Development of a hyperbranched polymer-based methotrexate nanomedicine for rheumatoid arthritis

• Published in: Acta biomaterialia Vol. 142; pp. 298 - 307
• Main Authors: Marasini, Nirmal, Er, Gerald, Fu, Changkui, Subasic, Christopher N., Ibrahim, Jibriil, Skwarczynski, Mariusz, Toth, Istvan, Whittaker, Andrew K., Kaminskas, Lisa M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2022; Elsevier BV
• Subjects: Animals; Arthritis; Arthritis, Rheumatoid - drug therapy; Collagenase 3; Drug delivery; Drug delivery systems; Ethylene glycol; Hepatotoxicity; Humans; Hyperbranched polymer; Inflammation; Intravenous administration; Joint diseases; Joints (anatomy); Liver; Liver diseases; Matrix metalloproteinase; Matrix Metalloproteinase 13; Matrix metalloproteinases; Metalloproteinase; Methotrexate; Methotrexate - pharmacology; Methotrexate - therapeutic use; Monocytes; Nanomedicine; Nanoparticles; Nanotechnology; Peptides; Polymers; Polymers - therapeutic use; Rats; Rheumatoid arthritis; Tissue Distribution; Toxicity; Hyperbranched polymer; Matrix metalloproteinase; Methotrexate; Nanomedicine; Rheumatoid arthritis; Liver
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2022.01.054

Methotrexate (MTX) is an effective disease modifying anti-rheumatic drug, but can cause significant hepatotoxicity and liver failure in some individuals. The goal of this work was to develop a MTX-conjugated hyperbranched polymeric nanoparticle based on oligo(ethylene glycol) methyl ether methacrylate (OEGMA) and examine its ability to selectively deliver MTX to rheumatic joints while sparing the liver. MTX was conjugated to the hyperbranched polymer via a matrix metalloproteinase-13 cleavable peptide linker. Two populations of nanoparticles were produced, with sizes averaging 20 and 200nm. Tri-peptide (FFK)-modified MTX was liberated in the presence of matrix metalloproteinase 13 (MMP-13)and showed 100 to 1000-fold lower antiproliferative capacity in monocytic THP-1 cells compared to unmodified MTX, depending on whether the gamma-carboxylate of MTX was functionalized with O-tert-butyl. Nanoparticles showed prolonged plasma exposure after intravenous injection with a terminal half-life of approximately 1 day, but incomplete (50%) absorption after subcutaneous administration. Nanoparticles selectively accumulated in inflamed joints in a rat model of rheumatoid arthritis and showed less than 5% biodistribution in the liver after 5 days. MTX-OtBu nanoparticles also showed no hepatocellular toxicity at 500 μM MTX equivalents. This work provides support for the further development of OEGMA-based hyperbranched polymers as MTX drug delivery systems for rheumatoid arthritis. Nanomedicines containing covalently conjugated methotrexate offer the potential for selective accumulation of the potent hepatotoxic drug in rheumatic joints and limited liver exposure. One limitation of the high surface presentation of methotrexate on a nanoparticle surface, however, is the potential for enhanced liver uptake. We developed several OEGMA-based hyperbranched polymers containing alpha-carboxyl modified and unmodified methotrexate conjugated via an MMP-13 cleavable hexapeptide linker. The modified methotrexate polymer showed promising in vitro and in vivo behavior warranting further development and optimization as an anti-rheumatic nanomedicine. This work presents a new avenue for further research into the development of hyperbranched polymers for rheumatoid arthritis and suggests interesting approaches that may overcome some limitations associated with the translation of anti-rheumatic nanomedicines into patients. [Display omitted]