Sticky Patches on Lipid Nanoparticles Enable the Selective Targeting and Killing of Untargetable Cancer Cells

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Targeting cancer cells with nanoparticles requires high receptor density for effective binding.
• Uniformly functionalized nanoparticles struggle to target cells with low receptor expression.

Purpose of the Study:

• To develop a novel nanoparticle strategy for selective cancer cell targeting with low receptor densities.
• To investigate the efficacy of clustered ligands on lipid vesicles for enhanced cancer cell interaction.

Main Methods:

• Lipid vesicles functionalized with clustered HER2-targeting peptides were designed to activate in acidic tumor environments.
• Comparison of "sticky vesicles" with uniformly functionalized vesicles on HER2-low breast cancer cells (MDA-MB-231, MCF7).
• Assessment of targeting, dissociation, and endocytosis rates, along with therapeutic efficacy using doxorubicin and (225)Ac.

Main Results:

• Sticky vesicles demonstrated specific targeting (KD ≈ 49-69 nM) on HER2-low breast cancer cells, unlike uniformly functionalized vesicles.
• Selective killing of cancer cells was achieved with sticky vesicles loaded with doxorubicin (32-40% viability) or (225)Ac (39-58% viability).
• No significant toxicity was observed in cardiomyocytes or normal breast cells, indicating high selectivity.

Conclusions:

• Tunable clustered ligand display on vesicles is a viable strategy for targeting cancer cells with low receptor densities.
• This approach enhances nanoparticle-based cancer therapy by overcoming limitations of receptor expression levels.
• The findings suggest a promising platform for developing more effective and selective cancer treatments.