Skip to main content
SpringerLink
Log in

Polymeric Micelles for Multiple-Drug Delivery

  • Chapter
  • First Online:
Multifunctional Nanoparticles for Drug Delivery Applications

Part of the book series: Nanostructure Science and Technology ((NST))

Abstract

Polymeric micelles have been widely studied in preclinical drug development for drug solubilization, controlled drug release, and drug targeting. Polymeric micelles are attractive because of their nanoscopic size, proven safety profile in humans over existing intravenous vehicles in clinical practice, and high capacity for drug solubilization. Hydrophobic interaction between polymeric micelles and poorly water-soluble drugs is the primary driving force for drug solubilization. In a prodrug strategy, amphiphilic block copolymer–drug conjugates also assemble into polymeric micelles, resulting in drug solubilization and triggered drug release in response to an acidic pH, aiming for tumor targeting. In both strategies, polymeric micelles entrain two or three different kinds of poorly water-soluble drugs, simplifying the delivery of drug “cocktails.” Polymeric micelles raise the prospective for simultaneous tumor targeting of multiple poorly water-soluble anticancer agents, aiming for synergistic efficacy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kataoka K, Kwon GS, Yokoyama M, Okano T, Sakurai Y (1993) Block copolymer micelles as vehicles for drug delivery. J Control Release 24:119–132

    Article  Google Scholar 

  2. Jones M-C, Leroux J-C (1999) Polymeric micelles—A new generation of colloidal drug carriers. Eur J Pharm Biopharm 48:101–111

    Article  Google Scholar 

  3. Lavasanifar A, Samuel J, Kwon GS (2002) Poly(ethylene oxide)-block-poly(l-amino acid) micelles for drug delivery. Adv Drug Deliv Rev 54:169–190

    Article  Google Scholar 

  4. Gaucher G, Marchessault RH, Leroux JC (2010) Polyester-based micelles and nanoparticles for the parenteral delivery of taxanes. J Control Release 143:2–12

    Article  Google Scholar 

  5. Kabanov AV, Batrakova EV, Alakhov VY (2002) Pluronic® block copolymers for overcoming drug resistance in cancer. Adv Drug Deliv Rev 54:759–779

    Article  Google Scholar 

  6. Shin H-C, Alani AWG, Rao DA, Rockich NC, Kwon GS (2009) Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs. J Control Release 140:294–300

    Article  Google Scholar 

  7. Bae Y, Diezi TA, Zhao A, Kwon GS (2007) Mixed polymeric micelles for combination cancer chemotherapy through the concurrent delivery of multiple chemotherapeutic agents. J Control Release 122:324–330

    Article  Google Scholar 

  8. Jonkman-de Vries JD, Flora KP, Bult A, Beijnen JH (1996) Pharmaceutical development of (investigational) anticancer agents for parenteral use—a review. Drug Dev Ind Pharm 22:475–494

    Article  Google Scholar 

  9. Mayer LD, Janoff AS (2007) Optimizing combination chemotherapy by controlling drug ratios. Mol Interv 7:216–223

    Article  Google Scholar 

  10. Greco F, Vicent MJ (2009) Combination therapy: Opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines. Adv Drug Deliv Rev 61:1203–1213

    Article  Google Scholar 

  11. Mayer LD, Harasym TO, Tardi PG, Harasym NL, Shew CR, Johnstone SA, Ramsay EC, Bally MB, Janoff AS (2006) Ratiometric dosing of anticancer drug combinations: Controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Mol Cancer Res 5:1854–1863

    Google Scholar 

  12. Hennenfent KL, Govindan R (2006) Novel formulations of taxanes: A review. Old wine in a new bottle? Ann Oncol 17:735–749

    Article  Google Scholar 

  13. Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265

    Article  Google Scholar 

  14. Gelderblom H, Verweij J, Nooter K, Sparreboom A, Cremophor EL (2001) The drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 37:1590–1598

    Article  Google Scholar 

  15. ten Tije AJ, Verweij J, Loos WJ, Sparreboom A (2003) Pharmacological effects of formulation vehicles implications for cancer therapy. Clin Pharmacokinet 42:665–685

    Article  Google Scholar 

  16. Stenger M (2005) Abraxane (nanoparticle albumin-bound paclitaxel) in metastatic breast cancer. Commun Oncol 2:214–215

    Google Scholar 

  17. Zhang X, Jackson JK, Burt HM (1996) Development of amphiphilic diblock copolymers as micellar carriers of Taxol. Int J Pharm 132:195–206

    Article  Google Scholar 

  18. Zhang X, Burt HM, Mangold G, Dexter D, Von Hoff D, Mayer L, Hunter WL (1997) Anti-tumor efficacy and biodistribution of intravenous polymeric micellar paclitaxel. Anti-Cancer Drugs 8:696–701

    Article  Google Scholar 

  19. Zhang X, Burt HM, Von Hoff D, Dexter D, Mangold G, Degen D, Oktaba AM, Hunter WL (1997) An investigation of the antitumor activity and biodistribution of polymeric micellar paclitaxel. Cancer Chemother Pharmacol 40:81–86

    Article  Google Scholar 

  20. Kim SC, Kim DW, Shim YH, Bang JS, Oh HS, Kim SW, Seo MH (2001) In vivo evaluation of polymeric micellar paclitaxel formulation: Toxicity and efficacy. J Control Release 72:191–202

    Article  Google Scholar 

  21. Sparreboom A, van Tellington O, Nooijen WJ, Beijen JH (1996) Tissue distribution, metabolism and excretion of paclitaxel in mice. Anti-Cancer Drugs 7:78–86

    Article  Google Scholar 

  22. Woodcock DM, Linsenmeyer ME, Chojnowski G, Kriegler AB, Nink V, Webster LK, Sawyer WH (1992) Reversal of multidrug resistance by surfactants. Br J Cancer 66:62–68

    Article  Google Scholar 

  23. Sparreboom A, van Tellington O, Huizing MT, Nooijen WJ, Beijen JH (1996) Determination of polyoxyethyleneglycerol triricinoleate 35 (cremophor el) in plasma by pre-column derivatization and reversed-phase high-performance liquid chromatography. J Chromatogr B 681:355–362

    Article  Google Scholar 

  24. Ramaswamy M, Zhang X, Burt HM, Wasan KM (1997) Human plasma distribution of free paclitaxel and paclitaxel associated with diblock copolymers. J Pharm Sci 86:460–464

    Article  Google Scholar 

  25. Chen H, Kim S, He W, Wang H, Low PS, Park K, Cheng J-X (2008) Fast release of lipophilic agents for circulating peg-pdlla micelles revealed by in vivo Förster resonance energy transfer imaging. Langmuir 24:5213–5217

    Article  Google Scholar 

  26. Yamamoto Y, Nagasaki Y, Kato Y, Sugiyama Y, Kataoka K (2001) Long-circulating poly(ethylene glycol)-poly(d, l-lactide) block copolymer micelles with modulated surface charge. J Control Release 77:27–38

    Article  Google Scholar 

  27. Kim T-Y, Kim D-W, Chung J-Y, Shin SG, Kim S-C, Dae SH, Kim NK, Bang Y-J (2004) Phase I and pharmacokinetic study of Genexol-pm, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin Cancer Res 10:3708–3716

    Article  Google Scholar 

  28. Kim D-W, Kim S-Y, Kim H-K, Kim S-W, Shin SW, Park K, Lee MY, Heo DS (2007) Multicenter phase II trial of Genexol-pm, a novel cremophor-free, polymeric micelle formulation of paclitaxel, with cisplatin in patients with advanced non-small-cell lung cancer. Ann Oncol 18:2009–2014

    Article  Google Scholar 

  29. Lee KS, Chung HC, Im SA, Park YH, Kim CS, Kim S-B, Rha SY, Lee MY, Ro J (2008) Multicenter phase II trial on Genexol-pm, a cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res Treat 108:241–250

    Article  Google Scholar 

  30. Green MR, Manikhas GM, Orlov S, Afansyev B, Makhson AM, Hawkins MJ (2006) Abraxane, a novel cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol 17:1263–1268

    Article  Google Scholar 

  31. Von Pawel J, Wagner H, Niederle N, Heider A, Koschel G, Hecker D, Hanske M (1996) Phase II study of paclitaxel and cisplatin in patients with non-small lung cancer. Semin Oncol 23:47–50

    Google Scholar 

  32. Gatzmeier U, von Pawel J, Gottfried M, ten Velde GP, Mattson K, DeMarins F, Harper P, Salvati F, Robinet G, Lucenti A, Bogaerts J, Gallent GJ (2000) Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. Clin Oncol 18:3390–3399

    Google Scholar 

  33. Rosell R, Gatzmeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Nicholson M, Ardizzoni A, Chmaissani A, Bogaerts J, Gallant G (2002) Phase III randomized trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: A cooperative multinational trial. Ann Oncol 13:1539–1549

    Article  Google Scholar 

  34. Ibrahim NK, Samuels B, Page R, Doval D, Patel KM, Rao SC, Nair MK, Bhar P, Desai N, Hortobagyi GN (2005) Multicenter phase II trial of Abi-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol 23:6019–6026

    Article  Google Scholar 

  35. Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN, Michaelson RA, Kirshner JA, Fleming GF, Perry MC, Graham ML, Sharp SA, Keresztes R, Henderson IC, Hudis C, Muss H, Norton L (2004) Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and leukemia group b trial 9342. J Clin Oncol 22:2061–2068

    Article  Google Scholar 

  36. Paridaens R, Biganzoli L, Bruning P, Klijn JG, Gamucci T, Huston S, Coleman R, Schachter J, van Vreckem A, Sylvester R, Awada A, Wildiers J, Piccart M (2000) Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: A European organization for research and treatment of cancer randomized study with cross-over. J Clin Oncol 18:724–733

    Google Scholar 

  37. Sledge GW, Neuberg D, Bernado P, Ingle JN, Martino S, Rowinsky EK, Wood WC (2003) Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An intergroup trial (e1193). J Clin Oncol 21:588–592

    Article  Google Scholar 

  38. Bishop JF, Dewar J, Toner GC, Smith J, Tattersall MH, Olver IN, Ackland S, Stephenson J, Canetta R (1999) Initial paclitaxel improves outcome compared with cmfp combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol 17:2355–2364

    Google Scholar 

  39. Dancey JE, Chen HX (2006) Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat Rev Drug Discov 5:649–659

    Article  Google Scholar 

  40. Grant S (2008) Co-targeting survival signaling pathways in cancer. J Clin Invest 118:3003–3006

    Article  Google Scholar 

  41. Nguyen DM, Chen A, Mixon A, Schrump DS (1999) Sequence-dependent enhancement of paclitaxel toxicity in non-small cell lung cancer by 17-allylamino-17-demethoxygeldanamycin. J Thorac Cardiovasc Surg 118:908–915

    Article  Google Scholar 

  42. Blanco E, Bey EA, Khemtong C, Yang S-G, Setti-Guthi J, Chen H, Kessinger CW, Carnvale KA, Bommann WG, Bothman DA, Gao J (2010) β-Lapachone micellar nanotherapeutics for non-small cell lung cancer therapy. Cancer Res 70:3896–3904

    Article  Google Scholar 

  43. Kim S-C, Chang E-O, Song I-S, Pai C-M, US Patent 6,322,805, 2001

    Google Scholar 

  44. Xiong MP, Yáñez JA, Kwon GS, Davies NM, Forrest ML (2009) A cremophor-free formulation of tanespimycin (17-AAG) using PEO-b-PDLLA micelles: Characterization and pharmacokinetics in rats. J Pharm Sci 98:1577–1586

    Article  Google Scholar 

  45. Aliabadi HM, Lavasanifar A (2006) Polymeric micelles for drug delivery. Expert Opin Drug Deliv 3:139–162

    Article  Google Scholar 

  46. Li P, Zhao L (2002) Cosolubilization of non-polar drugs in polysorbate 80 solutions. Int J Pharm 249:211–217

    Article  Google Scholar 

  47. Darwish IA, Florence AT, Saleh AM (1989) Effects of hydrotropic agents on the solubility, precipitation, and protein binding of etoposide. J Pharm Sci 7:577–581

    Article  Google Scholar 

  48. Solit DB, Chiosis G (2008) Development and applications of hsp90 inhibitors. Drug Discov Today 13:38–43

    Article  Google Scholar 

  49. Ramalingam SS, Egorin MJ, Ramanathan RK, Remick SC, Sikorski RP, Lagattuta TF, Chatta GS, Friedland DM, Stoller RG, Potter DM, Ivy SP, Belani CP (2008) A phase I study of 17-allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies. Clin Cancer Res 14:3456–3461

    Article  Google Scholar 

  50. Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N (2003) Inhibition of heat shock protein 90 function down-regulates akt kinase and sensitizes tumors to taxol. Cancer Res 63:2139–2144

    Google Scholar 

  51. Modi S, Stopeck AT, Gordon MS, Mendelson D, Solit DB, Bagatell R, Ma W, Wheler J, Rosen N, Norton L, Cropp GF, Johnson RG, Hannah AL, Hudis CA (2007) Combination of trastuzumab and tanespimycin (17-AAG), KOS-953) is safe and active in trastuzumab-refractory her-2-overexpressing breast cancer: A phase I dose-escalation study. J Clin Oncol 34:5410–5417

    Article  Google Scholar 

  52. Nishiyama N, Okazaki S, Cabral H, Miyamoto M, Kato Y, Sugiyama Y, Nishio K, Matsumura Y, Kataoka K (2003) Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. Cancer Res 63:8977–8983

    Google Scholar 

  53. Koizumi F, Kitagawa M, Negishi T, Onda T, Matsumoto S, Hamaguchi T, Matsumura Y (2006) Novel SN-38-incorporating polymeric micelles, NK012, eradicate vascular endothelial growth factor-secreting bulky tumors. Cancer Res 66:10048–10056

    Article  Google Scholar 

  54. Hamaguchi T, Matsumura Y, Suzuki M, Shimizu K, Goda R, Nakamura I, Nakatomi I, Yokoyama M, Kataoka K, Kakizoe T (2005) NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumor activity and reduce neurotoxicity of paclitaxel. Br J Cancer 92:1240–1246

    Article  Google Scholar 

  55. Matsumura Y, Kataoka K (2009) Preclinical and clinical studies of anticancer agent-incorporating polymer micelles. Cancer Sci 100:572–579

    Article  Google Scholar 

  56. Bae Y, Kataoka K (2009) Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers. Adv Drug Deliv Rev 61:768–784

    Article  Google Scholar 

  57. Bae Y, Fukushima S, Harada A, Kataoka K (2003) Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: Polymeric micelles that are responsive to intracellular pH change. Angew Chem Int Ed 42:4640–4643

    Article  Google Scholar 

  58. Bae Y, Nishiyama N, Fukushima S, Koyama H, Matsumura Y, Kataoka K (2005) Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: Tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjugate Chem 16:122–130

    Article  Google Scholar 

  59. Bae Y, Jang W-D, Nishiyama N, Fukushima S, Kataoka K (2005) Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. Mol BioSyst 1:242–250

    Article  Google Scholar 

  60. Bae Y, Nishiyama N, Kataoka K (2007) In vivo antitumor activity of the folate-conjugated pH-sensitive polymeric micelle selectively releasing adriamycin in the intracellular acidic compartments. Bioconjugate Chem 18:1131–1139

    Article  Google Scholar 

  61. Alani AWG, Bae Y, Rao DA, Kwon GS (2010) Polymeric micelles for the pH-dependent controlled, continuous low dose release of paclitaxel. Biomaterials 31:1765–1772

    Article  Google Scholar 

  62. Davis ME, Chen Z, Shin DM (2008) Nanoparticle therapeutics: An emerging treatment modality for cancer. Nat Rev Drug Discov 7:771–782

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI, 53705, USA

    Glen S. Kwon

Authors
  1. Glen S. Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Glen S. Kwon .

Editor information

Editors and Affiliations

  1. Drug Delivery Solutions LLC, Temple Street 16, Arlington, 02476, Massachusetts, USA

    Sonke Svenson

  2. Princeton University, n/a, Princeton, 08544, USA

    Robert K. Prud'homme

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Kwon, G.S. (2012). Polymeric Micelles for Multiple-Drug Delivery. In: Svenson, S., Prud'homme, R. (eds) Multifunctional Nanoparticles for Drug Delivery Applications. Nanostructure Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-2305-8_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-2305-8_7

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4614-2304-1

  • Online ISBN: 978-1-4614-2305-8

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics

Search

Navigation