Multifunctional nanomedicines with active targeting and stimuli-responsive drug release function utilizing pathophysiological features of the disease are regarded as an effective strategy for treatment of rheumatoid arthritis (RA). Under the inflammatory environment of RA, activated macrophages revealed increased expression of folate receptor and elevated intracellular reactive oxygen species (ROS) level. In this study, we successfully conjugated folate to polyethylene glycol 100 monostearate as film-forming material and further prepared methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes, herein, shortened to FOL-MTX&CAT-L, that could actively target to activated macrophages. Thereafter, elevated intracellular hydrogen peroxide, the main source of ROS, diffused into liposomes and encapsulated CAT catalyzed the decomposition of hydrogen peroxide into oxygen and water. Continuous oxygen-generation inside liposomes would eventually disorganize its structure and release the encapsulated MTX. We characterized the in vitro drug release, cellular uptake and cytotoxicity studies as well as in vivo pharmacokinetics, biodistribution, therapeutic efficacy and safety studies of FOL-MTX&CAT-L. In vitro results revealed that FOL-MTX&CAT-L possessed sufficient ROS-sensitive drug release, displayed an improved cellular uptake through folate-mediated endocytosis and exhibited a higher cytotoxic effect on activated RAW264.7 cells. Moreover, in vivo results showed prolonged blood circulation time of PEGylated liposomes, enhanced accumulation of MTX in inflamed joints of collagen-induced arthritis (CIA) mice, reinforced therapeutic efficacy and minimal toxicity toward major organs. These results imply that FOL-MTX&CAT-L may be used as an effective nanomedicine system for RA treatment.

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Multidrug resistance (MDR) due to P-glycoprotein (P-gp) overexpression is a major obstacle to successful leukemia chemotherapy. The combination of anticancer chemotherapy with a chemosensitizer of P-gp inhibitor is promising to overcome MDR, generate synergistic effects, and maximize the treatment effect. Herein, we co-encapsulated a chemotherapeutic drug of mitoxantrone (MTO) and a P-gp inhibitor of β-elemene (βE) in solid lipid nanoparticles (MTO/βE-SLNs) for reversing MDR in leukemia. The MTO/βE-SLNs with about 120 nm particle size possessed good colloidal stability and sustained release behavior. For the cellular uptake study, doxorubicin (DOX) was used as a fluorescence probe to construct SLNs. The results revealed that MTO/βE-SLNs could be effectively internalized by both K562/DOX and K562 cells through the pathway of caveolate-mediated endocytosis. Under the optimized combination ratio of MTO and βE, the in vitro cytotoxicity study indicated that MTO/βE-SLNs showed a better antitumor efficacy in both K562/DOX and K562 cells than other MTO formulations. The enhanced cytotoxicity of MTO/βE-SLNs was due to the increased cellular uptake and blockage of intracellular ATP production and P-gp efflux by βE. More importantly, the in vivo studies revealed that MTO/βE-SLNs could significantly prolong the circulation time and increase plasma half-life of both MTO and βE, accumulate into tumor and exhibit a much higher anti-leukemia effect with MDR than other MTO formulations. These findings suggest MTO/βE-SLNs as a potential combined therapeutic strategy for overcoming MDR in leukemia.