Dual size/charge-switchable and multi-responsive gelatin-based nanocluster for targeted anti-tumor therapy

Biopolymers with excellent biocompatibility and biodegradability show great potential for designing drug nanocarriers, while it's difficult to fabricate smart vehicles with multiple switching (size, surface, shape) based on biopolymers alone. Here, we report a dual size/charge-switchable and multi-responsive doxorubicin-loaded gelatin-based nanocluster (DOX-icluster) for improved tumor penetration and targeted anti-tumor therapy. The DOX-icluster was electrostatically assembled from folic acid and dimethylmaleic anhydride modified gelatin (FA-GelDMA) and small-sized DOX-loaded NH₂ modified hollow mesoporous organosilicon nanoparticles (DOX-HMON-NH₂). DOX-icluster had an initial size of about 199 nm at neutral pH. After accumulation in tumor tissue, the DMA bond of FA-GelDMA was cleaved and gelatin was degraded by matrix metalloproteinase (MMP-2), thus 48 nm and positively charged DOX-HMON-NH₂ was released to facilitate penetration and cell internalization. DOX-HMON-NH₂ was further degraded by intracellular glutathione (GSH) with releasing 48.1 % of DOX. The cellular uptake results indicated that the fabricated icluster promoted the uptake of DOX by 4T1 cells. With enhanced penetration efficacy, the tumor spheroids volume treated with DOX-icluster was reduced to 15.1 % on day 7. This cytocompatible multi-responsive gelatin-based icluster with size-shrinking and charge-reversible characteristics may be used as a significant drug carrier for tumor therapy.