title: Endogenous inspired biomineral-installed hyaluronan nanoparticles as pH-responsive carrier of methotrexate for rheumatoid arthritis.
abstract: Methotrexate (MTX), an anchor drug for rheumatoid arthritis (RA), has been suffered from refractoriness and high toxicity limiting effective dosage. To mitigate these challenges, the ability to selectively deliver MTX to arthritis tissue is a much sought-after modality for the treatment of RA. In this study, we prepared mineralized nanoparticles (MP-HANPs), composed of PEGylated hyaluronic acid (P-HA) as the hydrophilic shell, 5β-cholanic acid as the hydrophobic core, and calcium phosphate (CaP) as the pH-responsive mineral. Owing to the presence of CaP as the diffusion barrier, mineralized HANPs revealed the pH-responsiveness of release kinetics of MTX across neutral to acidic conditions. HANPs were internalized via receptor-mediated endocytosis in macrophages which involved molecular redundancy among major hyaladherins, including CD44, stabilin-2, and RHAMM. Following endocytosis, MP-HANPs loaded with doxorubicin revealed pH-dependent demineralization followed by dramatic acceleration of drug release into the cytosol compared to other HANPs. Furthermore, an in vivo study showed a significantly high paw-to-liver ratio of fluorescent intensity after systemic administration of MP-HANP-Cy5.5, indicating improved biodistribution of nanoparticles into arthritic paws in collagen-induced arthritis mice. Treatment with MTX-loaded MP-HANPs ameliorated inflammatory arthritis with remarkable safety at high dose of MTX. We highlight the distinct advantages of combining key benefits of biomineralization and PEGylation with HA-based nanoparticles for arthritis-selective targeting, thus suggesting MP-HANPs as a promising carrier of MTX for treatment of RA.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital 130 Dongdeok-ro, Junggu, Daegu 41944, Republic of Korea.
authors.forename: Md Mahmudul
authors.initials: MM
authors.lastname: Alam
authors.affiliation: Department of Polymer Science and Engineering, College of Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Hwa Seung
authors.initials: HS
authors.lastname: Han
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital 130 Dongdeok-ro, Junggu, Daegu 41944, Republic of Korea.
authors.forename: Shijin
authors.initials: S
authors.lastname: Sung
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital 130 Dongdeok-ro, Junggu, Daegu 41944, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital 130 Dongdeok-ro, Junggu, Daegu 41944, Republic of Korea.
authors.forename: Keum Hee
authors.initials: KH
authors.lastname: Sa
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital 130 Dongdeok-ro, Junggu, Daegu 41944, Republic of Korea.
authors.forename: Hasan
authors.initials: H
authors.lastname: Al Faruque
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital 130 Dongdeok-ro, Junggu, Daegu 41944, Republic of Korea.
authors.forename: Jungwan
authors.initials: J
authors.lastname: Hong
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital 130 Dongdeok-ro, Junggu, Daegu 41944, Republic of Korea.
authors.forename: Eon Jeong
authors.initials: EJ
authors.lastname: Nam
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea; Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.
authors.forename: In San
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Department of Polymer Science and Engineering, College of Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: jhpark1@skku.edu.
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital 130 Dongdeok-ro, Junggu, Daegu 41944, Republic of Korea; Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea; Department of Biochemistry and Cellular Biology, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea. Electronic address: ymkang@knu.ac.kr.
authors.forename: Young Mo
authors.initials: YM
authors.lastname: Kang
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002130:Calcium Phosphates / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D065546:Drug Liberation; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D014018:Tissue Distribution
chemical_list: D018501:Antirheumatic Agents; D002130:Calcium Phosphates; D004337:Drug Carriers; D004317:Doxorubicin; D006820:Hyaluronic Acid; C020243:calcium phosphate; D008727:Methotrexate
keywords: Drug delivery system; Hyaluronic acid nanoparticle; Inflammatory arthritis; Methotrexate; Mineralization; pH-responsive