Enhanced targeting of triple-negative breast carcinoma and malignant melanoma by photochemical internalization of CSPG4-targeting immunotoxins.
Enhanced targeting of triple-negative breast carcinoma and malignant melanoma by photochemical internalization of CSPG4-targeting immunotoxins.
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DOI：
10.1039/c7pp00358g
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发表时间：
2018-05-16
期刊：
影响因子：
--
通讯作者：
Selbo PK
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作者：
Eng MS;Kaur J;Prasmickaite L;Engesæter BØ;Weyergang A;Skarpen E;Berg K;Rosenblum MG;Mælandsmo GM;Høgset A;Ferrone S;Selbo PK
三阴性乳腺癌（TNBC）和恶性黑色素瘤是广泛表达细胞表面硫酸软骨素蛋白聚糖4（CSPG 4/NG 2）的高度侵袭性癌症。CSPG 4在肿瘤细胞生长和存活中起重要作用，并促进化疗和放疗抗性，表明CSPG 4是癌症治疗中有吸引力的靶点。在目前的工作中，我们将药物递送技术光化学内化（PCI）与新型CSPG 4靶向免疫毒素225.28-皂草素结合，作为杀死侵袭性TNBC和无黑色素黑色素瘤细胞的有效和特异性策略。发现临床相关光敏剂TPCS 2a（非马泊芬）和225.28-皂草素的光活化以协同方式起作用，并且在三种TNBC细胞系（MDA-MB-231、MDA-MB-435和SUM 149）和两种BRAFV 600 E突变的恶性黑素瘤细胞系（Melmet 1和Melmet 5）中优于皂草素的PCI和PCI-无药物（仅TPCS 2a+光）。细胞毒性效应高度依赖于光剂量和CSPG 4的表达，因为在CSPG 4阴性MCF-7细胞中观察到225.28-皂草素的PCI与皂草素的PCI相比没有增强的细胞毒性。一种较小的、临床相关的CSPG 4靶向毒素（scFvMEL-rGel）的PCI在体外验证了CSPG 4靶向概念，并在无色素性黑素瘤异种移植物A-375模型中诱导了对肿瘤生长的强烈抑制。总之，药物递送技术PCI和靶向CSPG 4的免疫毒素的组合是用于消除TNBC和恶性黑色素瘤来源的侵袭性细胞的有效、特异性和光控策略。本研究为PCI联合CSPG 4靶向治疗的进一步临床前评价奠定了基础。
Triple-negative breast cancer (TNBC) and malignant melanoma are highly aggressive cancers that widely express the cell surface chondroitin sulfate proteoglycan 4 (CSPG4/NG2). CSPG4 plays an important role in tumor cell growth and survival and promotes chemo- and radiotherapy resistance, suggesting that CSPG4 is an attractive target in cancer therapy. In the present work, we applied the drug delivery technology photochemical internalization (PCI) in combination with the novel CSPG4-targeting immunotoxin 225.28-saporin as an efficient and specific strategy to kill aggressive TNBC and amelanotic melanoma cells. Light-activation of the clinically relevant photosensitizer TPCS2a (fimaporfin) and 225.28-saporin was found to act in a synergistic manner, and was superior to both PCI of saporin and PCI-no-drug (TPCS2a + light only) in three TNBC cell lines (MDA-MB-231, MDA-MB-435 and SUM149) and two BRAFV600E mutated malignant melanoma cell lines (Melmet 1 and Melmet 5). The cytotoxic effect was highly dependent on the light dose and expression of CSPG4 since no enhanced cytotoxicity of PCI of 225.28-saporin compared to PCI of saporin was observed in the CSPG4-negative MCF-7 cells. The PCI of a smaller, and clinically relevant CSPG4-targeting toxin (scFvMEL-rGel) validated the CSPG4-targeting concept in vitro and induced a strong inhibition of tumor growth in the amelanotic melanoma xenograft A-375 model. In conclusion, the combination of the drug delivery technology PCI and CSPG4-targeting immunotoxins is an efficient, specific and light-controlled strategy for the elimination of aggressive cells of TNBC and malignant melanoma origin. This study lays the foundation for further preclinical evaluation of PCI in combination with CSPG4-targeting.