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Improved method for synthesis of low molecular weight protamine–siRNA conjugate

Acta Pharmaceutica Sinica B 2018年第1期8卷 116-126页

作者： Zhili Yu Junxiao Ye Xing Pei Lu Sun Ergang Liu Jianxin Wang Yongzhuo Huang Seung Jin Lee Huining He Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of PharmacyTianjin Medical University College of Pharmacy Tsinghua University Collaborative Innovation Center of Chemical Science and Chemical Engineering and Technology Tianjin University Key Laboratory of Smart Drug Delivery Ministry of Education & PLA Department of Pharmaceutics School of Pharmacy Fudan University Ministry of Education & PLA Shanghai Institute of Materia Medica Chinese Academy of Sciences Department of Pharmacy Ewha Womans University Seodaemun-gu

RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides(CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine(LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS–PEG–OPSS as a crosslinker to synthesize LMWP–siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation.

关键词： Cell penetrating peptide siRNA Conjugate conjugation yield Biomimetic delivery Crosslinker

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