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

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 manuscript, 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. Using 125I, 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 semi-quantitative 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’ 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 semi-quantitative 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.

Nanomedicines for the delivery of glucocorticoids and nucleic acids as potential alternatives in the treatment of rheumatoid arthritis

“…In addition, several PDCs based on PEG have been approved for clinical use (Alconcel, Baas, & Maynard, 2011). In one study involving HPMA-dexamethasone conjugates, the molecular weight was found to be the predominant factor impacting PDC pharmacokinetics (Wei et al, 2017). The increased molecular weight of HPMA-dexamethasone conjugates reduced elimination, leading to lower clearance, longer half-life, and higher systemic exposure (Wei et al, 2017).…”

“…In one study involving HPMA-dexamethasone conjugates, the molecular weight was found to be the predominant factor impacting PDC pharmacokinetics (Wei et al, 2017). The increased molecular weight of HPMA-dexamethasone conjugates reduced elimination, leading to lower clearance, longer half-life, and higher systemic exposure (Wei et al, 2017). In the CIA mouse model, Quan et al demonstrated a much better distribution of the HPMA conjugates (Quan et al, 2016).…”

Novel Drug Delivery Systems Tailored for Improved Administration of Glucocorticoids

“…In addition, a fraction of the material is taken up by blood leukocytes and thus actively transported to the site of action. While passive drug targeting using HPMA copolymers is widely believed to depend on the EPR effect [ 88 , 91 ], some authors argue that the ELVIS mechanism (Extravasation through Leaky Vasculature and Inflammatory cell-mediated Sequestration) might better explain the mode of action of these carriers, at least in the case of local and systemic inflammatory conditions [ 92 ]. Interestingly, the molecular weight and the drug content were found to impact the half-life and clearance of polymer-drug conjugates but not the rate of internalization by macrophages [ 92 ].…”

“…An HPMA copolymer containing doxorubicin and gemcitabine for instance was successfully used to simultanously target two anti-cancer drugs to tumors [ 89 ]. Furthermore, a polymer–Dex conjugate containing a near-infrared or a fluorescent dye could be used to determine its distribution in vivo by imaging analysis [ 92 ]. Polymer-Dex conjugates have also been evaluated for their capacity to circumvent GC side effects that often accompany the treatment of inflammatory diseases.…”

<p>Anti-inflammatory drug-eluting implant model system to prevent wear particle-induced periprosthetic osteolysis</p>

“…17,18 The main advantage of these systems is the local delivery of anti-inflammatory molecules, which simultaneously modulate inflammation and avoid possible side effects caused by a long-term and high concentration systemic drug administration, most notably the gastrointestinal and cardiovascular adverse effects. 19 Implantable biomaterials and devices with different anti-inflammatory delivery systems have been reported in literature, such as bone cements, 20 nanotubes, 21,22 dendrimer conjugates, 23,24 N-(2-hydroxypropyl) methacrylamide copolymer, 17,25 and poly(lactic-co-glycolic acid) microspheres. 26 Besides anti-inflammatory activity, 27 these systems have also shown several advantages in orthopedic applications such as improved biological activity in terms of osteoblasts attachment, proliferation, and differentiation.…”