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...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.展开更多
基金supported by Instituto de Salud CarlosⅢ(ISCIII,SpainCo-funding from FEDER,European Union)[PI18/00650,PIE15/00028,PI15/00378 and EU COST Action CA 17140 to Ramon Mangues,PI19/01661 to Xavier León,and PI17/00584 to Miquel Quer]+7 种基金Agencia Estatal de Investigación(AEI,Spain)and Fondo Europeo de Desarrollo Regional(FEDER,European Union)[grant BIO2016-76063-R,AEI/FEDER,UE to Antonio Villaverde and grant PID2019-105416RB-I00/AEI/10.13039/501100011033 to Esther Vazquez]CIBER-BBN(Spain)[CB06/01/1031 and 4NanoMets to Ramon Mangues,VENOM4CANCER to Antonio Villaverde,NANOREMOTE to Esther Vazquez,and NANOSCAPE to Ugutz Unzueta]AGAUR(Spain)2017-SGR865 to Ramon Mangues,and 2017SGR-229 to Antonio VillaverdeJosep Carreras Leukemia Research Institute(Spain)[P/AG to Ramon Mangues]supported by a predoctoral fellowship from AGAUR(Spain)(2020FI_B200168 and 2018FI_B2_00051)co-funded by European Social Fund(ESF investing in your future,European Union)supported by a postdoctoral fellowship from AECC(Spanish Association of Cancer Research,Spain)Antonio Villaverde received an Icrea Academia Award(Spain)supported by Grant PERIS SLT006/17/00093 from la Generalitat de Catalunya(Spain)and Miguel Servet fellowship(CP19/00028)from Instituto de Salud CarlosⅢ(Spain)co-funded by European Social Fund(ESF investing in your future,European Union)。
文摘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.
