Self-assembling protein nanocarrier for selective delivery of cytotoxic polypeptides to CXCR4^(+) head and neck squamous cell carcinoma tumors

摘要

Loco-regional recurrences and distant metastases represent the main cause of head and neck squamous cell carcinoma(HNSCC) mortality. The overexpression of chemokine receptor 4(CXCR4) in HNSCC primary tumors associates with higher risk of developing loco-regional recurrences and distant metastases, thus making CXCR4 an ideal entry pathway for targeted drug delivery. In this context, our group has generated the self-assembling protein nanocarrier T22-GFP-H6, displaying multiple T22 peptidic ligands that specifically target CXCR4. This study aimed to validate T22-GFP-H6 as a suitable nanocarrier to selectively deliver cytotoxic agents to CXCR4^(+)tumors in a HNSCC model. Here we demonstrate that T22-GFP-H6 selectively internalizes in CXCR4^(+)HNSCC cells, achieving a high accumulation in CXCR4^(+)tumors in vivo, while showing negligible nanocarrier distribution in non-tumor bearing organs. Moreover, this T22-empowered nanocarrier can incorporate bacterial toxin domains to generate therapeutic nanotoxins that induce cell death in CXCR4-overexpressing tumors in the absence of histological alterations in normal organs. Altogether, these results show the potential use of this T22-empowered nanocarrier platform to incorporate polypeptidic domains of choice to selectively eliminate CXCR4^(+)cells in HNSCC. Remarkably, to our knowledge, this is the first study testing targeted proteinonly nanoparticles in this cancer type, which may represent a novel treatment approach for HNSCC patients.