Biomedical Polymers Laboratory and 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 , China.
Biomacromolecules. 2020 Jan 13;21(1):104-113. doi: 10.1021/acs.biomac.9b01012. Epub 2019 Sep 18.
Metastasis is responsible for >90% of the deaths of breast cancer patients in the clinic. Here, we report on cross-linked multifunctional hyaluronic acid nanoparticles carrying docetaxel (DTX-CMHN) for enhanced suppression of highly metastatic 4T1 breast tumors . DTX-CMHN was formed from a single and all-natural hyaluronic acid--polytyrosine-lipoic acid conjugate (HA--PTyr-LA; HA, 20 kDa; PTyr, 2.2 kDa), and the size of DTX-CMHN increased from 69 to 78 to 96 nm as the increasing degree of substitution (DS) of PTyr increased from 4 to 11 to 15, respectively. Robust encapsulation of DTX was obtained when DS ≥ 11. DTX-CMHN while steady in a nonreducing environment was destabilized under 10 mM glutathione releasing ∼90% of the DTX within 24 h. It is noteworthy that DTX-CMHN exhibited better antitumor, antimigration, and anti-invasion activity in CD44-overexpressed 4T1-Luc breast cancer cells than free DTX. Interestingly, DTX-CMHN displayed a long elimination half-life of 5.75 h, in contrast to half-lives of 2.11 and 0.75 h for its non-cross-linked counterpart (DTX-MHN) and free DTX, respectively. therapeutic studies showed significantly better inhibition of primary 4T1-Luc tumor growth and lung metastasis and lower toxicity of DTX-CMHN compared with that of free DTX. These multifunctional nanoformulations based on a single and all-natural hyaluronic acid conjugate emerge as a potential nanoplatform for targeted treatment of CD44-positive metastatic tumors.
转移是导致临床中 90%以上乳腺癌患者死亡的原因。在这里，我们报告了载有多西紫杉醇（DTX-CMHN）的交联多功能透明质酸纳米粒子，用于增强抑制高转移性 4T1 乳腺癌。DTX-CMHN 由单一且全天然透明质酸-聚酪氨酸-硫辛酸缀合物（HA-PTyr-LA；HA，20 kDa；PTyr，2.2 kDa）形成，随着 PTyr 的取代度（DS）从 4 增加到 11 增加到 15，DTX-CMHN 的尺寸分别从 69 增加到 78 增加到 96nm。当 DS≥11 时，可获得 DTX 的强包封。在非还原环境中稳定的 DTX-CMHN 在 10 mM 谷胱甘肽存在下不稳定，在 24 小时内释放约 90%的 DTX。值得注意的是，与游离 DTX 相比，DTX-CMHN 在过表达 CD44 的 4T1-Luc 乳腺癌细胞中表现出更好的抗肿瘤、抗迁移和抗侵袭活性。有趣的是，与非交联对照物（DTX-MHN）和游离 DTX 的半衰期分别为 2.11 小时和 0.75 小时相比，DTX-CMHN 表现出更长的消除半衰期 5.75 小时。治疗研究表明，与游离 DTX 相比，DTX-CMHN 显著抑制原发性 4T1-Luc 肿瘤生长和肺转移，毒性更低。这些基于单一且全天然透明质酸缀合物的多功能纳米制剂为 CD44 阳性转移性肿瘤的靶向治疗提供了一种有潜力的纳米平台。
