Polymeric micelles for nano-scale drug delivery

Abstract This review describes the design of polymeric micelles from block copolymers and their performances as nano-scale drug delivery systems, with emphasis on our recent work. The basic drug delivery system platform developed by our group consists of polymeric micelles comprising a core–shell structure with a versatile drug-loading hydrophobic core and biocompatible hydrophilic shell, and are several tens to one hundred nanometer in size. These characteristics are preferable to bypass both renal clearance and entrapment by the reticuloendothelial system, thus allowing subsequent accumulation within tumor tissues by the enhanced permeability and retention effect. Furthermore, polymeric micelles may be designed for enhanced biological performance by modification of the block copolymers to contain chemistries that can sense a specific biological environment. These “smart” micelles allow for target site-triggered drug release by reversible stabilization of the micelle structure and controlled intracellular trafficking (efficient endosomal release). Smart micelles designed with responsive features have demonstrated the utility in many cases compared to controls lacking such functionality. Additionally, the ability to control the size of polymeric micelles in the range of several tens to hundreds of nanometer significantly affects their longevity in the blood stream and efficiency of tumor tissue accumulation and penetration. In hypovascular tumor tissues, smaller polymeric micelles are more effective for tissue accumulation/penetration, bringing about stronger anti-tumor activity. All together, fine-tuning the structure of block copolymers enables preparation of polymeric micelles with versatile functions for treatment of many diseases including intractable cancer.

[1]  K. Kataoka,et al.  Novel polyion complex micelles entrapping enzyme molecules in the core: Preparation of narrowly-distributed micelles from lysozyme and poly(ethylene glycol)-poly(aspartic acid) block copolymer in aqueous medium , 1998 .

[2]  Kazunori Kataoka,et al.  Current state, achievements, and future prospects of polymeric micelles as nanocarriers for drug and gene delivery. , 2006, Pharmacology & therapeutics.

[3]  Bradley D. Smith,et al.  High-generation polycationic dendrimers are unusually effective at disrupting anionic vesicles: membrane bending model. , 2000, Bioconjugate chemistry.

[4]  Kozo Nakamura,et al.  Evaluation by fluorescence resonance energy transfer of the stability of nonviral gene delivery vectors under physiological conditions. , 2002, Biomacromolecules.

[5]  K. Maruyama,et al.  Size-dependent extravasation and interstitial localization of polyethyleneglycol liposomes in solid tumor-bearing mice. , 1999, International journal of pharmaceutics.

[6]  K. Kataoka,et al.  Polymeric micelles from poly(ethylene glycol)–poly(amino acid) block copolymer for drug and gene delivery , 2009, Journal of The Royal Society Interface.

[7]  N. Nishiyama,et al.  Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats , 2005, British Journal of Cancer.

[8]  N. Nishiyama,et al.  Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[9]  Allan S. Hoffman,et al.  The origins and evolution of "controlled" drug delivery systems. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[10]  K. Kataoka,et al.  Glutathione-sensitive stabilization of block copolymer micelles composed of antisense DNA and thiolated poly(ethylene glycol)-block-poly(L-lysine): a potential carrier for systemic delivery of antisense DNA. , 2001, Biomacromolecules.

[11]  T. Onda,et al.  Novel SN-38-incorporating polymeric micelles, NK012, eradicate vascular endothelial growth factor-secreting bulky tumors. , 2006, Cancer research.

[12]  Y. Lim,et al.  Biodegradable, endosome disruptive, and cationic network-type polymer as a highly efficient and nontoxic gene delivery carrier. , 2002, Bioconjugate chemistry.

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

[14]  N. Nishiyama,et al.  Preparation and characterization of size-controlled polymeric micelle containing cis-dichlorodiammineplatinum(II) in the core. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[15]  N. Nishiyama,et al.  Intratracheal gene transfer of adrenomedullin using polyplex nanomicelles attenuates monocrotaline-induced pulmonary hypertension in rats. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  R. Jain,et al.  Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Oliver Germershaus,et al.  Bioreversibly crosslinked polyplexes of PEI and high molecular weight PEG show extended circulation times in vivo. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[18]  A. Eisenberg,et al.  Critical micellization phenomena in block polyelectrolyte solutions , 1993 .

[19]  K. Kataoka,et al.  Water-soluble polyion complex associates of DNA and poly(ethylene glycol)-poly(L-lysine) block copolymer. , 1997, Bioconjugate chemistry.

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

[21]  K. Kataoka,et al.  Study of the quantitative aminolysis reaction of poly(β-benzyl l-aspartate) (PBLA) as a platform polymer for functionality materials , 2007 .

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

[23]  K. Miyazono,et al.  Antiangiogenic gene therapy of solid tumor by systemic injection of polyplex micelles loading plasmid DNA encoding soluble flt-1. , 2010, Molecular pharmaceutics.

[24]  Sung-Bae Kim,et al.  Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer , 2008, Breast Cancer Research and Treatment.

[25]  Yuichi Yamasaki,et al.  In situ single cell observation by fluorescence resonance energy transfer reveals fast intra‐cytoplasmic delivery and easy release of plasmid DNA complexed with linear polyethylenimine , 2004, The journal of gene medicine.

[26]  D. Scherman,et al.  A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Joel A Swanson,et al.  Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities. , 2003, Advanced drug delivery reviews.

[28]  K. Ulbrich,et al.  Characterization of vectors for gene therapy formed by self-assembly of DNA with synthetic block co-polymers. , 1996, Human gene therapy.

[29]  Muri Han,et al.  Transfection study using multicellular tumor spheroids for screening non-viral polymeric gene vectors with low cytotoxicity and high transfection efficiencies. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[30]  S Moein Moghimi,et al.  A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene transfer/therapy. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  Y. Matsumura,et al.  Enhanced distribution of NK012, a polymeric micelle‐encapsulated SN‐38, and sustained release of SN‐38 within tumors can beat a hypovascular tumor , 2008, Cancer science.

[32]  R. Langer,et al.  Exploring polyethylenimine‐mediated DNA transfection and the proton sponge hypothesis , 2005, The journal of gene medicine.

[33]  Kazunori Kataoka,et al.  A protein nanocarrier from charge-conversion polymer in response to endosomal pH. , 2007, Journal of the American Chemical Society.

[34]  Kevin Braeckmans,et al.  The transport of nanosized gene carriers unraveled by live-cell imaging. , 2006, Angewandte Chemie.

[35]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[36]  A. Kabanov,et al.  DNA complexes with polycations for the delivery of genetic material into cells. , 1995, Bioconjugate chemistry.

[37]  F. Davis.  The origin of pegnology. , 2002, Advanced Drug Delivery Reviews.

[38]  Kazunori Kataoka,et al.  Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers. , 2009, Advanced drug delivery reviews.

[39]  G. Kwon,et al.  Polymeric micelles for delivery of poorly water-soluble compounds. , 2003, Critical reviews in therapeutic drug carrier systems.

[40]  M. Brady,et al.  Intraperitoneal therapy for ovarian cancer: a treatment ready for prime time. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  Hiroshi Kawaguchi,et al.  Bone regeneration by regulated in vivo gene transfer using biocompatible polyplex nanomicelles. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[42]  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 .

[43]  Jaroslav Pelisek,et al.  Toward synthetic viruses: endosomal pH-triggered deshielding of targeted polyplexes greatly enhances gene transfer in vitro and in vivo. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[44]  H. Burt,et al.  Polymeric drug delivery of platinum-based anticancer agents. , 2009, Journal of pharmaceutical sciences.

[45]  T. Okano,et al.  Preparation and Characterization of Self-Assembled Polymer−Metal Complex Micelle from cis-Dichlorodiammineplatinum(II) and Poly(ethylene glycol)−Poly(α,β-aspartic acid) Block Copolymer in an Aqueous Medium , 1999 .

[46]  K. Kataoka,et al.  ON-OFF CONTROL OF ENZYMATIC ACTIVITY SYNCHRONIZING WITH REVERSIBLE FORMATION OF SUPRAMOLECULAR ASSEMBLY FROM ENZYME AND CHARGED BLOCK COPOLYMERS , 1999 .

[47]  K. Kataoka,et al.  Block copolymer micelles for drug delivery: design, characterization and biological significance. , 2001, Advanced drug delivery reviews.

[48]  Jindrich Kopecek,et al.  Intracellular Processing of Poly(Ethylene Imine)/Ribozyme Complexes Can Be Observed in Living Cells by Using Confocal Laser Scanning Microscopy and Inhibitor Experiments , 2002, Pharmaceutical Research.

[49]  K. Kataoka,et al.  Environment-Sensitive Stabilization of Core−Shell Structured Polyion Complex Micelle by Reversible Cross-Linking of the Core through Disulfide Bond , 1999 .

[50]  J. Kopeček,et al.  Effect of molecular weight (Mw) of N-(2-hydroxypropyl)methacrylamide copolymers on body distribution and rate of excretion after subcutaneous, intraperitoneal, and intravenous administration to rats. , 1987, Journal of biomedical materials research.

[51]  Kazunori Kataoka,et al.  Block copolymer micelles for delivery of gene and related compounds. , 2002, Advanced drug delivery reviews.

[52]  F. Liu,et al.  Polyethylene glycol-grafted poly-L-lysine as polymeric gene carrier. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[53]  D. Wirtz,et al.  Efficient active transport of gene nanocarriers to the cell nucleus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Y. Sugiyama,et al.  Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. , 2003, Cancer research.

[55]  Thomas Kissel,et al.  In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. , 2003, Biomaterials.

[56]  M. Gottesman,et al.  Multidrug resistance in cancer: role of ATP–dependent transporters , 2002, Nature Reviews Cancer.

[57]  S. Fukushima,et al.  Biocompatible micellar nanovectors achieve efficient gene transfer to vascular lesions without cytotoxicity and thrombus formation , 2007, Gene Therapy.

[58]  Yuichi Yamasaki,et al.  Block catiomer polyplexes with regulated densities of charge and disulfide cross-linking directed to enhance gene expression. , 2004, Journal of the American Chemical Society.

[59]  K. Kataoka,et al.  Biodegradable polyamino acid-based polycations as safe and effective gene carrier minimizing cumulative toxicity. , 2010, Biomaterials.

[60]  M. Ranson,et al.  SP1049C as first-line therapy in advanced (inoperable or metastatic) adenocarcinoma of the oesophagus: A phase II window study. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  K. Rice,et al.  In vivo gene transfer using sulfhydryl cross-linked PEG-peptide/glycopeptide DNA co-condensates. , 2003, Journal of pharmaceutical sciences.

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

[63]  A. Mikos,et al.  Tracking the intracellular path of poly(ethylenimine)/DNA complexes for gene delivery. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[64]  N. Nishiyama,et al.  Environment-responsive block copolymer micelles with a disulfide cross-linked core for enhanced siRNA delivery. , 2009, Biomacromolecules.

[65]  J. Kinsella,et al.  Ready separation of proteins from nucleoprotein complexes by reversible modification of lysine residues. , 1980, The Biochemical journal.

[66]  I. Aoki,et al.  Visible drug delivery by supramolecular nanocarriers directing to single-platformed diagnosis and therapy of pancreatic tumor model. , 2010, Cancer research.

[67]  Atsushi Harada,et al.  Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. , 2003, Angewandte Chemie.

[68]  Norased Nasongkla,et al.  Functionalized Micellar Systems for Cancer Targeted Drug Delivery , 2007, Pharmaceutical Research.

[69]  Kozo Nakamura,et al.  Polyion complex micelles from plasmid DNA and poly(ethylene glycol)-poly(L-lysine) block copolymer as serum-tolerable polyplex system: physicochemical properties of micelles relevant to gene transfection efficiency. , 2003, Biomaterials.

[70]  R. Duncan.  The dawning era of polymer therapeutics , 2003, Nature Reviews Drug Discovery.

[71]  M. Bawendi,et al.  Renal clearance of quantum dots , 2007, Nature Biotechnology.

[72]  K. Kataoka,et al.  Biosignal-sensitive polyion complex micelles for the delivery of biopharmaceuticals , 2009 .

[73]  S. Fukushima,et al.  A PEG‐Based Biocompatible Block Catiomer with High Buffering Capacity for the Construction of Polyplex Micelles Showing Efficient Gene Transfer toward Primary Cells , 2006, ChemMedChem.

[74]  K. Kataoka,et al.  NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel , 2005, British Journal of Cancer.

[75]  N. Nishiyama,et al.  Efficient delivery of bioactive antibodies into the cytoplasm of living cells by charge-conversional polyion complex micelles. , 2010, Angewandte Chemie.

[76]  H. Kawakami,et al.  Design of aminated poly(1-vinylimidazole) for a new pH-sensitive polycation to enhance cell-specific gene delivery. , 2007, Bioconjugate chemistry.

[77]  V. Torchilin,et al.  Micellar Nanocarriers: Pharmaceutical Perspectives , 2006, Pharmaceutical Research.

[78]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.

[79]  C. S. Pillay,et al.  Endolysosomal proteolysis and its regulation. , 2002, The Biochemical journal.

[80]  D. M. Morré,et al.  Cell Surface NADH Oxidases (ECTO-NOX Proteins) with Roles in Cancer, Cellular Time-keeping, Growth, Aging and Neurodegenerative Diseases , 2003, Free radical research.

[81]  Yuichi Yamasaki,et al.  Freeze-dried formulations for in vivo gene delivery of PEGylated polyplex micelles with disulfide crosslinked cores to the liver. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[82]  S. Fukushima,et al.  Polyplexes from poly(aspartamide) bearing 1,2-diaminoethane side chains induce pH-selective, endosomal membrane destabilization with amplified transfection and negligible cytotoxicity. , 2008, Journal of the American Chemical Society.

[83]  K. Kataoka,et al.  Preclinical and clinical studies of anticancer agent‐incorporating polymer micelles , 2009, Cancer science.

[84]  D. Fischer,et al.  Recent advances in rational gene transfer vector design based on poly(ethylene imine) and its derivatives , 2005, The journal of gene medicine.

[85]  Y. Anraku,et al.  Spontaneous formation of nanosized unilamellar polyion complex vesicles with tunable size and properties. , 2010, Journal of the American Chemical Society.

[86]  F. Szoka,et al.  Chloride Accumulation and Swelling in Endosomes Enhances DNA Transfer by Polyamine-DNA Polyplexes* , 2003, Journal of Biological Chemistry.

[87]  T. Bieber,et al.  Intracellular route and transcriptional competence of polyethylenimine-DNA complexes. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[88]  N. Nishiyama,et al.  Charge-conversional polyionic complex micelles-efficient nanocarriers for protein delivery into cytoplasm. , 2009, Angewandte Chemie.

[89]  M. Wu,et al.  Inhibition of a reductive function of the plasma membrane by bacitracin and antibodies against protein disulfide-isomerase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[90]  N. Nishiyama,et al.  A Photo-Activated Targeting Chemotherapy Using Glutathione Sensitive Camptothecin-Loaded Polymeric Micelles , 2008, Pharmaceutical Research.

[91]  Kazunori Kataoka,et al.  Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling , 2007, Proceedings of the National Academy of Sciences.

[92]  L. Seymour,et al.  Triggered intracellular activation of disulfide crosslinked polyelectrolyte gene delivery complexes with extended systemic circulation in vivo , 2001, Gene Therapy.