School of Pharmacy, China Pharmaceutical University, No. 639, Longmian Road, Nanjing 210009, PR China.
School of Pharmacy, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Mol Pharm. 2021 May 3;18(5):2039-2052. doi: 10.1021/acs.molpharmaceut.1c00036. Epub 2021 Mar 26.
Up to now, insufficient drug accumulation in tumor remains a major challenge for nanochemotherapy. However, the spherical nanocarriers with large diameter, which are beneficial for blood circulation and tumor extravasation, cannot travel deep in a tumor. Additionally, high tumor interstitial fluid pressure (IFP) in the tumor microenvironment may promote the efflux of the penetrable nanodrugs. Therefore, the size and shape of nanocarriers as well as the tumoral IFP can be regulated synchronously for improved tumor penetration and combined chemotherapy. Herein, a novel dual-functional polymer-polypeptide (Biotin-PEG-GKGPRQITITK) for both verified tumor targeting and responsiveness was synthesized to construct the "peel" of nanopomegranate-like nanovectors (DI-MPL), in which docetaxel-loaded micelles was encapsulated as "seeds". Interestingly, DI-MPL was endowed multi-abilities of tunable size/shape switch and controlled release of IFP alleviator imatinib (IM), which were developed with one and the same strategy-alteration of membrane fluidity under the cleavage of polymer-polypeptide and PEGylation. As a result, the peel of DI-MPL could turn into small pieces with the seed scattered out in response to matrix metalloproteinase-9 (MMP-9), making nanopomegranate (180 nm) switch into spheres/disks (40 nm), during which IM is released to reduce IFP synchronously. With prominent tumor penetration ability in both multicellular tumor spheroids (MCTS) and tumor tissue, DI-MPL exhibited optimal inhibition of MCTS growth and the enhanced chemotherapy in comparison to other preparations. Meanwhile, the improved penetrability of DI-MPL in tumor tissue was found to be related to the reduced IFP, which is achieved via inhibiting expression of phosphorylated platelet-derived growth factor receptor-β (-PDGFR-β) by IM. Altogether, the bilateral adjusting strategies from nanocarrier size/shape and tumoral IFP with a single enzyme-responsive material could provide a potential combined chemotherapy to improve tumor penetration.
到目前为止，肿瘤内药物蓄积不足仍然是纳米化学疗法的主要挑战。然而，大直径的球形纳米载体有利于血液循环和肿瘤外渗，但不能深入肿瘤内部。此外，肿瘤微环境中的高肿瘤间质流体压力（IFP）可能会促进可穿透纳米药物的外流。因此，可以同步调节纳米载体的大小和形状以及肿瘤 IFP，以提高肿瘤穿透率和联合化疗效果。在这里，合成了一种新型的多功能聚合物-多肽（生物素-PEG-GKGPRQITITK），用于验证肿瘤靶向和响应性，以构建纳米石榴状纳米载体（DI-MPL）的“果皮”，其中包载多西紫杉醇的胶束作为“种子”。有趣的是，DI-MPL 具有可调节的尺寸/形状开关和 IFP 缓解剂伊马替尼（IM）的控制释放的多种能力，这是通过在聚合物-多肽和 PEG 化的切割下改变膜流动性而采用的相同策略开发的。结果，DI-MPL 的果皮会在基质金属蛋白酶-9（MMP-9）的作用下变成小块，种子散落出来，使纳米石榴（180nm）变成球体/圆盘（40nm），同时同步释放 IM 以降低 IFP。DI-MPL 在多细胞肿瘤球体（MCTS）和肿瘤组织中均具有出色的肿瘤穿透能力，与其他制剂相比，它表现出最佳的 MCTS 生长抑制和增强化疗效果。同时，发现 DI-MPL 在肿瘤组织中的渗透性提高与 IFP 降低有关，这是通过 IM 抑制磷酸化血小板衍生生长因子受体-β（-PDGFR-β）的表达来实现的。总之，通过单一酶响应材料从纳米载体尺寸/形状和肿瘤 IFP 进行双边调节的策略，可以提供一种潜在的联合化疗方法来提高肿瘤穿透率。
