Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.
Biomacromolecules. 2023 Aug 14;24(8):3545-3556. doi: 10.1021/acs.biomac.3c00308. Epub 2023 Jul 14.
Core cross-linked polymeric micelles (CCPMs) are designed to improve the therapeutic profile of hydrophobic drugs, reduce or completely avoid protein corona formation, and offer prolonged circulation times, a prerequisite for passive or active targeting. In this study, we tuned the CCPM stability by using bifunctional or trifunctional cross-linkers and varying the cross-linkable polymer block length. For CCPMs, amphiphilic thiol-reactive polypept(o)ides of polysarcosine--poly(-ethylsulfonyl-l-cysteine) [pSar--pCys(SOEt)] were employed. While the pCys(SOEt) chain lengths varied from = 17 to 30, bivalent (derivatives of dihydrolipoic acid) and trivalent (sarcosine/cysteine pentapeptide) cross-linkers have been applied. Asymmetrical flow field-flow fraction (AF4) displayed the absence of aggregates in human plasma, yet for non-cross-linked PM and CCPMs cross-linked with dihydrolipoic acid at [pCys(SOEt)], increasing the cross-linking density or the pCys(SOEt) chain lengths led to stable CCPMs. Interestingly, circulation time and biodistribution in mice of non-cross-linked and bivalently cross-linked CCPMs are comparable, while the trivalent peptide cross-linkers enhance the circulation half-life from 11 to 19 h.
核交联聚合胶束（CCPMs）旨在改善疏水性药物的治疗效果，减少或完全避免蛋白质冠形成，并提供延长的循环时间，这是被动或主动靶向的先决条件。在这项研究中，我们通过使用双官能或三官能交联剂并改变可交联聚合物链段的长度来调整 CCPM 的稳定性。对于 CCPMs，使用两亲性硫醇反应性多肽（聚琥珀酰-聚（-乙基磺酰基-L-半胱氨酸）[pSar-pCys（SOEt）]。当 pCys（SOEt）链长从 = 17 变化到 30 时，使用了二价（二氢硫辛酸的衍生物）和三价（肌氨酸/半胱氨酸五肽）交联剂。不对称流场流分离（AF4）显示在人血浆中不存在聚集体，但对于非交联 PM 和用二氢硫辛酸交联的 CCPMs（pCys（SOEt）），增加交联密度或 pCys（SOEt）链长会导致稳定的 CCPMs。有趣的是，非交联和双价交联 CCPMs 的循环时间和在小鼠中的生物分布是可比的，而三价肽交联剂将循环半衰期从 11 小时延长至 19 小时。
