A Multiscale Study of Phosphorylcholine Driven Cellular Phenotypic Targeting.
A Multiscale Study of Phosphorylcholine Driven Cellular Phenotypic Targeting.
复制标题
磷酸胆碱驱动的细胞表型靶向的多尺度研究。
DOI：
10.1021/acscentsci.2c00146
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发表时间：
2022-07-27
影响因子：
18.2
通讯作者：
Battaglia, Giuseppe
中科院分区：
文献类型：
--
作者：
Acosta-Gutierrez, Silvia;Matias, Diana;Avila-Olias, Milagros;Gouveia, Virginia M.;Scarpa, Edoardo;Forth, Joe;Contini, Claudia;Duro-Castano, Aroa;Rizzello, Loris;Battaglia, Giuseppe
表型靶向需要药物传递系统区分表达特定受体组合的细胞群的能力。这种选择性控制可以通过用多个配体修饰的多价载体来实现。在这里，我们证明了单一配体的混杂性可以被利用来创建多路多价载体，从而实现表型靶向。我们展示了聚（2-（甲基丙烯氧基）乙基磷酸胆碱）-聚（2-（二异丙胺）乙基甲基-晚）（PMPC-PDPA）聚合体的细胞摄取如何根据受体在不同细胞中的表达而变化。我们利用全原子分子模型研究了PMPC-PDPA聚合体在单链/受体水平上的插入。我们提出了一个基于理论统计机制的聚合物-细胞结合模型，该模型明确考虑了聚合物与细胞糖萼的相互作用，揭示了其对聚合物结合的影响。我们通过实验验证了我们的模型，并表明结合能是一个非线性函数，允许我们通过改变聚合半径和程度来调整相互作用。最后，我们发现PMPC-PDPA聚合体可以在体内靶向单核细胞，因为它们与SRB1、CD36和CD81混杂相互作用。据报道，一项多尺度研究显示了如何利用混杂配体在体内实现表型靶向，以及在纳米药物设计中明确考虑细胞糖萼的重要性。
Phenotypic targeting requires the ability of the drug delivery system to discriminate over cell populations expressing a particular receptor combination. Such selectivity control can be achieved using multiplexed-multivalent carriers often decorated with multiple ligands. Here, we demonstrate that the promiscuity of a single ligand can be leveraged to create multiplexed-multivalent carriers achieving phenotypic targeting. We show how the cellular uptake of poly(2-(methacryloyloxy)ethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacry-late) (PMPC-PDPA) polymersomes varies depending on the receptor expression among different cells. We investigate the PMPC–PDPA polymersome insertion at the single chain/receptor level using all-atom molecular modeling. We propose a theoretical statistical mechanics-based model for polymersome–cell association that explicitly considers the interaction of the polymersome with the cell glycocalyx shedding light on its effect on the polymersome binding. We validate our model experimentally and show that the binding energy is a nonlinear function, allowing us to tune the interaction by varying the radius and degree of polymerization. Finally, we show that PMPC–PDPA polymersomes can be used to target monocytes in vivo due to their promiscuous interaction with SRB1, CD36, and CD81. A multiscale study is reported showing how to leverage a promiscuous ligand to achieve phenotypic targeting in vivo and the importance of explicitly taking into account the cell glycocalyx in nanomedicines design.
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影响因子：
8.6
作者：
Angioletti-Uberti, Stefano
通讯作者：
Angioletti-Uberti, Stefano
影响因子：
5.4
作者：
Gouveia, Virginia M.;Rizzello, Loris;Battaglia, Giuseppe
通讯作者：
Battaglia, Giuseppe
影响因子：
46.9
作者：
Fredriksson, S;Gullberg, M;Landegren, U
通讯作者：
Landegren, U
影响因子：
15
作者：
Kitov, PI;Bundle, DR
通讯作者：
Bundle, DR
影响因子：
17.1
作者：
Fenaroli, Federico;Robertson, James D.;Rizzello, Loris
通讯作者：
Rizzello, Loris