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. 2020 Aug 10:324:560-573.
doi: 10.1016/j.jconrel.2020.05.028. Epub 2020 May 20.

Structural optimization of HPMA copolymer-based dexamethasone prodrug for improved treatment of inflammatory arthritis

Zhenshan Jia  1 , Gang Zhao  1 , Xin Wei  2 , Dexuan Kong  3 , Yuanyuan Sun  1 , You Zhou  4 , Subodh M Lele  5 , Edward V Fehringer  6 , Kevin L Garvin  6 , Steven R Goldring  7 , Dong Wang  8
Affiliations

Structural optimization of HPMA copolymer-based dexamethasone prodrug for improved treatment of inflammatory arthritis

Zhenshan Jia et al. J Control Release. .

Abstract

Despite their notorious adverse effects, glucocorticoids (GC, potent anti-inflammatory drugs) are used extensively in clinical management of rheumatoid arthritis (RA) and other chronic inflammatory diseases. To achieve a sustained therapeutic efficacy and reduced toxicities, macromolecular GC prodrugs have been developed with promising outcomes for the treatment of RA. Fine-tuning the activation kinetics of these prodrugs may further improve their therapeutic efficacy and minimize the off-target adverse effects. To assess the feasibility of this strategy, five different dexamethasone (Dex, a potent GC)-containing monomers with distinctively different linker chemistries were designed, synthesized, and copolymerized with N-(2-hydroxypropyl) methacrylamide (HPMA) to obtain 5 macromolecular Dex prodrugs. Their Dex releasing rates were analyzed in vitro and shown to display a wide spectrum of activation kinetics. Their therapeutic efficacy and preliminary toxicology profiles were assessed and compared in vivo in an adjuvant-induced arthritis (AA) rat model in order to identify the ideal prodrug design for the most effective and safe treatment of inflammatory arthritis. The in vivo data demonstrated that the C3 hydrazone linker-containing prodrug design was the most effective in preserving joint structural integrity. The results from this study suggest that the design and screening of different activation mechanisms may help to identify macromolecular prodrugs with the most potent therapeutic efficacy and safety for the management of inflammatory arthritis.

Keywords: Controlled release; Dexamethasone; HPMA copolymer; Inflammation; Prodrug; Rheumatoid arthritis.

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Figures

Figure 1.
Figure 1.
In vitro Dex release kinetics of P-Dex-A, P-Dex-B, P-Dex-C, P-Dex-D and P-Dex-E in the different releasing buffers. Each sample was measured three times. The mean values and standard deviation were calculated using GraphPad Prism 7.
Figure 2.
Figure 2.
HPMA copolymer-based Dex prodrugs with different releasing mechanisms demonstrated different therapeutic effects on amelioration of joint inflammation in an adjuvant-induced arthritis (AA) rat model. (A) The changes in the left ankle joint diameter of AA rats treated with different Dex-containing polymeric prodrugs during the entire experiment; (B) The changes in the articular index scores of AA rats treated with different Dex-containing polymeric prodrugs during the entire experiment. The red arrow indicated the day when rats received the single polymeric prodrug injection or the first injection of the four daily free Dex treatments. The green arrow indicated the day when daily Dex-treated rats received their last injection. The sustained amelioration of arthritic ankle swelling by single injection of P-Dex-A and P-Dex-E lasted for about 1 month from day 15 to day 44.
Figure 3.
Figure 3.
Micro-CT analyses of the hind paw of the rats from different treatment groups. (A) Bone morphometric parameters of the trabecular bone ROI within calcaneus bone. (B) Bone morphometric parameters of the entire calcaneus bone. (C) Representative images of 3-D rendering of the arthritic ankle joints. (*, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001).
Figure 4.
Figure 4.
Histological evaluation of ankle joints from different treatment groups. (A) Representative images of the H&E-stained joint sections (400×) and semiquantitative comparisons of histology scores of all treatment groups (*, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001) were presented. (B) Representative images of the Safranin O-stained joint sections (400×). Scale bar = 0.5 mm. Black arrow indicated bone destruction. Red arrow indicated cellular infiltration in cartilage.
Figure 5.
Figure 5.
The quantitative analysis of the 5th lumbar vertebrate using micro-CT. *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001.
Scheme 1.
Scheme 1.
The design of Dex-containing monomers (A, B, C, D, E) for the synthesis of HPMA copolymer-based Dex prodrugs with different releasing rates. Red colored structures represent the different linker chemistries.
Scheme 2.
Scheme 2.
The synthesis of monomer A
Scheme 3.
Scheme 3.
Synthesis of monomer B
Scheme 4.
Scheme 4.
Synthesis of monomer C
Scheme 5.
Scheme 5.
Synthesis of monomer D
Scheme 6.
Scheme 6.
Synthesis of monomer E
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