Traditional methods for cancer drug delivery present numerous challenges, including toxicity to non-cancerous cells, poor tissue penetration, and lack of specificity in tumor targeting. Cell-based delivery strategies are of recent interest in treating several diseases, including cancer. In this project, we are specifically interested in using macrophage-based vehicles. These cells are recruited to cancer sites with great specificity and can penetrate to reach hypoxic/necrotic tumor cores. To further circumvent the issues of untimely cargo release and thus harm of healthy cells, we propose to improve upon macrophage-based delivery by attaching entities to cell surfaces using cleavable linkers that are labile under conditions specific to the tumor microenvironment. The tumor microenvironment contains a higher concentration of matrix metalloproteinases (MMPs), serine proteases that promote wound healing, tumor invasion, and tissue remodeling. By utilizing peptides that are labile in the presence of MMP enzymes, chemotherapeutics can be released specifically at the tumor site, reducing off-target effects. We have synthesized MMP-sensitive and control peptide linkers that will be modified with biotin and fluorophores as cell-surface attachment moieties and imaging entities/therapeutic surrogates, respectively. In the future, we will tether these constructs to macrophages and evaluate their cleavage abilities in vitro and in vivo, and incorporate drug conjugates for studies of therapeutic specificity and efficacy.

Metalloproteinase-sensitive peptide linkers for cell-surface modification of macrophages toward use in cell-based drug delivery

ACS Spring Meeting 2021

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