Research paper In vivo fate of unimers and micelles of a poly(ethylene glycol)-block-poly(caprolactone) copolymer in mice following intravenous administration Jubo Liu, Faquan Zeng, Christine Allen * Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ont., Canada Received 29 June 2006; accepted in revised form 1 November 2006 Available online 23 November 2006 Abstract Methoxy poly(ethylene glycol)-b-poly(caprolactone) (MePEG-b-PCL) copolymers with varying PEG block lengths and a constant PCL block length were synthesized by cationic ring-opening polymerization and used to form nano-sized micelles. Due to their small size and superior in vitro stability, the MePEG 5000 -b-PCL 5000 micelles were selected for further in vitro characterization and an in vivo evaluation of their fate and stability following intravenous (i.v.) administration. Specifically, 3 H-labelled MePEG 5000 -b-PCL 5000 micelles were i.v. administered to Balb/C mice at copolymer doses of 250, 2 and 0.2 mg/kg in order to examine the distribution kinetics of (1) copolymer assembled as thermodynamically stable micelles, (2) copolymer assembled as thermodynamically unstable micelles and (3) copolymer unimers, respectively. Overall, it was found that when the copolymer is assembled as thermodynamically stable micelles the material is effectively restricted to the plasma compartment. Interestingly, the copolymer was found to have a relatively long circu- lation half-life even when administered at a dose that would likely fall to concentrations below the CMC following distribution. Analysis of plasma samples from this group revealed that even 24 h post-administration a significant portion of the copolymer remained assem- bled as intact micelles. In this way, this study demonstrates that the hydrophobic and semi-crystalline nature of the PCL core imparts a high degree of kinetic stability to this micelle system. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Block copolymer micelle; Poly(ethylene glycol)-block-poly(caprolactone); Drug delivery; In vivo fate; Kinetic stability; Pharmacokinetics; Biodistribution 1. Introduction In aqueous media, amphiphilic block copolymers self-as- semble to form micelles when the copolymer concentration is at or above the critical micelle concentration (CMC). At concentrations below the CMC the copolymer is present in solution as unimers [1]. Hydrophobic (e.g. paclitaxel) or amphiphilic (e.g. amphotericin B) drugs may be incorporat- ed into the copolymer micelles as a means to formulate or deliver these drugs [2–6]. These formulations have been studied quite extensively with many reports on the in vivo fate of the drug following i.v. administration in micelles [3,6–11]. However, only a few studies have examined the in vivo fate of the copolymer micelles [6,12–16] and unimers [6,13,15]. Specifically, Burt et al. studied the in vivo fate of paclitaxel and MePEG-b-poly(D,L-lactide) (MePEG-b- PDLLA) copolymers in rats following i.v. administration of a MePEG-b-PDLLA micelle formulation of this drug [6]. The in vivo pharmacokinetics and biodistribution for micelles prepared from tyrosine (Tyr)-PEG-b-PDLLA and tyrosyl-glutamic acid (Tyr-Glu)-PEG-b-PDLLA copoly- mers were also investigated by Kataoka’s group [13]. To this point, the effect of the administered copolymer dose on the in vivo behavior of micelles as well as the fate of copolymer unimers and micelles remains relatively 0939-6411/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2006.11.010 * Corresponding author. Department of Pharmaceutical Sciences, Uni- versity of Toronto, 19 Russell St., Toronto, Ont., Canada M5S 2S2. Tel.: +1 416 946 8594; fax: +1 416 978 8511. E-mail address: cj.allen@utoronto.ca (C. Allen). www.elsevier.com/locate/ejpb European Journal of Pharmaceutics and Biopharmaceutics 65 (2007) 309–319