Network formation employed a formaldehyde-assisted step to generate hydrogel precursors, which were subsequently converted into nanogels via sodium tripolyphosphate (STPP)-mediated ionic condensation. This two-stage approach yielded a shear-thinning, porous hydrogel precursor and pH-responsive nanogels suitable for injectable formulations.
BOS functions as a bioactive network modifier and provides hydrophobic domain-forming constituents (triterpenoids) within the chitosan matrix. The introduction of hydrophobic domains creates a heterogeneous network architecture that influences mesh size and the diffusion pathways available for encapsulated molecules.
Comprehensive physicochemical analyses were performed to evaluate structural, morphological, and mechanical properties after BOS incorporation. Characterization techniques included 1H NMR and FTIR for chemical confirmation, SEM and AFM for morphology, DLS and zeta potential for colloidal properties, thermal stability assays, and rheological analyses. The authors report that BOS incorporation altered morphology, swelling behavior, and rheological response, consistent with formation of heterogeneous, hydrophobic domain-containing networks.
The CS-g-BOS nanogels were used to encapsulate sunitinib malate (SUN). The formulation achieved a high encapsulation efficiency of 95.52%, indicating effective drug loading within the hybrid network. The high loading efficiency is attributed to the interplay between hydrophobic BOS domains and chitosan network features that favor SUN entrapment.
Drug release studies showed sustained, pH-dependent release of sunitinib over an 18-day period. Release was accelerated under acidic, tumor-mimicking conditions relative to neutral pH, demonstrating intended pH-responsive behavior. The results indicate the CS-g-BOS network swells differentially with pH, modulating mesh size and enhancing diffusion under acidic conditions commonly associated with tumor microenvironments.
The observed release profile supports the concept of a tumor-triggered increase in drug availability, leveraged by the BOS-modified chitosan matrix.
To interpret release mechanisms, the authors applied several kinetic models to the release data. Among the models tested, the Korsmeyer–Peppas model provided the best fit. This fit suggests that release of sunitinib is primarily diffusion-dominated and that diffusion is modulated by pH-dependent swelling of the CS-g-BOS network rather than by purely erosion-controlled mechanisms.
In vitro studies using A549 human lung cancer cells demonstrated cytotoxic activity and induction of apoptosis when treated with the sunitinib-loaded CS-g-BOS nanogels. These findings indicate biological efficacy against a lung cancer cell line relevant to the intended application.
Hemolysis assays were performed to assess blood compatibility. Results indicated favorable hemocompatibility in the conducted assays, suggesting the formulation does not produce overt erythrocyte lysis in the tested conditions.
Efficacy testing extended to in vivo and ex ovo models. Mouse xenograft experiments showed tumor growth suppression following treatment with the nanogel formulation, supporting antitumor activity in an animal model. Complementary antiangiogenic activity was observed in the chick chorioallantoic membrane (CAM) assay, indicating effects on blood vessel formation that are relevant to tumor growth control.
Together, these models demonstrate both direct tumoricidal effects (A549 cytotoxicity and xenograft suppression) and modulation of angiogenesis (CAM assay).
Although efficacy endpoints were promising, histological assessment revealed alterations in the liver, lungs, and kidneys after systemic exposure. These histological changes indicate potential off-target or systemic toxicity that requires further investigation and optimization of the formulation or dosing regimen to improve safety.
The authors note that systemic safety profiles must be optimized before clinical translation, as organ-level histopathology showed changes that offset some benefits of tumor suppression.
This work presents a hybrid-network strategy that couples network engineering and intrinsic therapeutic functionality by integrating a bio-derived small molecule (BOS) into a chitosan network. Key advantages demonstrated include high sunitinib encapsulation (95.52%), pH-responsive sustained release over 18 days with accelerated release under acidic conditions, diffusion-dominated release behavior consistent with the Korsmeyer–Peppas model, in vitro cytotoxicity against A549 cells, in vivo tumor growth suppression, and antiangiogenic activity in CAM assays.
However, observed histological alterations in liver, lung, and kidney tissue underscore the need for safety optimization. Future development steps cited implicitly by the reported data would include formulation tuning to reduce systemic exposure, targeted delivery strategies to limit off-target effects, and more extensive toxicology to define therapeutic windows.
Overall, the CS-g-BOS nanogel platform offers a scalable, bio-derived alternative to conventional chitosan nanogels with integrated transport control and therapeutic potential for tumor-responsive drug delivery applications.