Grigoletto Antonella, Martinez Gabriele, Gabbia Daniela, Tedeschini Tommaso, Scaffidi Michela, Martin Sara De, Pasut Gianfranco
Pharmaceutical and Pharmacological Sciences Department, University of Padua, Via F. Marzolo 5, 35131 Padova, Italy.
Pharmaceutics. 2021 Jun 23;13(7):929. doi: 10.3390/pharmaceutics13070929.
Although selective tumor delivery of anticancer drugs has been sought by exploiting either passive targeting or by ligand-mediated targeting, a selective anticancer therapy remains an unmet medical need. Despite the advances which have been achieved by nanomedicines, nanosystems such as polymer-drug conjugates still miss the goal of clinical efficacy. In this study, we demonstrated that polymer-drug conjugates require a thoroughly chemical design and the right targeting agent/polymer ratio to be selective and effective towards cancer cells. In particular, two PEG conjugates carrying paclitaxel and targeted with different folic acid (FA)/PEG ratios (one or three) were investigated. The cytotoxicity study in positive (HT-29) and negative (HCT-15) FA receptor (FR)-cell lines demonstrated that the conjugates with one or three FAs were 4- or 28-fold more active in HT-29 cells, respectively. The higher activity of the 3-FA conjugate was confirmed by its strong impact on cell cycle arrest. Furthermore, FA targeting had a clear effect on migration and invasiveness of HT-29 cells, which were significantly reduced by both conjugates. Interestingly, the 3-FA conjugate showed also an improved pharmacokinetic profile in mice. The results of this study indicate that thorough investigations are needed to optimize and tune drug delivery and achieve the desired selectivity and activity towards cancer cells.
尽管通过利用被动靶向或配体介导的靶向来实现抗癌药物的选择性肿瘤递送，但选择性抗癌治疗仍然是未满足的医学需求。尽管纳米药物已经取得了进展，但诸如聚合物-药物偶联物之类的纳米系统仍未达到临床疗效的目标。在本研究中，我们证明聚合物-药物偶联物需要彻底的化学设计以及合适的靶向剂/聚合物比例，才能对癌细胞具有选择性和有效性。特别地，研究了两种携带紫杉醇并以不同叶酸（FA）/聚乙二醇（PEG）比例（1或3）靶向的PEG偶联物。在阳性（HT-29）和阴性（HCT-15）FA受体（FR）细胞系中的细胞毒性研究表明，具有1个或3个FA的偶联物在HT-29细胞中的活性分别高4倍或28倍。3-FA偶联物对细胞周期停滞的强烈影响证实了其更高的活性。此外，FA靶向对HT-29细胞的迁移和侵袭性有明显影响，两种偶联物均使其显著降低。有趣的是，3-FA偶联物在小鼠中还显示出改善的药代动力学特征。本研究结果表明，需要进行深入研究以优化和调整药物递送，并实现对癌细胞所需的选择性和活性。
