Doxorubicin-loaded poly(ethylene glycol)-poly(beta-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance.

Doxorubicin (DOX) was physically loaded into micelles prepared from poly(ethylene glycol)-poly(beta-benzyl-L-aspartate) block copolymer (PEG-PBLA) by an o/w emulsion method with a substantial drug loading level (15 to 20 w/w%). DOX-loaded micelles were narrowly distributed in size with diameters of approximately 50-70 nm. Dimer derivatives of DOX as well as DOX itself were revealed to be entrapped in the micelle, the former seems to improve micelle stability due to its low water solubility and possible interaction with benzyl residues of PBLA segments through pi-pi stacking. Release of DOX compounds from the micelles proceeded in two stages: an initial rapid release was followed by a stage of slow and long-lasting release of DOX. Acceleration of DOX release can be obtained by lowering the surrounding pH from 7.4 to 5.0, suggesting a pH-sensitive release of DOX from the micelles. A remarkable improvement in blood circulation of DOX was achieved by use of PEG-PBLA micelle as a carrier presumably due to the reduced reticuloendothelial system uptake of the micelles through a steric stabilization mechanism. Finally, DOX loaded in the micelle showed a considerably higher antitumor activity compared to free DOX against mouse C26 tumor by i.v. injection, indicating a promising feature for PEG-PBLA micelle as a long-circulating carrier system useful in modulated drug delivery.

[1]  K. Kataoka,et al.  Functional poly[(ethylene oxide)-co-(β-benzyl-L-aspartate)] polymeric micelles : block copolymer synthesis and micelles formation , 1995 .

[2]  Yokoyama Masayuki,et al.  Block copolymer micelles as vehicles for drug delivery , 1993 .

[3]  Teruo Okano,et al.  Introduction of cisplatin into polymeric micelle , 1996 .

[4]  F. Arcamone,et al.  Self-association of doxorubicin and related compounds in aqueous solution. , 1984, Journal of pharmaceutical sciences.

[5]  Atsushi Harada,et al.  Formation of Polyion Complex Micelles in an Aqueous Milieu from a Pair of Oppositely-Charged Block Copolymers with Poly(ethylene glycol) Segments , 1995 .

[6]  T. Okano,et al.  Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood. , 1991, Cancer research.

[7]  Teruo Okano,et al.  Block copolymer micelles for drug delivery: Loading and release of doxorubicin , 1997 .

[8]  N. Isaacs,et al.  Structure of daunomycin; x-ray analysis of N-Br-acetyl-daunomycin solvate. , 1971, Nature: New biology.

[9]  J. Feijen,et al.  Design of soluble conjugates of biodegradable polymeric carriers and adriamycin , 1992 .

[10]  G. Storm,et al.  Doxorubicin decomposition on storage: effect of pH, type of buffer and liposome encapsulation , 1985 .

[11]  T. Okano,et al.  Selective delivery of adriamycin to a solid tumor using a polymeric micelle carrier system. , 1999, Journal of drug targeting.

[12]  J. Kreuter,et al.  Colloidal Drug Delivery Systems , 1994 .

[13]  T. Okano,et al.  Design of functional polymeric micelles as site-specific drug vehicles based on poly (α-hydroxy ethylene oxide-co-β-benzyl l-aspartate) block copolymers , 1997 .

[14]  S. Martin Absorption and circular dichroic spectral studies on the self‐association of daunorubicin , 1980, Biopolymers.

[15]  K. Kataoka,et al.  Preparation of adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer. A new type of polymeric anticancer agent , 1987 .

[16]  S. Eksborg Extraction of daunorubicin and doxorubicin and their hydroxyl metabolites: self-association in aqueous solution. , 1978, Journal of pharmaceutical sciences.

[17]  Teruo Okano,et al.  Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly(ethylene oxide-aspartate) block copolymer-Adriamycin conjugates , 1994 .

[18]  N. Melik-Nubarov,et al.  The neuroleptic activity of haloperidol increases after its solubilization in surfactant micelles , 1989, FEBS letters.

[19]  John K. Jackson,et al.  Development of amphiphilic diblock copolymers as micellar carriers of taxol , 1996 .

[20]  T. Okano,et al.  Improved synthesis of adriamycin-conjugated poly (ethylene oxide)-poly (aspartic acid) block copolymer and formation of unimodal micellar structure with controlled amount of physically entrapped adriamycin , 1994 .

[21]  T. Okano,et al.  Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[22]  T. Okano,et al.  Micelles based on AB block copolymers of poly(ethylene oxide) and poly(.beta.-benzyl L-aspartate) , 1993 .

[23]  Kui Yu,et al.  Soluble Stoichiometric Complexes from Poly(N-ethyl-4-vinylpyridinium) Cations and Poly(ethylene oxide)-block-polymethacrylate Anions , 1996 .

[24]  Yokoyama Masayuki,et al.  Polymer micelles as novel drug carrier: Adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer , 1990 .

[25]  R. Lenkinski,et al.  A nuclear magnetic resonance study of the self-association of adriamycin and daunomycin in aqueous solution , 1985 .

[26]  Kinam Park,et al.  Controlled drug delivery : challenges and strategies , 1997 .

[27]  Kazunori Kataoka,et al.  Block copolymer micelles as long-circulating drug vehicles , 1995 .

[28]  P. Righetti,et al.  Protolytic equilibria of doxorubicin as determined by isoelectric focusing and ‘electrophoretic titration curves’ , 1979, FEBS letters.

[29]  J. Beijnen,et al.  Aspects of the degradation kinetics of doxorubicin in aqueous solution , 1986 .

[30]  Atsushi Harada,et al.  Spontaneous Formation of Polyion Complex Micelles with Narrow Distribution from Antisense Oligonucleotide and Cationic Block Copolymer in Physiological Saline , 1996 .

[31]  K. Kataoka,et al.  Site Specific Drug-Carriers : Polymeric Micelles as High Potential Vehicles for Biologically Active Molecules , 1996 .

[32]  K. Kataoka,et al.  Effect of the secondary structure of poly(L-lysine) segments on the micellization in aqueous milieu of poly(ethylene glycol)-poly(L-lysine) block copolymer partially substituted with a hydrocinnamoyl group at the N∈-position , 1998 .

[33]  J. Kopeček,et al.  Targetable polymeric drugs , 1990 .

[34]  J. Maurizot,et al.  Self‐association of daunorubicin , 1974, FEBS letters.