Investigating Bio-Nano Interactions of PEGylated Cationic Polyamidoamine (PAMAM) Dendrimers within Synovial Joints

Abstract

Delivering therapeutics directly to synovial joints to treat osteoarthritis (OA) is challenging due to the dense negatively charged cartilage matrix and rapid turnover of synovial fluid, leading to high clearance rates. Our lab has identified polyamidoamine (PAMAM) dendrimers as optimal nanocarriers to overcome delivery challenges to cartilage due to their positive charge and small size, which enables them to bind to cartilage and diffuse through tissue to deliver therapeutics to chondrocytes. Previously, we have developed and characterized dendrimers functionalized with polyethylene glycol (PEG), demonstrating improved biocompatibility and enhanced transport through cartilage matrix. To improve the design of our therapeutic system, in this next phase of work, we characterized dendrimer-protein interactions or protein coronas that form on dendrimers after being immersed in synovial fluid. We also analyzed how synovial fluid protein coronas affect biological outcomes of dendrimers in synovial joints, specifically uptake in cartilage and internalization by chondrocytes. We identified that protein coronas can reduce dendrimer uptake in cartilage and chondrocytes; however, uptake reduction is mitigated by varying PEG chain length and density. Although protein coronas can be perceived as "biological barriers" to uptake, we demonstrate that dendrimers conjugated with insulin-like growth factor 1 (IGF-1) have better engagement with IGF-1 receptors after being pre-coated with a synovial fluid protein corona. Overall, these studies offer further insight into the mechanisms of how positively charged dendrimers target and transport through cartilage, bridging knowledge gaps between ex vivo and in vivo work. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/668990v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@9298ccorg.highwire.dtl.DTLVardef@6d85aeorg.highwire.dtl.DTLVardef@63838dorg.highwire.dtl.DTLVardef@151ca4a_HPS_FORMAT_FIGEXP M_FIG C_FIG