The Evaluation of the Therapeutic Efficacy and Side Effects of a Macromolecular Dexamethasone Prodrug in the Collagen-Induced Arthritis Mouse Model.
OBJECTIVE
To investigate the efficacy and safety of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) in the collagen-induced arthritis (CIA) mouse model.


METHODS
HPMA copolymer labeled with a near infrared fluorescence (NIRF) dye was administered to mice with CIA to validate its passive targeting to inflamed joints and utility as a drug carrier system. The CIA mice were treated with P-Dex, dexamethasone (Dex) or saline and the therapeutic efficacy and skeletal toxicity evaluated using clinical scoring and micro-computed tomography (μ-CT).


RESULTS
The NIRF signal of the HPMA copolymer localized to arthritic joints consistent with its passive targeting to sites of inflammation. While the CIA mice responded more rapidly to P-Dex compared to Dex, the final clinical score and endpoint μ-CT analyses of localized bone erosions indicated that both single dose P-Dex and dose equivalent daily Dex led to comparable clinical efficacy after 30 days. μ-CT analysis of the proximal tibial metaphyses showed that P-Dex treatment was associated with significantly higher BMD and BV/TV compared to Dex and the saline control, consistent with reduced glucocorticoid (GC) skeletal toxicity.


CONCLUSIONS
These results validate the therapeutic efficacy of P-Dex in the CIA mouse model. P-Dex treatment averted the adverse effects of GC's on systemic bone loss, supporting its utility in clinical development for the management of rheumatoid arthritis.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
Lingdong
L
Quan
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
Yijia
Y
Zhang
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
Anand
A
Dusad
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
Ke
K
Ren
Hospital for Special Surgery, New York, New York, 10021, USA.
P Edward
PE
Purdue
Hospital for Special Surgery, New York, New York, 10021, USA.
Steven R
SR
Goldring
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA. dwang@unmc.edu.
Dong
D
Wang
D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy*; D015519:Bone Density; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D046911:Macromolecular Substances / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008689:Methacrylates; D051379:Mice; D008811:Mice, Inbred DBA; D010024:Osteoporosis / Q000188:drug therapy; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013977:Tibia / Q000000981:diagnostic imaging; D014057:Tomography, X-Ray Computed
D046911:Macromolecular Substances; D008689:Methacrylates; D011355:Prodrugs; D003907:Dexamethasone; C032802:hydroxypropyl methacrylate
ELVIS; HPMA copolymer; collagen-induced arthritis; glucocorticoid; prodrug