Camptothecin loaded casein nanosystem for tuning the therapeutic efficacy against highly metastatic triple-negative breast cancer cells

Abstract

The heterogenic of TNBC and the side effects of chemo drugs lead to the failure of therapy. Protein-based nanoplatforms have emerged as an important domain in protein-engineered biomedicine for delivering anticancer therapeutics. Protein-based nanosystems are biocompatible and biodegradable, with a long half-life and high purity. TNBC is sensitive to DNA-damaging chemo drugs. In this study, we used 10-hydroxy camptothecin, which causes DNA damage in cancer cells. However, the inappropriate solubility and toxic side effects limit its application in cancer therapy. We encapsulated 10-Hydroxycamptothecin in biocompatible casein by synthesizing nanoparticles from it. The synthesized CS and CCS NPs showed excellent biocompatibility in fibroblast cell lines L929, NIH-3T3, and zebrafish embryos. Enhanced uptake of CCS NPs in zebrafish embryos and 4T1 cells, cancer cell toxicity of nearly 80–85%, sub-cellular mitochondrial localization, alterations of mitochondrial membrane potential, lysosomal localization, and reactive oxygen species generation that causes cancer cell apoptosis have been observed. Growth inhibition of 4T1 cell colonies and antimetastatic activity were also noted. Further upregulation of γ-H2AX which causes DNA damage, downregulation of the PARP protein related to DNA repair, and increased level of the CHOP protein marker for endoplasmic reticulum stress-mediated cell death were observed. The 3-D model of 4T1 cells exhibited deep tumor penetration with significant therapeutic efficacy for CCS NPs. These results imply that casein-based nanoformulation could open a new scope for safe and affordable cancer therapy in TNBC.