Beta-cyclodextrin-based polymerized nanocarriers for doxorubicin delivery to cancer cells

In-depth drug penetration is significant for achieving optimal therapeutic effects; particularly, anticancer drugs must penetrate deep into tumours to exert toxic effects on cancer cells. Drug-loaded nanocarriers are promising for targeted drug delivery. However, in vivo barriers often impede drug delivery to target sites. To overcome these barriers, we designed a strategy based on pH-responsive agglomeration and de-agglomeration of nanocarriers. For this, β-cyclodextrin was modified with acryloyl chloride, polymerized with hydrophilic acrylic acid, and attached to polyethyleneimine and folate to obtain physiological environment-stable nanocarriers. These nanocarriers agglomerate into moderate-sized clusters during blood circulation to escape macrophage capture and renal excretion. Upon reaching the acidic tumour micro-environment, they de-agglomerate into individual nanocarriers for enhanced penetration into the tumour, following specific targeting and internalization of nanocarriers in cancer cells through ligand-receptor interaction. All modifications were confirmed by FTIR spectroscopy, UV-visible spectroscopy, and NMR. Particle size analysis and FESEM verified their agglomeration and de-agglomeration behaviours at different pH values. The hydrophilic surface modification of β-cyclodextrin enhanced the aqueous dispersion and doxorubicin encapsulation of nanocarriers. The nanocarriers showed pH-responsive drug release behaviour and followed the Korsmeyer-Peppas model. Alamar Blue assay against normal NIH3T3 fibroblast cells demonstrated the reduced toxicity of nanocarriers as compared to free doxorubicin. Moreover, CAM assay, bioimaging and MTT assay against SY5Y neuroblastoma confirmed the penetration, internalization and anticancer effects of nanocarriers. In conclusion, the synergistic interplay between agglomeration and de-agglomeration could facilitate nanocarrier penetration into tumour tissue, internalization into cancer cells and subsequent anticancer effects.