Endogenous inspired biomineral-installed hyaluronan nanoparticles as pH-responsive carrier of methotrexate for rheumatoid arthritis

• DOI: 10.1016/j.jconrel.2017.03.012
• Publication Date: 2017-03-11T01:18:07Z
• Authors: Md. Mahmudul Alam; Hwa Seung Han; Shijin Sung; Jin Hee Kang; Keum Hee Sa; Hasan Al Faruque; Jungwan Hong; Eon Jeong Nam; In San Kim; Jae Hyung Park; Young Mo Kang
• Keywords: Calcium Phosphates; Male; 0301 basic medicine; Drug Carriers; Hydrogen-Ion Concentration; Arthritis, Experimental; 3. Good health; Arthritis, Rheumatoid; Drug Liberation; Mice; 03 medical and health sciences; Methotrexate; Doxorubicin; Antirheumatic Agents; Animals; Humans; Nanoparticles; Tissue Distribution; Hyaluronic Acid; Particle Size; Hydrophobic and Hydrophilic Interactions

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.