In situ incorporation of boronate into carbonized alginate nanogels for targeted inhibition of triple-negative breast cancer metastasis by inducing cytoskeletal disruption, cell growth arrest, and apoptosis

Abstract

Metastasis is the primary cause of cancer mortality, and its prevention is particularly challenging due to the complex tumor microenvironment. Carbon nanomaterials are well known to act as drug delivery systems for therapeutics. Nonetheless, their inherent capabilities in combating tumor cells remain underexplored. In this study, we report the synthesis and characterization of novel boronate-incorporated alginate carbon nanogels (Bor/Alg-CNGs) as promising anti-metastatic agents for effectively suppressing migration and invasion of triple-negative breast cancer (TNBC) cells, while triggering cell-cycle arrest. Notably, Bor/Alg-CNGs decreased cell viability of TNBC cells through disorganization of F-actin, a critical factor mediating cellular migration. In an in vivo study, Bor/Alg-CNGs reduced metastatic lung nodules in a tumor-induced mouse model by >85 %, compared to the untreated controls. Transcriptomics and proteomics analyses further validated the in vivo results with an in-depth understanding of the role of Bor/Alg-CNGs in the stress response of reactive oxygen species-induced cells and downregulation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, leading to metabolic breakdown, cell growth arrest, and apoptosis. These findings underscore the potent anti-metastatic properties of Bor/Alg-CNGs based on their multifunctional role in inhibiting cellular mechanisms essential for metastasis. Compared to many existing carbon nanomaterials, Bor/Alg-CNGs offer enhanced specificity and efficiency in targeting metastatic pathways. Their ability to target and disrupt metastatic processes while minimizing side effects holds the potential for development as a new class of anti-metastatic agents in cancer therapy, warranting further mechanistic and clinical investigations to realize their full therapeutic potential.