Chemokine functionalized nanoparticles interactions with acute monocytic leukemia cells.

Biodegradable nanoparticles (NPs) aimed at drug/gene delivery can be functionalized with different molecules to have specific characteristics, like short bio-persistence, protection of the NP cargo and controlled release, specific cell/tissue targeting, as well as modulation of cellular signaling. To specifically improve NP selective targeting and modulation of immune responses, I focused my PhD project on the interactions between biocompatible NPs and immune cells. This goal was pursued by PLGA/Pluronic NP-surface decoration with two different chemokines, namely CXCL12 and CCL5. The first is a key mediator of homeostatic cell trafficking and it is involved in several pathologies, including cancers’ metastasis. On the contrary, CCL5 is an induced chemokine attracting leukocytes during the inflammatory leukocyte effector phase. The rationale of the project relies on these molecules’ roles to drive NPs towards specific cells exclusively expressing their cognate receptors, CXCR4 and CCR5. During the first two years I functionalized, characterized and tested the biological activity of chemokine-decorated PLGA-NPs in CXCR4 and CCR5 expressing human monocytic cells in vitro. I demonstrated CXCL12/CCL5-NPs stability in cell culture media and I proved that CXCL12-NPs enhanced binding/internalization abrogating CXCR4-mediated THP-1 leukemia cell chemotaxis. This result contributes to the search of biocompatible nanotools to quench tumor cell dysregulated migration. In the last year I optimized CCL5-NPs, further enhancing their cell targeting and internalization. I proved the dependence of CCL5-NP binding/internalization on the amount of surface-linked CCL5 and the unspecific adhesion of “naked” PLGA/Pluronic-NPs.