Drug-loaded Gold Plasmonic Nanoparticles for In Vivo Therapy of Multidrug Resistance in Cancer and Rheumatoid Arthritis

Abstract

Gold (Au) plasmonic nanoparticles (NPs) containing doxorubicin (DOX) for the treatment of multidrug resistance (MDR) in cancer were developed. To investigate the possibility of treating multidrug-resistant tumors with targeted chemo-photothermal treatment, in vitro and in vivo studies were conducted using a doxorubicin (DOX)-resistant DLD-1 cell line (DLD-1/DOX) and nude mice with human xenograft tumors, respectively. The chemo-photothermal treatment consisted of DOX-loaded-poly(lactic-co-glycolic acid, PLGA)-Au half-shell nanoparticles with targeting moieties of anti-death receptor-4 monoclonal antibody conjugated to the Au surface. The cells or xenografted tumors treated with nanoparticles were exposed to near infrared light for 10 min, which caused an increase in temperature to 45 °C. Chemo-photothermal treatment resulted in a large reduction in the rate of tumor xenograft growth on DLD-1/DOX tumor-bearing mice with a much smaller dose of DOX than conventional DOX chemotherapy. These results demonstrate that targeted chemo-photothermal treatment can provide high therapeutic efficacy and low toxicity in the treatment of multidrug-resistant tumors.

RGD-attached gold (Au) plasmonic nanoparticles (NPs) containing methotrexate (MTX) for the treatment of rheumatoid arthritis (RA) were also developed. The MTX is the most widely used disease modifying anti-rheumatic drug (DMARD) for the treatment of RA, and RGD peptide (arginine-glycine-aspartic acid) is a targeting moiety for inflammation. Upon near-infrared (NIR) irradiation, heat is locally generated due to Au half shells, and the drug release rate is enhanced, delivering heat and drug to the inflamed joints simultaneously. RA is a chronic inflammatory disease characterized by synovial inflammation in multiple joints within the penetration depth of NIR light. When combined with NIR irradiation, these nanoparticles containing a much smaller dosage of MTX (1/930 of MTX solution) showed greater therapeutic effects than that of a conventional treatment with MTX solution in collagen-induced arthritic (CIA) mice. This novel drug delivery system is a good way to maximize therapeutic efficacy and minimize dosage-related MTX side effects in the treatment of RA. Furthermore, these multifunctional nanoparticles could be applied to other DMARDs for RA or other inflammatory diseases.

Similar results were obtained using MTX-loaded PLGA gold (Au)/iron (Fe)/gold (Au) half-shell nanoparticles conjugated with RGD, which can be applied for magnetic targeted chemo-photothermal treatment, and in vivo multimodal imaging of RA. The Fe half-shell layer embedded between the Au half-shell layers enables in vivo T2

-magnetic resonance (MR) imaging in addition to NIR absorbance imaging. Furthermore, the delivery of the nanoparticles to the inflammation region in CIA mice, and their retention can be enhanced under external magnetic field. When combined with consecutive NIR irradiation and external magnetic field application, these nanoparticles provide enhanced therapeutic effects with an MTX dosages of only 0.05% dosage compared to free MTX therapy for the treatment of RA.