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Frontiers of Chemical Science and Engineering

ISSN 2095-0179

ISSN 2095-0187(Online)

CN 11-5981/TQ

Postal Subscription Code 80-969

2018 Impact Factor: 2.809

Front. Chem. Sci. Eng.    2016, Vol. 10 Issue (3) : 348-359    https://doi.org/10.1007/s11705-016-1582-2
REVIEW ARTICLE
Polymeric micelle nanocarriers in cancer research
Dae Hwan Shin,Yu Tong Tam,Glen S. Kwon()
School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
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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.

Keywords nanomedicine      parenteral      poly(ethylene glycol)      poly(lactic acid)      reformulation     
PACS:     
Fund: 
Corresponding Author(s): Glen S. Kwon   
Just Accepted Date: 08 July 2016   Online First Date: 27 July 2016    Issue Date: 23 August 2016
 Cite this article:   
Dae Hwan Shin,Yu Tong Tam,Glen S. Kwon. Polymeric micelle nanocarriers in cancer research[J]. Front. Chem. Sci. Eng., 2016, 10(3): 348-359.
 URL:  
https://academic.hep.com.cn/fcse/EN/10.1007/s11705-016-1582-2
https://academic.hep.com.cn/fcse/EN/Y2016/V10/I3/348
Fig.1  Physical and chemical drug loading of polymeric micelles
Fig.2  Key steps in drug delivery via unstable and stable polymeric micelles. (A) Unstable polymeric micelle; (B) Stable polymeric micelle
Fig.3  Examples of polymeric micelles for drug solubilization
Fig.4  Rapid release of paclitaxel after IV injection of Genexol-PM® and Abraxane®
Fig.5  Schematic illustration of Triolimus
Fig.6  Schematic illustration of NK911
Fig.7  The plasma clearance of PEG5000-b-PCL5000 micelles in Balb/C mice (n = 3, SD shown as error bars) following intravenous injection at a dose of 250 mg/kg (●, concentration of copolymer above CMC upon dilution following administration) 2 mg/kg (▲, concentration of copolymer above CMC prior to administration but falls below CMC upon dilution) or 0.2 mg/kg (■, copolymer unimers). The plasma concentration data for all groups were fit using compartmental open models by Scientist software and are shown as solid lines [35]
Cyclosporin A in Cremophor EL Cyclosporin A in polymeric micelles
AUC024 /(µg?h?mL–1) 25.3±7.64 167±18.8b)
AUC0–∞ /(µg?h?mL–1) 32.7±13.8 199±20.9b)
t1/2 /h 11.5±4.58 9.40±1.20
MRT /h 14.4±6.62 9.24±2.06
CL /(L?kg–1?h–1) 0.195±0.131 0.0255±0.00319b)
Vdss /(L?kg–1) 2.33±0.785 0.232±0.0425b)
Tab.1  Non-compartmental pharmacokinetic parameters (±SD) of cyclosporin A after intravenous administration of cyclosporin A in polymeric micellar formulation in comparison to cyclosporin A in Cremophor EL (Sandimmune®) formulationa) [3]
Fig.8  Schematic illustration of NK105
Fig.9  Plasma and tumor concentrations of paclitaxel after single i.v. administration of NK105 or paclitaxel to Colon 26-bearing CDF1 mice. Plasma (A) and tumor (B) concentrations of paclitaxel after NK105 administration at a paclitaxel-equivalent dose of 50 mg/kg (●), NK105 at a paclitaxel-equivalent dose of 100 mg/kg (▲), paclitaxel 50 mg/kg (○) and paclitaxel 100 mg/kg (?) [40]
Fig.10  Schematic illustration of PEG-b-p(Asp-Hyd-DOX)
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
https://doi.org/10.3322/caac.21338
2 Mehlen P, Puisieux A. Metastasis: A question of life or death. Nature Reviews. Cancer, 2006, 6(6): 449–458
https://doi.org/10.1038/nrc1886
3 Creixell P, Schoof E, Erler J, Linding R. Navigating cancer network attractors for tumor-specific therapy. Nature Biotechnology, 2012, 30(9): 842–848
https://doi.org/10.1038/nbt.2345
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
https://doi.org/10.1016/j.molmed.2015.01.001
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
https://doi.org/10.1016/j.biologicals.2015.05.006
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
https://doi.org/10.1038/nnano.2007.387
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
https://doi.org/10.1016/j.nantod.2012.08.005
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
https://doi.org/10.1016/j.jconrel.2011.12.012
9 Matsumura Y. The drug discovery by nanomedicine and its clinical experience. Japanese Journal of Clinical Oncology, 2014, 44(6): 515–525
https://doi.org/10.1093/jjco/hyu046
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
https://doi.org/10.1016/j.addr.2014.10.001
11 Nishiyama N. Nanocarriers shape up for long life. Nature Nanotechnology, 2007, 2(4): 203–204
https://doi.org/10.1038/nnano.2007.88
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
https://doi.org/10.1158/1078-0432.CCR-05-0518
15 Blois J, Smith A, Josephson L. The slow death response when screening chemotherapeutic agents. Cancer Chemotherapy and Pharmacology, 2011, 68(3): 795–803
https://doi.org/10.1007/s00280-010-1549-9
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
https://doi.org/10.1016/j.jconrel.2013.09.026
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
https://doi.org/10.1038/nnano.2011.166
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
https://doi.org/10.1016/S0168-3659(01)00275-9
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
https://doi.org/10.1158/1078-0432.CCR-03-0655
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
https://doi.org/10.2147/DDDT.S88023
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
https://doi.org/10.1016/j.bcp.2010.07.030
24 Woodcock J, Griffin J, Behrman R. Development of novel combination therapies. New England Journal of Medicine, 2011, 364(11): 985–987
https://doi.org/10.1056/NEJMp1101548
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
https://doi.org/10.1158/1078-0432.CCR-07-5088
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
https://doi.org/10.1097/CAD.0b013e3283400a20
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
https://doi.org/10.1016/S1470-2045(15)00051-0
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
https://doi.org/10.4161/cc.9.11.11924
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
https://doi.org/10.1021/mp2000549
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
https://doi.org/10.1016/j.jconrel.2012.04.024
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
https://doi.org/10.3109/10611869909085500
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
https://doi.org/10.1038/sj.bjc.6602204
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
https://doi.org/10.1016/j.ejpb.2006.11.010
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
https://doi.org/10.1016/j.biomaterials.2005.05.042
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
https://doi.org/10.1002/jps.21036
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
https://doi.org/10.1016/j.ejpb.2010.03.010
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
https://doi.org/10.1038/sj.bjc.6602479
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
https://doi.org/10.1007/s10637-011-9709-2
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
https://doi.org/10.1002/anie.200250653
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
https://doi.org/10.1021/bc0498166
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
https://doi.org/10.1111/j.1349-7006.2010.01745.x
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
https://doi.org/10.1002/marc.201000708
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
https://doi.org/10.1039/C3PY01112G
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
https://doi.org/10.1016/j.jconrel.2007.05.038
48 Torchilin V P. Targeted polymeric micelles for delivery of poorly soluble drugs. Cellular and Molecular Life Sciences, 2004, 61(19): 2549–2559
https://doi.org/10.1007/s00018-004-4153-5
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