Pautu Vincent, Lepeltier Elise, Mellinger Adélie, Riou Jérémie, Debuigne Antoine, Jérôme Christine, Clere Nicolas, Passirani Catherine
Micro & Nanomedecines Translationnelles (MINT), University of Angers, Inserm, The National Center for Scientific Research (CNRS), SFR ICAT, F-49000 Angers, France.
Center for Education and Research on Macromolecules (CERM), Complex and Entangled Systems from Atoms to Materials Research Unit (CESAM-RU), University of Liège, 4000 Liège, Belgium.
Cancers (Basel). 2021 Apr 22;13(9):2028. doi: 10.3390/cancers13092028.
Despite significant advances in melanoma therapy, low response rates and multidrug resistance (MDR) have been described, reducing the anticancer efficacy of the administered molecules. Among the causes to explain these resistances, the decreased intratumoral pH is known to potentiate MDR and to reduce the sensitivity to anticancer molecules. Nanomedicines have been widely exploited as the carriers of MDR reversing molecules. Lipid nanocapsules (LNC) are nanoparticles that have already demonstrated their ability to improve cancer treatment. Here, LNC were modified with novel copolymers that combine N-vinylpyrrolidone (NVP) to impart stealth properties and vinyl imidazole (Vim), providing pH-responsive ability to address classical chemoresistance by improving tumor cell entry. These copolymers could be post-inserted at the LNC surface, leading to the property of going from neutral charge under physiological pH to positive charge under acidic conditions. LNC modified with polymer P5 (C18H37-P(NVP21-co-Vim15)) showed in vitro pH-responsive properties characterized by an enhanced cellular uptake under acidic conditions. Moreover, P5 surface modification led to an increased biological effect by protecting the nanocarrier from opsonization by complement activation. These data suggest that pH-sensitive LNC responds to what is expected from a promising nanocarrier to target metastatic melanoma.
尽管黑色素瘤治疗取得了显著进展，但仍存在低反应率和多药耐药性（MDR）的情况，这降低了所施用分子的抗癌疗效。在解释这些耐药性的原因中，肿瘤内pH值降低已知会增强多药耐药性并降低对抗癌分子的敏感性。纳米药物已被广泛用作多药耐药逆转分子的载体。脂质纳米胶囊（LNC）是已证明具有改善癌症治疗能力的纳米颗粒。在此，LNC用新型共聚物进行了修饰，该共聚物结合了赋予隐身特性的N-乙烯基吡咯烷酮（NVP）和提供pH响应能力以通过改善肿瘤细胞进入来解决经典化学耐药性的乙烯基咪唑（Vim）。这些共聚物可以后插入到LNC表面，从而导致在生理pH下呈中性电荷而在酸性条件下呈正电荷的特性。用聚合物P5（C18H37-P（NVP21-co-Vim15））修饰的LNC在体外表现出pH响应特性，其特征是在酸性条件下细胞摄取增强。此外，P5表面修饰通过保护纳米载体免受补体激活的调理作用而导致生物效应增加。这些数据表明，pH敏感的LNC符合有望用于靶向转移性黑色素瘤的纳米载体的预期。
