Moshnikova Anna, DuPont Michael, Iraca Marissa, Klumpp Craig, Visca Hannah, Allababidi Dana, Pelzer Phoebe, Engelman Donald M, Andreev Oleg A, Reshetnyak Yana K
Physics Department, University of Rhode Island, Kingston, RI, United States.
Department of Chemical Engineering, University of Rhode Island, Kingston, RI, United States.
Front Pharmacol. 2024 Mar 1;15:1346756. doi: 10.3389/fphar.2024.1346756. eCollection 2024.
We have developed a delivery approach that uses two pHLIP peptides that collaborate in the targeted intracellular delivery of a single payload, dimeric STINGa (dMSA). dMSA was conjugated with two pHLIP peptides via S-S cleavable self-immolating linkers to form 2pHLIP-dMSA. Biophysical studies were carried out to confirm pH-triggered interactions of the 2pHLIP-dMSA with membrane lipid bilayers. The kinetics of linker self-immolation and dMSA release, the pharmacokinetics, the binding to plasma proteins, the stability of the agent in plasma, the targeting and resulting cytokine activation in tumors, and the biodistribution of the construct was investigated. This is the first study demonstrating that combining the energy of the membrane-associated folding of two pHLIPs can be utilized to enhance the targeted intracellular delivery of large therapeutic cargo payloads. Linking two pHLIPs to the cargo extends blood half-life, and targeted delivery of dimeric STINGa induces tumor eradication and the development of robust anti-cancer immunity.
我们开发了一种递送方法，该方法使用两种pHLIP肽，它们协同作用于单一负载二聚体STINGa（dMSA）的靶向细胞内递送。通过S-S可裂解的自毁连接子将dMSA与两种pHLIP肽偶联，形成2pHLIP-dMSA。进行了生物物理研究以确认2pHLIP-dMSA与膜脂双层的pH触发相互作用。研究了连接子自毁和dMSA释放的动力学、药代动力学、与血浆蛋白的结合、该制剂在血浆中的稳定性、在肿瘤中的靶向作用以及由此产生的细胞因子激活，以及该构建体的生物分布。这是第一项证明可以利用两种pHLIP的膜相关折叠能量来增强大型治疗性负载的靶向细胞内递送的研究。将两种pHLIP连接到负载上可延长血液半衰期，二聚体STINGa的靶向递送可诱导肿瘤根除并产生强大的抗癌免疫力。
