Published Online:11 Feb 2010https://doi.org/10.2217/nnm.09.108
Abstract
Aim: Delivery of doxorubicin could be achieved by a novel micellar system based on β-cyclodextrin-centered star-shaped amphiphilic polymers (sPEL/CD). This study specifically explored the effect of polylactide segments in sPEL/CD on various micelle properties, such as the critical micelle concentration, size, drug loading, cytotoxicity and drug resistance reversing effect. Method: The sPEL/CD was synthesized by the arm-first method. The critical micelle concentrations of polymeric micelles were determined by fluorescence spectrophotometry using pyrene as a probe. The oil/water method was applied to prepare doxorubicin-loaded micelles. 3-(4,5-dimethylthi-azol-2-yl)-2,5-diphenyltetrazolium bromide, confocal laser-scanning microscopy and flow cytometry were used to examine cell cytotoxicity and cellular uptake of the doxorubicin-loaded micelles. Finally, rhodamine-123 cellular uptake was determined to evaluate the polymer action on MCF-7 and MCF-7/ADR cells. Results: All polymers exhibited low cytotoxicity and their micelles had a desirable release-acceleration pH (pH 5.0) for cytoplasmic drug delivery. With the introduction of polylactide into the polymer, the micelle critical micelle concentration can be effectively decreased and the drug-loading content was enhanced. Most importantly, the drug resistance of MCF-7/ADR cells was significantly reversed via the interaction between polymer and Pgp. Therefore, this type of polymer has potential superiority for cancer therapy.
Bibliography
- 1 Adams ML, Lavasanifar A, Kwon GS: Amphiphilic block copolymers for drug delivery. J. Pharm. Sci.92(7),1343–1355 (2003).
- 2 Torchilin VP: Structure and design of polymeric surfactant-based drug delivery systems. J. Control. Release73(2–3),137–172 (2001).
- 3 Nishiyama N, Kataoka K: Nanostructured devices based on block copolymer assemblies for drug delivery: designing structures for enhanced drug function. Adv. Polym. Sci.193,67–101 (2006).
- 4 Yanez J, Forrest M, Ohgami Y, Kwon G, Davies N, Neal M: Pharmacometrics and delivery of novel nanoformulated PEG-b-poly(ε-caprolactone) micelles of rapamycin. Cancer Chemother. Pharmacol.61,133–144 (2008).
- 5 Qiu LY, Bae YH: Self-assembled polyethylenimine–graft–poly(ε-caprolactone) micelles as potential dual carriers of genes and anticancer drugs. Biomaterials28,4132–4142 (2007).
- 6 Genevieve G, Marie HD, Jean CL: Block copolymer micelles: preparation, characterization and application in drug delivery. J. Control. Release109,169–188 (2005).
- 7 Ho AK, Iin L, Gurr PA, Mills MF, Qiao GG: Synthesis and characterization of star-like microgels by one-pot free radical polymerization. Polymer46(18),6727–6735 (2005).
- 8 Liu H, Jiang A, Guo J, Uhrich KE: Unimolecular micelles: synthesis and characterization of amphiphilic polymer systems. J. Polym. Sci. A Polym. Chem.37,703–711 (1999).
- 9 Liu M, Kono K, Fréchet JMJ: Water-soluble dendritic unimolecular micelles: their potential as drug delivery agents. J. Control. Release65,121–131 (2000).
- 10 Kojima C, Kono K, Maruyama K, Takagishi T: Synthesis of polyamidoamine dendrimers having poly(ethylene glycol) grafts and their ability to encapsulate anticancer drugs. Bioconjug. Chem.11,910–917 (2000).
- 11 Bekers O, Beijnen JH, Otagiri M et al.: Inclusion complexation of doxorubicin and daunorubicin with cyclodextrins. J. Pharm. Biomed. Anal.8,671–674 (1990).
- 12 Davis ME, Brewster ME: Cyclodextrin-based pharmaceutics: past, present and future. Nat. Rev. Drug Discov.3(12),1023–1035 (2004).
- 13 Uekama K, Hirayama F, Irie T: Cyclodextrin drug carrier systems. Chem. Rev.98(5),2045–2076 (1998).
- 14 Shuai XT, Ai H, Nasongkla N et al.: Micellar carriers based on block copolymers of poly(ε-caprolactone) and poly(ethylene glycol) for doxorubicin delivery. J. Control. Release98(3),415–426 (2004).
- 15 Kataoka K, Matsumoto T, Yokoyama M et al.: Doxorubicin-loaded poly(ethylene glycol)–poly(β-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance. J. Control. Release64(1–3),143–153 (2000).
- 16 Bae Y, Diezi TA, Zhao A et al.: Mixed polymeric micelles for combination cancer chemotherapy through the concurrent delivery of multiple chemotherapeutic agents. J. Control. Release122(3),324–330 (2007).
- 17 Huang CK, Lo CL, Chen HH et al.: Multifunctional micelles for cancer cell targeting, distribution imaging, and anticancer drug delivery. Adv. Funct. Mater.17(14),2291–2297 (2007).
- 18 Fritze A, Hens F, Kimpfler A et al.: Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient. Biochem. Biophys. Acta1758(10),1633–1640 (2006).
- 19 Matsumura Y, Hamaguchi T, Ura T et al.: Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin. Br. J. Cancer91(10),1775–1781 (2004).
- 20 Jie C, Zhu KJ: Preparation, characterization and biodegradable characteristics of poly(D,L-lactide-co-1,3-trimethylene carbonate). Polym. Int.42(4),373–379 (1997).
- 21 Dong YC, Feng SS: Methoxy poly(ethylene glycol)–poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs. Biomaterials25(14),2843–2849 (2004).
- 22 Wilhelm M, Zhao CL, Wang YC et al.: Poly(styrene-ethylene oxide) block copolymer micelle formation in water: a fluorescence probe study. Macromolecules24(5),1033–1040 (1991).
- 23 Kwon G, Naito M, Yokoyama M et al.: Block copolymer micelles for drug delivery: loading and release of doxorubicin. J. Control. Release48(2–3),195–201 (1997).
- 24 Ignatius AA, Claes LE: In vitro biocompatibility of bioresorbable polymers: poly(L,D,L-lactide) and poly(L-lactide-co-glycolide). Biomaterials17(8),831–839 (1996).
- 25 International Organization for Standardization. Biological evaluation of medical devices. Part 6: Test for Local Effects After Implantation. ISO-10993, Geneva, Switzerland (2007).
- 26 Qiu LY, Wu XL, Jin Y: Doxorubicin-loaded polymeric micelles based on amphiphilic polyphosphazenes with poly(N -isopropylacrylamide-co-N, N -dimethylacrylamide) and ethyl glycinate as side groups: synthesis, preparation and In vitro evaluation. Pharm Res.26(4),946–957 (2009).
- 27 Croft AP, Bartsch RA: Synthesis of chemically modified cyclodextrins. Tetrahedron39(9),1417–1474 (1983).
- 28 Oikakis CS, Mamouzelow NJ, Tarantili PA, Andreopoulos AG: Swelling and hydrolytic degradation of poly(D,L-lactic acid) in aqueous solutions. Polym. Degrad. Stab.91,614–619 (2006).
- 29 Maysinger D, Berezovska O, Savic R et al.: Block copolymers modify the internalization of micelle-incorporated probes into neural cells. Biochim. Biophys. Acta1539,205–217 (2001).
- 30 Luo L, Tam J, Maysinger D et al.: Cellular internalization of poly(ethylene oxide)-b-poly(ε-caprolactone) diblock copolymer micelles. Bioconjug. Chem.13,1259– 1265 (2002).
- 31 Aller SG, Yu J, Ward A et al.: Structure of P-glycoprotein reveals a molecular basis for poly-specific. Science323,1718–1722 (2009).
- 32 Gottesman MM, Suresh VA, Xia D: Structure of a multidrug transporter. Nat. Biotech.27,546–547 (2009).
- 33 Batrakova EV, Kelly DL, Li S et al.: Alteration of genomic responses to doxorubicin and prevention of MDR in breast cancer cells by a polymer excipient: pluronic P85. Mol. Pharm.3,113–123 (2006).
- 34 Seelig A, Gerebtzoff G: Enhancement of drug absorption by noncharged detergents through membrane and P-glycoprotein binding. Expert Opin. Drug Metab. Toxicol.2,733–752 (2006).
- 35 Yadav AK, Mishra P, Mishra AK et al.: Development and characterization of hyaluronic acid–anchored PLGA nanoparticulate carriers of doxorubicin. Nanomedicine3,246– 257 (2007).
- 36 Park J, Fong PM, Lu J et al.: PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. Nanomedicine5(4),410–418 (2009)
- 37 Nakayama M, Okano T, Miyazaki T et al.: Molecular design of biodegradable polymeric micelles for temperature-responsive drug release. J. Control. Release115(1),46–56 (2006).
- 38 Allen TM, Martin FJ: Advantages of liposomal delivery systems for anthracyclines. Semin. Oncol.31,5–15 (2004).
