Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines.
Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines.
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DOI：
10.1038/s41598-017-06109-y
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发表时间：
2017-07-20
影响因子：
4.6
通讯作者：
MacRobert AJ
中科院分区：
文献类型：
--
作者：
Yaghini E;Dondi R;Tewari KM;Loizidou M;Eggleston IM;MacRobert AJ
许多有前景的纳米尺寸的生物治疗剂（包括大分子）的主要问题是，由于它们的尺寸，它们通过内吞作用而被细胞摄取，并且被截留，然后在内溶酶体内降解，这会显著损害它们的治疗功效。光化学内化（PCI）是一种用于诱导包埋剂的胞质释放的技术，其利用定位于内溶酶体膜中的光敏剂进行亚致死光动力疗法（PDT）。使用光来触发光敏化的内溶酶体膜的活性氧介导的破裂，PCI的时空选择性然后使得药剂能够在施用后的选定时间的胞质释放，使得它们可以到达它们的细胞内靶标。然而，临床上用于PDT的常规光敏剂由于其次优的细胞内定位而对光化学内化无效。在这项工作中，我们证明，这样的光敏剂，二氢卟酚e6，可以重新利用PCI通过共轭二氢卟酚的细胞穿透肽，使用生物正交连接化学。肽缀合使得能够靶向内体膜，使得可以实现截留的纳米尺寸的细胞毒素的光触发的胞质释放，从而改善细胞毒性。二氢卟酚部分的光性质也是保守的，发现与游离二氢卟酚的单线态氧量子产率相当。
A major problem with many promising nano-sized biotherapeutics including macromolecules is that owing to their size they are subject to cellular uptake via endocytosis, and become entrapped and then degraded within endolysosomes, which can significantly impair their therapeutic efficacy. Photochemical internalisation (PCI) is a technique for inducing cytosolic release of the entrapped agents that harnesses sub-lethal photodynamic therapy (PDT) using a photosensitiser that localises in endolysosomal membranes. Using light to trigger reactive oxygen species-mediated rupture of the photosensitised endolysosomal membranes, the spatio-temporal selectivity of PCI then enables cytosolic release of the agents at the selected time after administration so that they can reach their intracellular targets. However, conventional photosensitisers used clinically for PDT are ineffective for photochemical internalisation owing to their sub-optimal intracellular localisation. In this work we demonstrate that such a photosensitiser, chlorin e6, can be repurposed for PCI by conjugating the chlorin to a cell penetrating peptide, using bioorthogonal ligation chemistry. The peptide conjugation enables targeting of endosomal membranes so that light-triggered cytosolic release of an entrapped nano-sized cytotoxin can be achieved with consequent improvement in cytotoxicity. The photoproperties of the chlorin moiety are also conserved, with comparable singlet oxygen quantum yields found to the free chlorin.
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影响因子：
4.6
作者：
Lönn P;Kacsinta AD;Cui XS;Hamil AS;Kaulich M;Gogoi K;Dowdy SF
通讯作者：
Dowdy SF
影响因子：
3.3
作者：
Haedener, Marianne;Gjuroski, Ilche;Vermathen, Martina
通讯作者：
Vermathen, Martina
影响因子：
3.1
作者：
Bastien, Estelle;Schneider, Raphael;Lassalle, Henri-Pierre
通讯作者：
Lassalle, Henri-Pierre
影响因子：
9.3
作者：
Choi, Jun-Ho;Oh, Dongwook;Park, Do Hyun
通讯作者：
Park, Do Hyun
影响因子：
48
作者：
Erazo-Oliveras, Alfredo;Najjar, Kristina;La Dayani, Lai;Wang, Ting-Yi;Johnson, Gregory A.;Pellois, Jean-Philippe
通讯作者：
Pellois, Jean-Philippe