Polymeric micelle nanocarriers in cancer research

Abstract

Amphiphilic block copolymers (ABCs) assemble into a spherical nanoscopic supramolecular core/shell nanostructure termed a polymeric micelle that has been widely researched as an injectable nanocarrier for poorly water-soluble anticancer agents. The aim of this review article is to update progress in the field of drug delivery towards clinical trials, highlighting advances in polymeric micelles used for drug solubilization, reduced off-target toxicity and tumor targeting by the enhanced permeability and retention (EPR) effect. Polymeric micelles vary in stability in blood and drug release rate, and accordingly play different but key roles in drug delivery. For intravenous (IV) infusion, polymeric micelles that disassemble in blood and rapidly release poorly water-soluble anticancer agent such as paclitaxel have been used for drug solubilization, safety and the distinct possibility of toxicity reduction relative to existing solubilizing agents, e.g., Cremophor EL. Stable polymeric micelles are long-circulating in blood and reduce distribution to non-target tissue, lowering off-target toxicity. Further, they participate in the EPR effect in murine tumor models. In summary, polymeric micelles act as injectable nanocarriers for poorly water-soluble anticancer agents, achieving reduced toxicity and targeting tumors by the EPR effect.

Graphical abstract

Keywords

nanomedicine / parenteral / poly(ethylene glycol) / poly(lactic acid) / reformulation

References

[1] Chen W, Zheng R, Baade P, Zhang S, Zeng H, Bray F, Jemal A, Yu X, He J. Cancer statistics in China, 2015. CA: a Cancer Journal for Clinicians, 2016, 16(2): 115–132

[2] Mehlen P, Puisieux A. Metastasis: A question of life or death. Nature Reviews. Cancer, 2006, 6(6): 449–458

[3] Creixell P, Schoof E, Erler J, Linding R. Navigating cancer network attractors for tumor-specific therapy. Nature Biotechnology, 2012, 30(9): 842–848

[4] Xu X, Ho W, Zhang X, Betrand N, Farokhzad O. Cancer nanomedicine: From targeted delivery to combination therapy. Trends in Molecular Medicine, 2015, 21(4): 223–232

[5] Hamilton G. Antibody-drug conjugates for cancer therapy: The technological and regulatory challenges of developing drug-biologic hybrids. Biologicals, 2015, 43(5): 318–332

[6] Peer D, Karp J, Hong S, Farokhzad O, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology, 2007, 2(12): 751–760

[7] Deng C, Jiang Y, Cheng R, Meng F, Zhong Z. Biodegradable polymeric micelles for targeted and controlled anticancer drug delivery: Promises, progress and prospects. Nano Today, 2012, 7(5): 467–480

[8] Gong J, Chen M, Zheng Y, Wang S, Wang Y. Polymeric micelles drug delivery system in oncology. Journal of Controlled Release, 2012, 159(3): 312–323

[9] Matsumura Y. The drug discovery by nanomedicine and its clinical experience. Japanese Journal of Clinical Oncology, 2014, 44(6): 515–525

[10] Eetezadi S, Ekdawi S, Allen C. The challenges facing block copolymer micelles for cancer therapy: In vivo barriers and clinical translation. Advanced Drug Delivery Reviews, 2015, 91(8): 7–22

[11] Nishiyama N. Nanocarriers shape up for long life. Nature Nanotechnology, 2007, 2(4): 203–204

[12] Suk J, Xu Q, Kim N, Hanes J, Ensign L. Pegylation as a strategy for improving nanoparticle-based drug and gene delivery. Advanced Drug Delivery Reviews, 2016, 99(Pt A): 28–51

[13] Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophorel: The drawbacks and advantages of vehicle selection for drug formulation. European Journal of Cancer, 2001, 37(13): 159–198

[14] Banerji U, Walton M, Raynaud F, Grimshaw R, Kelland L, Valenti M, Judson I, Workman P. Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allyamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft model. Clinical Cancer Research, 2005, 11(19): 7023–7032

[15] Blois J, Smith A, Josephson L. The slow death response when screening chemotherapeutic agents. Cancer Chemotherapy and Pharmacology, 2011, 68(3): 795–803

[16] Stirland D, Nichols J, Miura S, Bae Y. Mind the gap: A survey of how cancer drug carriers are susceptible to the gap between research and practice. Journal of Controlled Release, 2013, 172(3): 1045–1064

[17] Cabral H, Matsumoto Y, Mizuno K, Chen Q, Murakami M, Kimura M, Terada Y, Kano M, Miyazono K, Uesaka M, Nishiyama N, Kataoka K. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nature Nanotechnology, 2011, 6(12): 815–823

[18] Kim S, Kim D, Shim Y, Bang J, Oh H, Kim S, Seo M. In vivo evaluation of polymeric micellar paclitaxel formulation: Toxicity and efficacy. Journal of Controlled Release, 2001, 72(1-3): 191–202

[19] Cho H, Gao J, Kwon G. PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels for drug delivery. Journal of Controlled Release, 2015, doi: 10.1016/j.jconrel.2015.12.015

[20] Kim T, Kim D, Chung J, Shin S, Kim S, Heo D, Kim N, Bang Y. Phase I and pharmacokinetics study of genexol-pm, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clinical Cancer Research, 2004, 10(11): 3708–3716

[21] Kundranda M, Niu J. Albumin-bound paclitaxel in solid tumors: Clinical development and future directions. Drug Design, Development and Therapy, 2015, 9(6): 3767–3777

[22] Desai N, De T, Ci S, Louie L, Trieu V. Characterization and in vitro/in vivo dissolution of nab-paclitaxel nanoparticles. Cancer Research, 2005, 11(5): 5624

[23] Perego P, Cossa G, Zuco V, Zunino F. Modulation of cell sensitivity to antitumor agents by targeting survival pathways. Biochemical Pharmacology, 2010, 80(10): 1459–1465

[24] Woodcock J, Griffin J, Behrman R. Development of novel combination therapies. New England Journal of Medicine, 2011, 364(11): 985–987

[25] Ramalingam S, Egorin M, Ramanathan R, Remick S, Sikorski R, Lagattuta T, Chatta G, Friedland D, Stoller R, Potter D, Ivy S, Belani C. A phase I study of 17-allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies. Clinical Cancer Research, 2008, 14(11): 3456–3461

[26] O’Reilly T, McSheehy P, Wartmann M, Lassota P, Brandt R, Lane H. Evaluation of the mtor inhibitor, everolimus, in combination with antitumor agents using human tumor models in vitro and in vivo. Anti-Cancer Drugs, 2011, 22(1): 58–78

[27] Solit D, Basso A, Olshen A, Scher H, Rosen N. Inhibition of heat shock protein 90 function down-regulates akt kinase and sensitizes tumors to taxol. Cancer Research, 2003, 63(9): 2139–2144

[28] Hurvitz S, Andre F, Jiang Z, Shao Z, Mano M, Neciosup S, Tseng L, Zhang Q, Shen K, Liu D, Dreosti L, Burris H, Toi M, Buyse M, Cabaribere D, Lindsay M, Rao S, Pacaud L, Taran T, Slamon D. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with her2-positive advanced breast cancer (bolero-1): A phase 3, randomized, double-blind, multicentre trial. Lancet Oncology, 2015, 16(7): 816–829

[29] Stoeltzing O. Dual-targeting of mtor and hsp90 for cancer therapy: Facing oncogenic feed-back-loops and acquired mTOR resistance. Cell Cycle (Georgetown, Tex.), 2010, 9(11): 2051–2052

[30] Shin H, Alani A, Cho H, Bae Y, Kolesar J, Kwon G. A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs. Molecular Pharmaceutics, 2011, 8(4): 1257–1265

[31] Hasenstein J, Shin H, Kasmerchak K, Buehler D, Kwon G, Kozak K. Antitumor activity of triolimus: A novel multi-drug-loaded micelle containing paclitaxel, rapamycin and 17-aag. Molecular Cancer Therapeutics, 2012, 11(1): 1–10

[32] Shin H, Cho H, Lai T, Kozak K, Kolesar J, Kwon G. Pharmacokinetic study of 3-in-1 poly(ethylene glycol)-block-poly(<?A3B2 th=7pt?>D,L<?A3B2 th?>-lactic acid) micelles carrying paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin. Journal of Controlled Release, 2012, 163(1): 93–99

[33] Yokoyama M, Okano T, Sakurai Y, Fukushima S, Okamoto K, Kataoka K. Selective delivery of adriamycin to a solid tumor using a polymeric micelle carrier system. Journal of Drug Targeting, 1999, 7(3): 171–186

[34] Matsumura Y, Hamaguchi T, Ura T, Muro K, Yamada Y, Shimada Y, Shiro K, Okusaka T, Ueno H, Ikeda M, Watanabe N. Phase I clinical trial and pharmacokinetic evaluation of nk911, a micelle-encapsulated doxorubicin. British Journal of Cancer, 2004, 91(10): 1775–1781

[35] Liu J, Zeng F, Allen C. In vivo fate of unimers and micelles of a poly(ethylene glycol)-block-poly(caprolactone) copolymer in mice following intravenous administration. European Journal of Pharmaceutics and Biopharmaceutics, 2007, 65(3): 309–319

[36] Montazeri Aliabadi H, Brocks D R, Lavasanifar A. Polymeric micelles for the solubilization and delivery of cyclosporine A: Pharmacokinetics and biodistribution. Biomaterials, 2005, 26(35): 7251–7259

[37] Aliabadi H, Elhasi S, Brocks D, Lavasanifar A. Polymeric micellar delivery reduces kidney distribution and nephrotoxic effects of cyclosporine after multiple dosing. Journal of Pharmaceutical Sciences, 2008, 97(5): 1916–1926

[38] Binkhathlan Z, Hamdy D A, Brocks D R, Lavanifar A. Development of a polymeric micelle formulation for valspodar and assessment of its pharmacokinetics in rat. European Journal of Pharmaceutics and Biopharmaceutics, 2010, 75(2): 90–95

[39] Matsumura M, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanisms of tumoritropic accumulation of proteins and the anticancer agent smancs. Cancer Research, 1986, 46(12 Pt 1): 6387–6392

[40] Hamaguchi T, Matsumura Y, Suzuki M, Shimizu K, Goda R, Nakamura I, Nakatomi I, Yokoyama M, Kataoka K, Kakizoe T. Nk105, a paclitaxel-incorporating micellar nanoparticle formulation can extend in vivo antitumor activity and reduce the neurotoxicity of paclitaxel. British Journal of Cancer, 2005, 92(7): 1240–1246

[41] Kato K, Chin K, Yoshikawa T, Yamaguchi K, Tsuji Y, Esaki T, Sakai K, Kimura M, Hamaguchi T, Shimada Y, Matsumura Y, Ikeda R. Phase II study of nk105, a paclitaxel-incorporating micellar nanoparticle, for previously treated advanced or recurrent gastric cancer. Investigational New Drugs, 2012, 30(4): 1621–1627

[42] Bae Y, Fukushima S, Harada A, Kataoka K. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: Polymeric micelles that are responsive to intracellular ph change. Angewandte Chemie International Edition, 2003, 42(38): 4640–4643

[43] Bae Y, Hishiyama N, Fukushima S, Koyama H, Yosuhiro M, Kataoka K. Preparation and biological characterization of polymeric micelles drug carriers with intracellular pH-triggered drug release property: Tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjugate Chemistry, 2005, 16(1): 122–130

[44] Harada M, Bobe J, Saito H, Shibata N, Tanaka R, Hayashi T, Kato Y. Improved anti-tumor activity of stabilized anthracycline polymeric micelle formulation, nc-6300. Cancer Science, 2011, 102(1): 1192–1199

[45] Wei C, Guo J, Wang C. Dual stimuli-responsive polymeric micelles exhibiting “and” logic gate for controlled release of adriamycin. Macromolecular Rapid Communications, 2011, 32(5): 451–455

[46] Lai T, Cho H, Kwon G. Reversibly core-cross-linked polymeric micelles with ph-and reduction-sensitivities: Effects of cross-linking degree on particle stability, drug release kinetics and anti-tumor efficacy. Polymer Chemistry, 2014, 5(5): 1650–1661

[47] Bae Y, Diezi T, Zhao A, Kwon G. Mixed polymeric micelles for combination cancer chemotherapy through concurrent delivery of multiple chemotherapeutic agents. Journal of Controlled Release, 2007, 122(3): 324–330

[48] Torchilin V P. Targeted polymeric micelles for delivery of poorly soluble drugs. Cellular and Molecular Life Sciences, 2004, 61(19): 2549–2559

Funding

RIGHTS & PERMISSIONS

2016 Higher Education Press and Springer-Verlag Berlin Heidelberg