Co-Delivery of Prednisolone and Curcumin in Human Serum Albumin Nanoparticles for Effective Treatment of Rheumatoid Arthritis

Feili Yan, Hui Li, Zhirong Zhong, Meiling Zhou, Yan Lin, Can Tang, Chunhong Li, Feili Yan, Hui Li, Zhirong Zhong, Meiling Zhou, Yan Lin, Can Tang, Chunhong Li

Abstract

Background: Prednisolone (PD) is extremely effective for treating rheumatoid arthritis (RA). However, it distributes nonspecifically throughout the body and its use is associated with serious side effects, which promoted us to compound it into a phytomedicine for greater efficacy and safety.

Methods: We combined PD with curcumin (CU), an effective monomer from traditional Chinese medicine, and human serum albumin (HSA) in a nanoparticulate system (N-PD/CU) to compensate for the poor bioavailability of PD and CU. N-PD/CU was prepared by high-pressure homogenization, and its characteristics were evaluated in vitro. Next, we investigated its toxicity and mechanism of anti-inflammatory to macrophages. Finally, its pharmacokinetics, biodistribution and therapeutic efficacy were assessed in rats with adjuvant-induced arthritis (AIA).

Results: N-PD/CU showed a narrow size distribution around 150.4 ± 2.4 nm, a polydispersity index of 0.22 ± 0.02 and drug loading efficiency (DLE) of 88.75 ± 1.82% for PD and 85.79 ± 1.43% for CU. N-PD/CU showed sustained release of both drugs in vitro. N-PD/CU had no toxicity to macrophages in vitro on concentrations between 0.1 and 1.2 μmol/mL. In activated macrophages, N-PD decreased levels of pro-inflammatory cytokines, while N-CU increased levels of anti-inflammatory IL-10, and N-PD/CU exhibited best therapeutic effect in vitro, suggesting co-delivery of PD and CU may synergistically control the course of RA. In AIA rats, N-PD/CU accumulated in inflamed joints through the effect of extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS effect) in inflammatory lesion and showed higher therapeutic efficacy than single-loaded nanoparticles, either free drug on its own, or a simple mixture of the two drugs.

Conclusion: This codelivery system based on HSA is a promising platform for combination chemotherapy in RA.

Keywords: co-delivery; curcumin; human serum albumin; prednisolone; rheumatoid arthritis.

Conflict of interest statement

The authors report no conflicts of interest in this work.

© 2019 Yan et al.

Figures

Figure 1
Figure 1
Size of N-PD/CU (A), N-PD (B), N-CU (C) and blank nanoparticles (D). (E) Morphologies of diffferent human serum albumin nanoparticles as measured by TEM.
Figure 2
Figure 2
Characteristic of nanoparticles. (A) Size, PDI, zeta potential EE and DLE of nanoparticles, Data represent the mean ± SD (n=3). (B) Cumulative release of PD from N-PD/CU and free PD solution. (C) Cumulative release of CU from N-PD/CU and free CU solution. Data represent the mean ± SD (n=3).
Figure 3
Figure 3
The effect of N-PD/CU, blank nanoparticle and PD/CU for RAW264.7 cells viability. Data represent mean ± SD (n=5).
Figure 4
Figure 4
Expression of pro-inflammatory cytokines and anti-inflammatory cytokine in cell-free supernatant of activated macrophage treated with different preparations. Levels of (A) TNF- α, (B) IL-1β, (C) IL-6 and (D) IL-10 were assayed. Data shown are mean ± SD (n=3). *p<0.05, **p<0.001, ***p<0.0001 vs cells treated with N-PD/CU, #p<0.05, ##p<0.001, ###p<0.0001 vs cells treated with PBS.
Figure 5
Figure 5
Biodistribution profiles of N-PD/CU and PD/CU. (A)The concentration of PD in different plasma, organs and joints at different time points in AIA rats treated by N-PD/CU and PD/CU. (B)The distribution of CU in different plasma, organs and joints at different time points in AIA rats treated with N-PD/CU and PD/CU. Data represent the mean ± SD (n=5). *p<0.05, **p<0.001, ***p<0.0001 vs animals treated with PD/CU.
Figure 6
Figure 6
Plasma concentration-time curves of N-PD/CU and PD/CU. (A) Concentration-time curves of PD. (B) Concentration-time curves of CU. Data represent the mean ± SD (n=5). (C) Pharmacokinetic parameters of N-PD/CU and PD/CU (n=5).
Figure 7
Figure 7
Joints concentration-time curves of N-PD/CU and PD/CU. (A) Concentration-time curves of PD. (B) Concentration-time curves of CU. Data represent the mean ± SD (n=5). (C) Pharmacokinetic parameters of N-PD/CU and PD/CU (n=5).
Figure 8
Figure 8
The real-time fluorescence imaging of AIA rats. Rats were administrated by intravenous injection with saline, free DID or DID/N-PD/CU, respectively (n=3). Abbreviation: DID, Dioctadecyl tetramethyl Indocarbocyanine.
Figure 9
Figure 9
Therapeutic efficacy of nanoparticles in vivo. (A) Body weight variation after given different treatments. (B) Mean arthritis scores were calculated for the joints in the right hind limb following different treatments. Data shown are mean ± SD (n=3). (C) Photomicrographs of histological sections of ankle joints from animals after different treatments. Arrows indicate finger-like pannus formation; asterisks, bone destruction. Bar, 100 nm.
Figure 10
Figure 10
Production of pro-inflammatory cytokines and anti-inflammatory cytokines in arthritic rats treated with different preparations. Healthy, untreated animals served as a control (Normal). Serum levels of (A) TNF-α, (B) IL-1β, (C) IL-6 and (D) IL-10 were assayed. Data shown are mean ± SD (n=3). *p<0.05, **p<0.001, ***p<0.0001 vs animals treated with N-PD/CU.

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