Abstract
The C-X-C chemokine receptor type 4 (CXCR4, CD184) pathway is a key regulator of cancer metastasis. Existing therapeutics that block CXCR4 signaling are dependent on single molecule-receptor interactions or silencing CXCR4 expression. CXCR4 localizes in lipid rafts and forms dimers therefore CXCR4 targeting and signaling may depend on ligand density. Herein, we report liposomes presenting a CXCR4 binding peptide (DV1) as a three-dimensional molecular array, ranging from 9k to 74k molecules μm−2, target triple negative breast cancer (TNBC). TNBC cells exhibit a maxima in binding and uptake of DV1-functionalized liposomes (L-DV1) in vitro at a specific density, which yields a significant reduction in cell migration. This density inhibits metastasis from a primary tumor for 27 days, resulting from peptide density dependent gene regulation. We show that complementing cell membrane receptor expression may be a strategy for targeting cells and regulating signaling.
Highlights
The C-X-C chemokine receptor type 4 (CXCR4, CD184) pathway is a key regulator of cancer metastasis
High-performance liquid chromatography (HPLC) data indicated that the DV1-N3 peptide reached 98% purity (Supplementary Fig. S1a, b)
To interrogate the mechanism behind the inhibition of cancer cell migration in vitro and metastasis in vivo, we measured the expression of three effectors involved in cell migration and proliferation: the guanine nucleotide exchange factor for Rho family GTPases (p-115 RhoGEF), the p55γ regulatory subunit of phosphatidylinositol 3-kinase (PI3K)
Summary
The C-X-C chemokine receptor type 4 (CXCR4, CD184) pathway is a key regulator of cancer metastasis. We report liposomes presenting a CXCR4 binding peptide (DV1) as a threedimensional molecular array, ranging from 9k to 74k molecules μm−2, target triple negative breast cancer (TNBC). TNBC cells exhibit a maxima in binding and uptake of DV1functionalized liposomes (L-DV1) in vitro at a specific density, which yields a significant reduction in cell migration. This density inhibits metastasis from a primary tumor for 27 days, resulting from peptide density dependent gene regulation. We show that liposomes, functionalized at a specific peptide density, exhibit higher cancer cell uptake in vitro relative to other formulations. We establish that liposome surfaces may be engineered to exhibit therapeutic outcomes without encapsulation of a drug
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