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

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
• prednisolone
• curcumin
• human serum albumin
• rheumatoid arthritis

Acknowledgements

This work was supported by Sichuan Science and Technology Program (2017RZ0048) and the National Natural Science Foundation of China (Grant No. 81803478).

Abbreviations

OA, oleic acid; lipoid E80, purified yolk lecithin; RA, rheumatoid arthritis; PD, prednisolone; CU, curcumin; HSA, human serum albumin; N-PD/CU, Co-delivery of prednisolone and curcumin in human serum albumin nanoparticles; N-PD, prednisolone in HSA-based nanoparticles; N-CU, curcumin in HAS-based nanoparticles; EE, encapsulation efficiency; DLE, drug loading efficiency; blank, blank HSA-based nanoparticles; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DID, Dioctadecyl tetramethyl Indodicarbocyanine; ELISA, Enzyme-linked immunosorbent assay; ELVIS, extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration; EPR, enhanced permeability and retention; PBS, phosphate-buffered saline.

Disclosure

The authors report no conflicts of interest in this work.