TY - JOUR
T1 - Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model
AU - Wei, Xin
AU - Li, Fei
AU - Zhao, Gang
AU - Chhonker, Yashpal Singh
AU - Averill, Christine
AU - Galdamez, Josselyn
AU - Purdue, P. Edward
AU - Wang, Xiaoyan
AU - Fehringer, Edward V.
AU - Garvin, Kevin L.
AU - Goldring, Steven R.
AU - Alnouti, Yazen
AU - Wang, Dong
N1 - Funding Information:
This study was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health of the United States of America (R01AR062680) and the University of Nebraska Medical Center College of Pharmacy. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
KW - ELVIS
KW - HPMA copolymer
KW - biodistribution
KW - dexamethasone
KW - implant loosening
KW - inflammation targeting
KW - pharmacokinetics
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U2 - 10.1021/acs.molpharmaceut.7b00045
DO - 10.1021/acs.molpharmaceut.7b00045
M3 - Article
C2 - 28343392
AN - SCOPUS:85018442751
SN - 1543-8384
VL - 14
SP - 1418
EP - 1428
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 5
ER -