Introduction

Cancer remains one of the leading causes of mortality worldwide, and gastric cancer is among the most aggressive malignancies because of its high incidence, late diagnosis, and poor prognosis. Conventional treatments such as surgery, radiotherapy, and chemotherapy are often associated with systemic toxicity, severe side effects, and drug resistance. Cisplatin (CDP), a widely used chemotherapeutic drug for gastric cancer, induces apoptosis through DNA damage; however, its clinical use is limited by toxicity and resistance. Nanotechnology has enabled the development of smart nanocarriers that improve drug stability, bioavailability, and targeted delivery. Cellulose nanocrystals (CNCs) are attractive drug carriers because of their biodegradability, mechanical strength, and controlled-release properties. In addition, bovine serum albumin (BSA), polyvinyl alcohol (PVA), polyethylene glycol (PEG), and hyaluronic acid (HA) improve biocompatibility and targeting efficiency through interactions with CD44 receptors overexpressed on gastric cancer cells.

Aims

This study aimed to design and evaluate a smart nanocarrier system composed of CNCs, BSA, PVA, PEG, and HA for targeted cisplatin delivery to AGS gastric cancer cells. The study investigated physicochemical properties, pH-responsive drug release, cytotoxicity, selectivity toward cancer cells, and apoptosis induction to determine the therapeutic potential of the synthesized nanocapsules.

Materials and Methods

Cellulose nanocrystals were extracted from raw cellulose using sulfuric acid hydrolysis (64%), followed by ultrasonication, centrifugation, and dialysis. Cisplatin was loaded onto CNCs at different concentrations, and drug-loading efficiency was measured spectrophotometrically at 370 nm. Multifunctional BSA-PVA-CNC-CDP nanoparticles coated with PEG-hyaluronic acid were synthesized through sequential coating and hydrogel formation processes. First, CNC-CDP complexes were coated with bovine serum albumin and stabilized in a PVA hydrogel matrix. The nanoparticle surface was then functionalized with NH2-PEG-HA using EDC/NHS coupling chemistry to enhance targeting ability and biological stability. The synthesized nanoparticles were characterized using XRD, TGA, and DLS analyses to evaluate crystalline structure, thermal stability, particle size, and zeta potential. Drug release behavior was investigated at pH 7.4 and pH 5.8 to simulate physiological and tumor microenvironments. Cytotoxicity and biocompatibility were assessed in AGS gastric cancer cells and normal GES-1 cells using the MTT assay. The selectivity index (SI) was calculated to evaluate preferential toxicity toward cancer cells. In addition, apoptosis induction was analyzed using Annexin V/PI staining and flow cytometry. Statistical analysis was performed using one-way ANOVA followed by Duncan’s multiple range test.

Results

XRD analysis demonstrated that all synthesized nanoparticles and nanocapsules exhibited predominantly amorphous structures, confirming successful incorporation of CNC-CDP complexes into the BSA-PVA matrix. TGA results showed that increasing CNC concentration from 50 to 200 mg significantly improved the thermal stability of CNC-CDP nanoparticles. Furthermore, BPC(100 mg)CP-HA nanocapsules displayed greater structural stability and lower thermal degradation compared with drug-free nanocapsules. DLS analysis indicated that increasing CNC concentration increased particle size from 322 to 363 nm while reducing zeta potential from +13.05 to +2.14 mV. Surface coating with BSA, PVA, PEG, and HA further increased particle size to 476 nm, confirming the formation of multilayered nanocapsules. Drug release studies demonstrated significantly higher cisplatin release under acidic conditions (pH 5.8) compared with physiological conditions (pH 7.4). In contrast, increasing CNC concentration reduced the release rate because of the formation of denser polymeric networks.

Biological evaluations showed that drug-free nanocapsules exhibited negligible toxicity against both AGS and GES-1 cells, confirming favorable biocompatibility. In contrast, cisplatin-loaded nanocapsules significantly reduced AGS cell viability. Among all formulations, BPC(50 mg)CP-HA demonstrated the strongest anticancer activity, with an IC50 value of 224.75 µg.mL⁻¹ and the highest selectivity index (SI=1.75). Flow cytometry analysis further revealed that this formulation induced the highest levels of apoptosis in AGS cells, whereas free cisplatin predominantly caused necrotic cell death.

Conclusion

The BPCCP-HA smart nanocapsules developed in this study represent a promising strategy for targeted gastric cancer therapy. The nanocarrier system improved physicochemical stability, enabled pH-responsive controlled release of cisplatin, enhanced selective toxicity toward AGS cancer cells, and promoted apoptosis-mediated cell death while maintaining low toxicity toward healthy cells. These findings suggest that the designed nanocarrier system may effectively overcome major therapeutic limitations associated with conventional cisplatin treatment.