Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model

Xin Wei, Fei Li, Gang Zhao, Yashpal Singh Chhonker, Christine Averill, Josselyn Galdamez, P. Edward Purdue, Xiaoyan Wang, Edward V. Fehringer, Kevin L. Garvin, Steven R. Goldring, Yazen Alnouti, Dong Wang

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1418-1428
Number of pages11
JournalMolecular Pharmaceutics
Volume14
Issue number5
DOIs
StatePublished - May 1 2017

Keywords

  • ELVIS
  • HPMA copolymer
  • biodistribution
  • dexamethasone
  • implant loosening
  • inflammation targeting
  • pharmacokinetics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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    Wei, X., Li, F., Zhao, G., Chhonker, Y. S., Averill, C., Galdamez, J., Purdue, P. E., Wang, X., Fehringer, E. V., Garvin, K. L., Goldring, S. R., Alnouti, Y., & Wang, D. (2017). Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model. Molecular Pharmaceutics, 14(5), 1418-1428. https://doi.org/10.1021/acs.molpharmaceut.7b00045