Cholesterol-modified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery

Zhiren Wang, Wenpan Li, Yanhao Jiang, Jonghan Park, Karina Marie Gonzalez, Xiangmeng Wu, Qing-Yu Zhang and Jianqin Lu ()
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Zhiren Wang: The University of Arizona
Wenpan Li: The University of Arizona
Yanhao Jiang: The University of Arizona
Jonghan Park: The University of Arizona
Karina Marie Gonzalez: The University of Arizona
Xiangmeng Wu: The University of Arizona
Qing-Yu Zhang: The University of Arizona
Jianqin Lu: The University of Arizona

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Cholesterol (Chol) fortifies packing and reduces fluidity and permeability of the lipid bilayer in vesicles (liposomes)-mediated drug delivery. However, under the physiological environment, Chol is rapidly extracted from the lipid bilayer by biomembranes, which jeopardizes membrane stability and results in premature leakage for delivered payloads, yielding suboptimal clinic efficacy. Herein, we report a Chol-modified sphingomyelin (SM) lipid bilayer via covalently conjugating Chol to SM (SM-Chol), which retains membrane condensing ability of Chol. Systemic structure activity relationship screening demonstrates that SM-Chol with a disulfide bond and longer linker outperforms other counterparts and conventional phospholipids/Chol mixture systems on blocking Chol transfer and payload leakage, increases maximum tolerated dose of vincristine while reducing systemic toxicities, improves pharmacokinetics and tumor delivery efficiency, and enhances antitumor efficacy in SU-DHL-4 diffuse large B-cell lymphoma xenograft model in female mice. Furthermore, SM-Chol improves therapeutic delivery of structurally diversified therapeutic agents (irinotecan, doxorubicin, dexamethasone) or siRNA targeting multi-drug resistant gene (p-glycoprotein) in late-stage metastatic orthotopic KPC-Luc pancreas cancer, 4T1-Luc2 triple negative breast cancer, lung inflammation, and CT26 colorectal cancer animal models in female mice compared to respective FDA-approved nanotherapeutics or lipid compositions. Thus, SM-Chol represents a promising platform for universal and improved drug delivery.

Date: 2024
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DOI: 10.1038/s41467-024-46331-7

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