Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model.
N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers were previously found to represent a versatile delivery platform for the early detection and intervention of orthopedic implant loosening. In this article, we evaluated the impact of different structural parameters of the HPMA copolymeric system (e.g., molecular weight (MW), drug content) to its pharmacokinetics and biodistribution (PK/BD) profile. Using125I, Alexa Fluor 488, and IRDye 800 CW-labeled HPMA copolymer-dexamethasone (P-Dex) conjugates with different MW and dexamethasone (Dex) contents, we found the MW to be the predominant impact factor on the PK/BD profiles of P-Dex, with Dex content as a secondary impact factor. In gamma counter-based PK/BD studies, increased MW of P-Dex reduced elimination, leading to lower clearance, longer half-life, and higher systemic exposure (AUC and MRT). In the semiquantitative live animal optical imaging evaluation, the distribution of P-Dex to the peri-implant inflammatory lesion increased when MW was increased. This result was further confirmed by FACS analyses of cells isolated from peri-implant regions after systemic administration of Alexa Fluor 488-labeled P-Dex. Since the in vitro cell culture study suggested that the internalization of P-Dex by macrophages is generally independent of P-Dex's MW and Dex content, the impact of the MW and Dex content on its PK/BD profile was most likely exerted at physiological and pathophysiological levels rather than at the cellular level. In both gamma counter-based PK/BD analyses and semiquantitative optical imaging analyses, P-Dex with 6 wt % Dex content showed fast clearance. Dynamic light scattering analyses unexpectedly revealed significant molecular aggregation of P-Dex at this Dex content level. The underlining mechanisms of the aggregation and fast in vivo clearance of the P-Dex warrant further investigation.
Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Xin
0000-0003-4213-451X
X
Wei
Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Fei
F
Li
Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Gang
G
Zhao
Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Yashpal Singh
0000-0001-6455-5388
YS
Chhonker
Hospital for Special Surgery , New York, New York 10021, United States.
Christine
C
Averill
Hospital for Special Surgery , New York, New York 10021, United States.
Josselyn
J
Galdamez
Hospital for Special Surgery , New York, New York 10021, United States.
P Edward
PE
Purdue
Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Xiaoyan
X
Wang
Department of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Edward V
EV
Fehringer
Department of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Kevin L
KL
Garvin
Hospital for Special Surgery , New York, New York 10021, United States.
Steven R
SR
Goldring
Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Yazen
Y
Alnouti
Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.|Department of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Dong
0000-0002-8340-2763
D
Wang
D000818:Animals; D003907:Dexamethasone / Q000737:chemistry*; D005434:Flow Cytometry; D008297:Male; D008689:Methacrylates / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008856:Microscopy, Fluorescence; D011108:Polymers / Q000737:chemistry* / Q000493:pharmacokinetics
D008689:Methacrylates; D011108:Polymers; D003907:Dexamethasone; C032802:hydroxypropyl methacrylate
ELVIS; HPMA copolymer; biodistribution; dexamethasone; implant loosening; inflammation targeting; pharmacokinetics