Abstract
Silk fibroin nanoparticles are emerging as promising nanomedicines, but their full therapeutic potential is yet to be realized. These nanoparticles can be readily PEGylated to improve colloidal stability and to tune degradation and drug release profiles; however, the relationship between silk fibroin nanoparticle PEGylation and macrophage activation still requires elucidation. Here, we used in vitro assays and nuclear magnetic resonance based metabolomics to examine the inflammatory phenotype and metabolic profiles of macrophages following their exposure to unmodified or PEGylated silk fibroin nanoparticles. The macrophages internalized both types of nanoparticles, but they showed different phenotypic and metabolic responses to each nanoparticle type. Unmodified silk fibroin nanoparticles induced the upregulation of several processes, including production of proinflammatory mediators (e.g., cytokines), release of nitric oxide, and promotion of antioxidant activity. These responses were accompanied by changes in the macrophage metabolomic profiles that were consistent with a proinflammatory state and that indicated an increase in glycolysis and reprogramming of the tricarboxylic acid cycle and the creatine kinase/phosphocreatine pathway. By contrast, PEGylated silk fibroin nanoparticles induced milder changes to both inflammatory and metabolic profiles, suggesting that immunomodulation of macrophages with silk fibroin nanoparticles is PEGylation-dependent. Overall, PEGylation of silk fibroin nanoparticles reduced the inflammatory and metabolic responses initiated by macrophages, and this observation could be used to guide the therapeutic applications of these nanoparticles.
Highlights
The clinical approval of Abraxane in 2005 for the treatment of solid breast tumors was followed by a surge in the use of novel materials in the design of intravenous anticancer nanoparticles that target tumors
PEGylation of silk fibroin nanoparticles reduced the inflammatory and metabolic responses initiated by macrophages, and this observation could be used to guide the therapeutic applications of these nanoparticles
An increase in particle size was noted between the unmodified silk fibroin nanoparticles (96.0 nm) and the PEGylated and FITC-PEGylated silk fibroin nanoparticles (105.3 and 106.4 nm, respectively)
Summary
The clinical approval of Abraxane in 2005 for the treatment of solid breast tumors was followed by a surge in the use of novel materials in the design of intravenous anticancer nanoparticles that target tumors. Drug-loaded nanoparticles can enter tumor tissues either passively, using the enhanced permeability and retention effect,[1] or actively, using targeting moieties such as peptides, monoclonal antibodies, or aptamers.[2,3] The physicochemical properties of nanoparticles have a direct impact on their biological performance at the systemic, tissue, cellular, and subcellular levels.[4,5] Factors such as the particle size, shape, and chemical composition dictate the likelihood of undesirable nanoparticle interactions with complement proteins and immunoglobulins in the circulating blood and with extracellular matrix proteins These interactions lead to rapid (
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