Biomedical Polymers Laboratory, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P. R. China.
Department of Biology, Chemistry and Pharmacy, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin 14195, Germany.
Biomacromolecules. 2022 Jan 10;23(1):100-111. doi: 10.1021/acs.biomac.1c01065. Epub 2021 Dec 16.
Targeted nanomedicines particularly armed with monoclonal antibodies are considered to be the most promising advanced chemotherapy for malignant cancers; however, their development is hindered by their instability and drug leakage problems. Herein, we constructed a robust cetuximab-polymersome-mertansine nanodrug (C-P-DM1) for highly potent and targeted therapy of epidermal growth factor receptor (EGFR)-positive solid tumors. C-P-DM1 with a tailored cetuximab surface density of 2 per P-DM1 exhibited a size of ca. 60 nm, high stability with minimum DM1 leakage, glutathione-triggered release of native DM1, and 6.0-11.3-fold stronger cytotoxicity in EGFR-positive human breast (MDA-MB-231), lung (A549), and liver (SMMC-7721) cancer cells (IC = 27.1-135.5 nM) than P-DM1 control. Notably, intravenous injection of C-P-DM1 effectively repressed subcutaneous MDA-MB-231 breast cancer and orthotopic A549-Luc lung carcinoma in mice without inducing toxic effects. Strikingly, intratumoral injection of C-P-DM1 completely cured 60% of mice bearing breast tumor without recurrence. This robust cetuximab-polymersome-mertansine nanodrug provides a promising new strategy for targeted treatment of EGFR-positive solid malignancies.
靶向纳米药物，特别是武装有单克隆抗体的靶向纳米药物，被认为是治疗恶性癌症最有前途的先进化疗药物；然而，它们的发展受到不稳定性和药物泄漏问题的阻碍。在此，我们构建了一种稳健的西妥昔单抗-聚合物囊泡-美登素纳米药物（C-P-DM1），用于表皮生长因子受体（EGFR）阳性实体瘤的高活性和靶向治疗。具有 2 个西妥昔单抗/每个 P-DM1 的定制西妥昔单抗表面密度的 C-P-DM1 表现出约 60nm 的尺寸、最小 DM1 泄漏的高稳定性、谷胱甘肽触发的天然 DM1 释放以及在 EGFR 阳性的人乳腺癌（MDA-MB-231）、肺癌（A549）和肝癌（SMMC-7721）细胞中 6.0-11.3 倍更强的细胞毒性（IC=27.1-135.5nM），优于 P-DM1 对照。值得注意的是，静脉注射 C-P-DM1 能有效抑制荷瘤小鼠皮下 MDA-MB-231 乳腺癌和原位 A549-Luc 肺癌，而不引起毒副作用。引人注目的是，肿瘤内注射 C-P-DM1 可完全治愈 60%的荷瘤小鼠，无复发。这种稳健的西妥昔单抗-聚合物囊泡-美登素纳米药物为治疗 EGFR 阳性实体恶性肿瘤提供了一种有前途的新策略。
