Ministry of Education (MOE), Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China.
Biomater Sci. 2021 May 4;9(9):3348-3361. doi: 10.1039/d0bm01987a.
The in vivo delivery of nanomedicine is severely hampered by the limited enhanced permeability and retention effect (EPR) in tumors. Aiming at overcoming this limitation and achieving high anti-tumor effect of chemotherapeutics, we specially addressed an available strategy from a viewpoint of increasing the drug loading of nano-carriers. Here, we constructed a novel pH-responsive polymersome based on the drug-driven self-assembly of amphiphilic polyphosphazenes PAP containing the ortho ester group ABD and mPEG2000. Due to the non-covalent attractive forces between PAP and doxorubicin hydrochloride (DOX·HCl), DOX·HCl can induce the self-assembly of PAP via embedding itself in the lamella to form vesicles and the subsequent location in the center aqueous chamber of the resultant nano-vesicles, which resulted in the high drug loading content of 35.77 wt%. In addition, with the incorporation of cholesteryl hemisuccinate (CholHS), the premature leakage of DOX·HCl was significantly inhibited under physiological conditions. Meanwhile, the pH-sensitive drug release occurred at pH 5.5 by the advantage of the pH-sensitive biodegradation of ABD in PAP. Consequently, this CholHS-incorporated DOX·HCl-driven PAP vesicle achieved excellent anti-tumor effect with tumor growth inhibition up to 82.4% in S180 tumor-bearing mice. Taken together, our newly developed drug-driven vesicles may promote the development of efficient drug delivery systems for application in cancer therapy.
纳米医学的体内传递受到肿瘤中有限的增强渗透和保留效应（EPR）的严重阻碍。为了克服这一限制并实现化疗药物的高抗肿瘤效果，我们专门从增加纳米载体药物载药量的角度提出了一种可行的策略。在这里，我们构建了一种基于含有邻酯基 ABD 的两亲性聚膦腈 PAP 的药物驱动自组装的新型 pH 响应聚合物囊泡。由于 PAP 和盐酸阿霉素（DOX·HCl）之间的非共价吸引力，DOX·HCl 可以通过将自身嵌入层中诱导 PAP 的自组装，形成囊泡，并随后位于所得纳米囊泡的中心水腔室中，从而导致 35.77wt%的高药物载药量。此外，通过掺入胆甾醇半琥珀酸酯（CholHS），在生理条件下可以显著抑制 DOX·HCl 的过早泄漏。同时，由于 PAP 中 ABD 的 pH 敏感生物降解，在 pH 5.5 时发生 pH 敏感的药物释放。因此，这种含有 CholHS 的 DOX·HCl 驱动的 PAP 囊泡在 S180 荷瘤小鼠中实现了优异的抗肿瘤效果，肿瘤生长抑制率高达 82.4%。总之，我们新开发的药物驱动囊泡可能会促进高效药物传递系统的发展，以应用于癌症治疗。
