Tumor targeting has revolutionized cancer research, especially active cellular targeting of nanoparticles, where they are specifically homed to the pathological site to deliver the therapeutics. This strategy, which involves the utilization of affinity ligands on the surface of the nanocarriers, minimizes the nonspecific uptake of nanocarriers and the subsequent harmful side effects in healthy cells. Estrone, one of the mammalian estrogens, has affinity for estrogen receptors (ERα), which are overexpressed in hormone-responsive breast cancers. Despite holding promise, the potential of estrone in active targeting of nanoparticles has barely been explored. Herein, we developed an estrone-appended polyion complex (PIC) micelle to deliver melittin, a cytotoxic peptide, to breast cancer cells. Amino functionalization of estrone was performed to conjugate estrone to the diblock polymer synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Estrone-conjugated poly(ethylene glycol) methyl ether methacrylate-b-poly tert-butyl methacrylate (POEGMEMA-PtBuMA) could complex with melittin to form PIC micelles of size around 60 nm ensuing from the electrostatic interaction of the deprotected polymer and melittin in aqueous media. Poly(ethylene glycol) methyl ether acrylate-b-poly acrylic acid (POEGMEA-PAA) was also later incorporated to afford PIC micelles that could exhibit similar cytotoxicity to free melittin in the cytotoxicity studies. The estrone-attached PIC micelles exhibited improved cytotoxicity in two-dimensional (2D) and three-dimensional (3D) cellular models of MCF-7 cells. Cross-linking of the PIC micelles was also performed to improve the stability of the micelles and prevent melittin degradation from enzymatic attack. Flow cytometry demonstrated an enhanced cellular uptake greater than sixfold with the estrone-conjugated PIC micelles, thereby establishing a profound difference in the targeting efficacy of the PIC micelles between MCF-7 and MDA-MB-231 cells. Furthermore, the distribution of the PIC micelles in the spheroids was revealed by light sheet microscopy. The results demonstrate the potential of estrone-anchored PIC micelles for targeted delivery of therapeutics to hormone-responsive breast cancer cells.

中文翻译：

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雌酮修饰的聚离子复合物胶束，用于将蜂毒素靶向递送至激素反应性乳腺癌细胞。

靶向肿瘤已经彻底改变了癌症研究，尤其是针对纳米颗粒的主动细胞靶向，在纳米颗粒中，它们专门归巢到病理部位以提供治疗剂。该策略涉及利用纳米载体表面上的亲和配体，从而最大程度地减少了纳米载体的非特异性吸收以及随后对健康细胞造成的有害副作用。雌激素是一种雌激素，对雌激素受体（ERα）具有亲和力，雌激素受体在激素反应性乳腺癌中过度表达。尽管有希望，雌激素在主动靶向纳米颗粒方面的潜力尚未被开发。在本文中，我们开发了雌激素附加的聚离子复合物（PIC）胶束，以将蜂毒蛋白（一种细胞毒性肽）传递给乳腺癌细胞。进行雌酮的氨基官能化以使雌酮与通过可逆加成-断裂链转移（RAFT）聚合合成的二嵌段聚合物共轭。由于去保护的聚合物和蜂毒肽在水溶液中的静电相互作用，雌酮共轭的聚（乙二醇）甲基丙烯酸甲酯（b-聚甲基丙烯酸叔丁酯）可以与蜂毒肽络合形成大小约为60 nm的PIC胶束。媒体。后来也掺入了聚（乙二醇）甲基醚丙烯酸酯-b-聚丙烯酸（POEGMEA-PAA），以提供在细胞毒性研究中可能表现出与游离蜂毒类似的细胞毒性的PIC胶束。附有雌酮的PIC胶束在MCF-7细胞的二维（2D）和三维（3D）细胞模型中显示出改善的细胞毒性。还进行了PIC胶束的交联，以提高胶束的稳定性，并防止蜂毒肽因酶的攻击而降解。流式细胞术表明，与雌酮结合的PIC胶束的细胞摄取增强了六倍以上，从而在MCF-7和MDA-MB-231细胞之间的PIC胶束的靶向功效方面建立了深刻的差异。此外，通过光片显微术揭示了PIC胶束在球体中的分布。结果表明，雌激素锚定的PIC胶束有潜力将治疗剂靶向递送至激素反应性乳腺癌细胞。流式细胞术表明，与雌酮结合的PIC胶束的细胞摄取增强了六倍以上，从而在MCF-7和MDA-MB-231细胞之间的PIC胶束的靶向功效方面建立了深刻的差异。此外，通过光片显微术揭示了PIC胶束在球体中的分布。结果表明，雌激素锚定的PIC胶束有潜力将治疗剂靶向递送至激素反应性乳腺癌细胞。流式细胞术表明，与雌酮结合的PIC胶束的细胞摄取增强了六倍以上，从而在MCF-7和MDA-MB-231细胞之间的PIC胶束的靶向功效方面建立了深刻的差异。此外，通过光片显微术揭示了PIC胶束在球体中的分布。结果表明，雌激素锚定的PIC胶束具有针对激素响应性乳腺癌细胞靶向治疗的潜力。