Optimizing Targeted Drug Delivery to Polarized Macrophages Via Arginine-Based Surface Modifications of Liposomes

Tumor associated macrophages (TAMs) have been shown to facilitate tumor growth and share significant characteristics with macrophages alternatively activated by interleukin-4 (IL-4). Previous investigations of interactions between alternatively activated macrophages and doxorubicin loaded liposomes yielded promising results regarding the practicality of targeting TAMs for a customized immune response in combating certain types of adenocarcinomas. Liposomes, unilamellar lipid bilayer nanoparticles, have inspired extensive contemporary research for improving targeted drug delivery vehicles due to their biocompatibility, biodegradability, and tunable surface chemistry. In this study, two arginine-based compounds, 3-guanidinopropionic acid (B) and N-carbamyl-alpha-aminoisobutyric acid (I), were utilized to modify the surfaces of liposomes synthesized from 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Unmodified and modified liposome phospholipids were combined to synthesize 25%, 50%, and 75% modified liposome surfaces of each type and were subsequently loaded with doxorubicin, a well-documented cancer medication. The surface coverage of these modifications were thus varied in order to evaluate the minimum extent of surface modification needed for optimized macrophage internalization. Dilutions of these particles were incubated with three distinct RAW 264.7 macrophage phenotypes—naïve, classically activated via lipopolysaccharide (LPS), and alternatively activated via IL-4—to assess the half maximal inhibitory concentration (IC₅₀) of the liposome encapsulated doxorubicin.