Oleyl Conjugated Histidine-Arginine Cell-Penetrating Peptides as Promising Agents for siRNA Delivery

Authors

Muhammad Imran Sajid, Chapman UniversityFollow
Dindyal Mandal, Chapman UniversityFollow
Naglaa Salem El-Sayed, Chapman UniversityFollow
Sandeep Lohan, Chapman UniversityFollow
Jonathan Moreno, Chapman UniversityFollow
Rakesh Kumar Tiwari, Chapman UniversityFollow

Document Type

Article

Publication Date

4-18-2022

Abstract

Recent approvals of siRNA-based products motivated the scientific community to explore siRNA as a treatment option for several intractable ailments, especially cancer. The success of approved siRNA therapy requires a suitable and safer drug delivery agent. Herein, we report a series of oleyl conjugated histidine–arginine peptides as a promising nonviral siRNA delivery tool. The conjugated peptides were found to bind with the siRNA at N/P ratio ≥ 2 and demonstrated complete protection for the siRNA from early enzymatic degradation at N/P ratio ≥ 20. Oleyl-conjugated peptide -siRNA complexes were found to be noncytotoxic in breast cancer cells (MCF-7 and MDA-MB-231) and normal breast epithelial cells (MCF 10A) at N/P ratio of ~40. The oleyl-R₃-(HR)₄ and oleyl-R₄-(HR)₄ showed ~80-fold increased cellular uptake in MDA-MB-231 cells at N/P 40. Moreover, the conjugated peptides-siRNA complexes form nanocomplexes (~115 nm in size) and have an appropriate surface charge to interact with the cell membrane and cause cellular internalization. Furthermore, this study provides a proof-of-concept that oleyl-R₅-(HR)₄ can efficiently silence STAT-3 gene (~80% inhibition) in MDA-MB-231 cells with similar effectiveness to Lipofectamine. Further exploration of this approach holds a great promise in discovering a successful in vivo siRNA delivery agent with a favorable pharmacokinetic profile.

Comments

This article was originally published in Pharmaceutics, volume 14, in 2022. https://doi.org/10.3390/pharmaceutics14040881

Recommended Citation

Sajid, M.I.; Mandal, D.; El-Sayed, N.S.; Lohan, S.; Moreno, J.; Tiwari, R.K. Oleyl Conjugated Histidine-Arginine Cell-Penetrating Peptides as Promising Agents for siRNA Delivery. Pharmaceutics 2022, 14, 881. https://doi.org/10.3390/pharmaceutics14040881

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This work is licensed under a Creative Commons Attribution 4.0 License.