Tumor targeted and GSH stimuli-response α‑lactalbumin nanotubes co-delivering doxorubicin and siRNA for cancer therapy

Abstract

α-Lactalbumin (α-lac), a natural food-sourced protein, exhibits high biocompatibility as delivery systems for small bioactive molecules or RNA. However, their potential clinical application as a delivery system is greatly limited due to the lack of targeting to desired tissues, such as tumors. Here, a delivery system/nanocarrier of nanotube (NT) was fabricated by the self-assembly of peptides hydrolyzed from α-lac. Among the loading of anti-tumor agents of doxorubicin (Dox) and siRNA, NTs were conjugated with the tLyp-1 peptide to specifically target the neuropilin 1 receptor, which exists on the membrane of MDA-MB-231 cancer cells. The micromorphology of NTs was not affected during the processes of loading and targeting modification. Additionally, no significant changes in the size and zeta potential of the tLyp-1/NTs/Dox/siRNA nanocarrier were observed when stored in phosphate buffered saline for 7 days, indicating outstanding stability. Moreover, both the cellular uptake efficiency and tumor accumulation effects of NTs on MDA-MB-231 breast cancer cells were significantly improved after modification with tLyp-1. The relative viability of MDA-MB-231 cells was decreased by 70.1% in vitro after treatment with tLyp-1/NTs/Dox/siRNA (5 μg/mL Dox). Finally, a synergistic anticancer effect of Dox and siRNA co-loaded in tLyp-1/NTs was achieved in the anticancer treatment of MDA-MB-231 tumor-bearing mice. These findings indicate that food-sourced protein α‑lac nanocarriers could be used for the co-delivery of bioactive molecules and RNA, achieving synergistic and efficient therapeutic effects.