Block copolymer micelles as long-circulating drug vehicles ☆ Glen S. Kwon a , Kazunori Kataoka b, ⁎ a Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 3118 Dentistry/Pharmacy Centre, Edmonton, Alberta T6G 2N8, Canada b Department of Materials Science and Technology, Research Institute for Biosciences, Science University of Tokyo, Yamazaki, 2641, Noda-shi, Chiba 278, Japan abstract article info Article history: Accepted 13 April 1995 Available online 13 September 2012 Keywords: Drug delivery system AB block copolymer ABA block copolymer Poly(ethylene oxide) Poly(L-amino) Polymer-drug conjugate Doxorubicin The development of block copolymer micelles as long-circulating drug vehicles is described. As well, a recent fundamental study of block copolymer micelles, where much insight into their structures and properties has been realized, is briefly summarized in order to shed light on their properties in vivo. There is emphasis on block copolymer micelles having poly(ethylene oxide) as the hydrophilic block and poly(L-amino acid) as the hydrophobic block, with some discussion on the properties of poly(ethylene oxide). Comparisons are drawn with other drug vehicles and with micelles formed from low molecular weight surfactants. Micelle-forming, block copolymer-drug conjugates are described. Hydrophobic drugs, such as doxorubicin, distribute into block copolymer micelles, and details of several examples are given. Finally, the paper pre- sents studies that evidence the long circulation times of block copolymer micelles. Like long-circulating lipo- somes, block copolymers that form micelles accumulate passively at solid tumors and thus have great potential for anti-cancer drug delivery. © 2012 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 2. Block copolymer micelIes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 2.1. Core/shell structure of PEO-BM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 2.2. Polymeric brush of PEO-BM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 2.3. Block copolymers that form micelles in aqueous systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 2.4. Micelle-forming, block copolymer-drug conjugates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 2.5. Unique properties of PEO-BM in comparison with low molecular weight surfactant micelles . . . . . . . . . . . . . . . . . . . . . 239 3. Entrapment of hydrophobic molecules in PEO-BM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 3.1. Aromatic versus aliphatic molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 3.2. Pyrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 3.3. Doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 3.4. Haloperidol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 4. Pharmacokinetics and disposition of PEO-BM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 4.1. Poly(ethylene oxide-block-aspartate)-doxorubicin conjugates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 4.2. Poly(ethylene oxide-block-isoprene-block-ethylene oxide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 1. Introduction Recent efforts in the design of drug delivery systems (DDS) have led to the development of vehicles that circulate for prolonged periods in the vascular system, contrasting with vehicles of the past that were rapidly and efficiently sequestered by the reticuloendothe- lial system (RES). Nowadays vehicles deliver drugs more effectively to sites other than the RES, e.g., solid tumors at extravascular sites [1–3]. Furthermore it is noteworthy that long-circulating liposomes are studied in clinical trials for the treatment of Kaposi's sarcoma [4]. An intriguing aspect of long-circulating drug vehicles is their po- tential of achieving specificity of delivery through the use of targeting Advanced Drug Delivery Reviews 64 (2012) 237–245 ☆ PII of original article: 0169-409X(95)00031-3. The article was originally published in Advanced Drug Delivery Reviews 16 (1995) 295-309. ⁎ Corresponding author. Tel.: +81047102415; fax: +8104710239362. E-mail address: kataoka@bmw.t.u-tokyo.ac.jp (K. Kataoka). 0169-409X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.addr.2012.09.016 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr