Editorial For reprint orders, please contact [email protected]
Galactosylated block copolymers: a versatile nano-based tool for effective intracellular drug delivery? “A spoonful of sugar may very well help the medicine go down; combining polymer science with glycotargeting has considerable therapeutic potential, particularly when utilizing galactosylated ligands. Understanding the cellular sugar codes in sufficient detail to enable design of appropriate polymeric carriers is the key to progress in this fast-moving field.” Keywords: block copolymers n cell targeting n drug delivery n galactose n galectins n lectins n nanoparticles n sugar ligands
Interest in the design of biomimetic systems to tackle clinical problems is growing among the nanomedicine community. Nature’s design principles have inspired some polymer chemists to adopt similar strategies. This so-called biokleptic (‘stolen from Nature’) approach has produced wholly synthetic polymer-based vehicles that mimic the chemical structure of biological entities (e.g., viral particles, mammalian cell membranes and liposomes) in order to enhance the chemical stability of drugs, their bioavailability and the effective water solubility of hydrophobic drugs [1]. In principle, the surface of these vehicles can be engineered to actively deliver drug payloads to a specific target tissue (e.g., a tumor). The most common approach for targeted drug delivery is to introduce a ligand that recognizes a cell-specific receptor. Active targeting has been mainly achieved using protein-based ligands, such as short peptides or antibodies [2]. In their quest for more effective targeting, nanotechnologists are paying increasing attention to the importance of natural sugar interactions in cell biology. Given the vast density of information that sugars can encode, it is perhaps not surprising that such interactions can be far more specific than many other ligand-binding systems [3]. A spoonful of sugar may very well help the medicine go down; combining polymer science with glycotargeting has considerable therapeutic potential, particularly when utilizing galactosylated ligands. Understanding the cellular sugar codes in sufficient detail to enable design of appropriate polymeric carriers is the key to progress in this fast-moving field. Exploiting controlled radical polymerization techniques, such as atom transfer radical polymerization, reversible addition– fragmentation chain transfer polymerization or
nitroxide-mediated polymerization, synthetic polymer chemists have designed a remarkable range of functional glycopolymers with various well-defined architectures. These include dendritic and hyperbranched copolymers, various types of block copolymers and surface-confined polymer brushes [4]. Combining sugar-based ligands with such versatile polymer chemistry is attractive for drug-delivery applications because of their low-molecular weight, enormous structural diversity and the potential to selectively target various receptors from any cell types via receptor-mediated endocytosis (RME). In particular, galactose residues have been widely used as glycan ligands for RME. Indeed, the first report on such glycotargeting was in the early 1970s, when Ashwell and Morrell described selective targeting of hepatocytes by removal of terminal sialic acid residues from native mammalian serum glycoproteins, thereby exposing the galactose terminal residues [5]. Subsequently, the asialoglycoprotein receptor was isolated, characterized and demonstrated to be responsible for such cell targeting. The specificity of this process stems from the terminal galactose, as shown by modification of this residue with b-galactosidase or galactose oxidase, as well as by enzymatic resialylation [5]. This high affinity of the hepatocyte asialoglycoprotein receptor (ASGPR) towards galactose ligands has been evaluated by the drugdelivery community. For example, chitosan has been functionalized with galactose residues to improve liver targeting [6]. Similarly, the nontoxic and nonimmunogenic properties of biocompatible synthetic polymers such as poly(2-hydroxypropyl) methacrylamide [or poly(HPMA)] have also led to encouraging preclinical studies [7]. In particular, HPMA-based copolymers bearing terminal N-acylatedgalactosamine and a conjugated
10.4155/TDE.13.141 © 2014 Future Science Ltd
Ther. Deliv. (2014) 5(2), 105–107
Irene Canton Author for correspondence: Department of Biomedical Sciences, University of Sheffield, Sheffield, South Yorkshire, S10 2TN, UK E-mail: [email protected]
Burcin Ustbas Department of Biomedical Sciences, University of Sheffield, Sheffield, South Yorkshire, S10 2TN, UK
Steven P Armes Department of Chemistry, University of Sheffield, Sheffield, South Yorkshire, S3 7HF, UK
ISSN 2041-5990
105
Editorial | Canton, Ustbas & Armes anticancer drug [8] or protein have been reported to allow ASGPR targeting in the liver [9]. In fact, the first Phase I trial to examine a synthetic polymer drug conjugate for the treatment of liver cancer was based on HPMA copolymer-Gly-Phe-LeuGly-doxorubicin modified with a galactosamine ligand [8]. Strong evidence for galactose-mediated targeting has been demonstrated since the doxorubicin–polymer conjugate without galactosamine showed no targeting and the concentration of drug in the hepatoma cells was 12- to 50-fold higher than that during administration of the free drug. However, the proportion of drug delivered to the tumor tissue was only approximately 20% of that localized to normal hepatic parenchyma [8]. This is presumably because normal hepatocytes also express the ASGPR on their cell surface. Furthermore, there are also reports suggesting that expression of ASGPR can be suppressed by the malignant differentiation of hepatomas, as well as by proliferative, premature hepatocytes [10], which could potentially prohibit the use of galactosylated polymers for the treatment of liver disease. In this context, it is clear that further detailed molecular studies of receptor–ligand specificity in diseased versus healthy tissue are highly desirable. Similarly, there have been few attempts to design new monovalent ligands with high binding affinities towards ASGPR as a possible replacement for N-acylatedgalactosamine [11]. More potent ligands that are highly selective towards specific liver cells are essential for improving galactose ligand-mediated hepatic delivery of therapeutic agents.
“Combining sugar-based ligands with such versatile polymer chemistry is attractive for drug-delivery applications because of their low-molecular weight, enormous structural diversity and the potential to selectively target various receptors…” Nevertheless, galactosylated ligands are not exclusively intended for the targeting of the liver-specific C-type lectin, ASGPR. Recently, researchers have begun to realise that galectins may offer therapeutic potential for galactosylated-ligand drugs. Minko reviewed the use of galectins as targets in colon cancer therapy [12] and Belardi and co-workers created a new methodology to investigate the biological significance of galectin lattices on live cell membranes using fluorescently-labeled synthetic glycopolymers [13]. Very recently, our group has demonstrated 106
Ther. Deliv. (2014) 5(2)
the avid uptake of galactosylated diblock copolymer vesicles by primary human dermal fibroblast cells that express galectin-3, with subsequent intracellular release of a model payload [14]. Indeed, galectins are over-expressed in many diseases, including HIV infection, inflammation, arthritis, various cancers, asthma, diabetes, neural degeneration and atherosclerosis [15,16]. Galectins, or S-type lectins, are highly conserved throughout eukaryotic species. Approximately 15 members of the galectin family have been identified in mammals based on structural similarities in the carbohydrate binding domains. They are often located on the cell surface, as well as in the cytoplasm and in the nucleus of various cells, performing key roles in cellular homeostasis processes such as cell adhesion, apoptosis and receptor turnover and endocytosis. In mammals, galectins exhibit strong affinity for specific b-galactose-containing glycoconjugates through the presence of a highly conserved core [15]. This core is a sequence of approximately 130 amino acids known as the carbohydrate recognition domain and is responsible for the binding of specific sugars. The biological implications of the preference of individual galectins for specific glycoproteins are as yet unknown but specificity in targeting may be implied. Recently, Klyosov described galectins as ‘cellular antennae’ that specialize in the control of many cellular processes via ligand binding, acting either as blockers or enhancers as required [16]. In principle, unraveling such codes should allow the development of synthetic ligand mimics that enable stopping, enhancing or correcting specific messages for therapeutic purposes. However, the complexity of the technical challenge should not be underestimated. Galectins exhibit complex biology, because they are both ubiquitous and highly mobile inside the cell. They have specific functions within the nuclear region, the cytosol and the cell surface. Such multifunctionality is in part achieved via the multiplicity of available galectins [15,16]. Furthermore, galectin-mediated cellular receptor internalization and recycling processes can be very rapid. Once internalized via endocytosis, many galectins, together with their cargoes, have been identified in rab11-positive recycling endosomes, which are traversed in the forward pathway of apical cargo molecules [17]. Although the detailed internalization and recycling mechanism has not yet been established, they seem to be able to avoid lysosomal compartments [17]. Thus it seems plausible that, on entering the cell future science group
Galactosylated block copolymers from the extracellular milieu, galectins can modulate the transport and sorting of cargoes inside the cell. If this hypothesis is correct, it suggests new therapeutic targets for nanomedicine. Future perspective In conclusion, galactosylated doligosaccharide ligands contain encoded biological information in their sequences and conformations. However, this does not necessarily translate into maximum specificity for a particular cell type. The cellular glyco-code must be further deciphered and interpreted in order to create the desired highly specific delivery systems that are likely to underpin important future advances in nanomedicine. It is well worth bearing in mind that many pathogens (e.g., viruses, bacteria and protozoa) have evolved to colonize the host organism while avoiding attack by the host’s immune system. Some of these pathogens mimick the cell’s sugar codes and then rely on the host’s self-recognition molecules (such as galectins) for infection in a dual purpose ‘Trojan horse’ approach. Thus, they evade destruction by the immune system and are simultaneously granted cell entry via galectin-driven RME mechanisms [18]. The design of new synthetic ligands with even greater binding affinity than current
| Editorial
naturally-occurring ligands, combined with the use of stealthy polymers (i.e. PEGylated polymers), is expected to be invaluable for the development of much more target-effective galactosylated drug carriers. In addition to the ubiquitous problems of selectivity and affinity, the optimization of biocompatibility, biodegradability and immunogenicity (as well as the precise intracellular fate) are likely to complicate the designs of successful carriers. The judicious design of appropriate delivery systems that can escape the degradative lysosomal environment and/or direct the cargo to specific subcellular compartments (i.e., cytosolic or nuclear compartments) is essential if the maximum therapeutic potential of many drugs (including proteins and nucleic acids) is to be achieved. Financial & competing interests disclosure The authors acknowledge financial support from EPSRC funding I Canton (Grant NO. EP/I001967/1) and YCR (SPP062) for funding B Ustbas. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
References 1
2
3
4
5
6
7
Avila-Olias M, Pegoraro C, Battaglia G, Canton I. Inspired by nature: fundamentals in nanotechnology design to overcome biological barriers. Ther. Deliv. 4(1), 27–43 (2013). Muro S. Challenges in design and characterization of ligand-targeted drug delivery systems. J. Control. Release 164(2), 125–137 (2012). Davis BG, Robinson MA. Drug delivery systems based on sugar-macromolecule conjugates. Curr. Opin. Drug Discov. Devel. 5(2), 279–288 (2002). Vazquez-Dorbatt V, Lee J, Lin EW, Maynard HD. Synthesis of glycopolymers by controlled radical polymerization techniques and their applications. Chembiochem 13(17), 2478–2487 (2012). Ashwell G, Harford J. Carbohydrate-specific receptors of the liver. Annu. Rev. Biochem. 51(1), 531–554 (1982). Gao S, Chen J, Xu X et al. Galactosylated low molecular weight chitosan as DNA carrier for hepatocyte-targeting. Int. J. Pharm. 255(1–2), 57–68 (2003). Ulbrich K, Subr V. Structural and chemical aspects of HPMA copolymers as drug
future science group
carriers. Adv. Drug Deliv. Rev. 62(2), 150–166 (2010). 8
Seymour LW, Ferry DR, Anderson D et al. Hepatic drug targeting: Phase I evaluation of polymer-bound doxorubicin. J. Clin. Oncol. 20(6), 1668–1676 (2002).
9
Wang X, Sun H, Meng F, Cheng R, Deng C, Zhong Z. Galactose-decorated reductionsensitive degradable chimaeric polymersomes as a multifunctional nanocarrier to efficiently chaperone apoptotic proteins into hepatoma cells. Biomacromolecules 14(8), 2873–2882 (2013).
10 Yura H, Ishihara M, Kanatani Y et al.
Interaction study between synthetic glycoconjugate ligands and endocytic receptors using flow cytometry. J. Biochem. 139(4), 637–643 (2006). 11 Mamidyala SK, Dutta S, Chrunyk BA et al.
Glycomimetic ligands for the human asialoglycoprotein receptor. J. Am. Chem. Soc. 134(4), 1978–1981 (2012). 12 Minko T. Drug targeting to the colon with
lectins and neoglycoconjugates. Adv. Drug Deliv. Rev. 56(4), 491–509 (2004).
www.future-science.com
13 Belardi B, O’Donoghue GP, Smith AW,
Groves JT, Bertozzi CR. Investigating cell surface galectin-mediated cross-linking on glycoengineered cells. J. Am. Chem. Soc. 134(23), 9549–9552 (2012). 14 Ladmiral V, Semsarilar M, Canton I, Armes
SP. Polymerization-induced self-assembly of galactose-functionalized biocompatible diblock copolymers for intracellular delivery. J. Am. Chem. Soc.135(36), 13574–13581 (2013). 15 Yang RY, Rabinovich GA, Liu FT. Galectins:
structure, function and therapeutic potential. Expert Rev. Mol. Med. 10, e17 (2008). 16 Klyosov A, Traber PG. Galectins and disease
implications for targeted therapeutics (Chapter 1). American Chemical Society, Washington, DC, USA, 3–43 (2012). 17 Straube T, von Mach T, Honig E, Greb C,
Schneider D, Jacob R. pH-dependent recycling of galectin-3 at the apical membrane of epithelial cells. Traffic 14(9), 1014–1027 (2013). 18 Vasta GR. Roles of galectins in infection. Nat.
Rev. Microbiol. 7(6), 424–438 (2009).
107
Galactosylated block copolymers: a versatile nano-based tool for effective intracellular drug delivery? “A spoonful of sugar may very well help the medicine go down; combining polymer science with glycotargeting has considerable therapeutic potential, particularly when utilizing galactosylated ligands. Understanding the cellular sugar codes in sufficient detail to enable design of appropriate polymeric carriers is the key to progress in this fast-moving field.” Keywords: block copolymers n cell targeting n drug delivery n galactose n galectins n lectins n nanoparticles n sugar ligands
Interest in the design of biomimetic systems to tackle clinical problems is growing among the nanomedicine community. Nature’s design principles have inspired some polymer chemists to adopt similar strategies. This so-called biokleptic (‘stolen from Nature’) approach has produced wholly synthetic polymer-based vehicles that mimic the chemical structure of biological entities (e.g., viral particles, mammalian cell membranes and liposomes) in order to enhance the chemical stability of drugs, their bioavailability and the effective water solubility of hydrophobic drugs [1]. In principle, the surface of these vehicles can be engineered to actively deliver drug payloads to a specific target tissue (e.g., a tumor). The most common approach for targeted drug delivery is to introduce a ligand that recognizes a cell-specific receptor. Active targeting has been mainly achieved using protein-based ligands, such as short peptides or antibodies [2]. In their quest for more effective targeting, nanotechnologists are paying increasing attention to the importance of natural sugar interactions in cell biology. Given the vast density of information that sugars can encode, it is perhaps not surprising that such interactions can be far more specific than many other ligand-binding systems [3]. A spoonful of sugar may very well help the medicine go down; combining polymer science with glycotargeting has considerable therapeutic potential, particularly when utilizing galactosylated ligands. Understanding the cellular sugar codes in sufficient detail to enable design of appropriate polymeric carriers is the key to progress in this fast-moving field. Exploiting controlled radical polymerization techniques, such as atom transfer radical polymerization, reversible addition– fragmentation chain transfer polymerization or
nitroxide-mediated polymerization, synthetic polymer chemists have designed a remarkable range of functional glycopolymers with various well-defined architectures. These include dendritic and hyperbranched copolymers, various types of block copolymers and surface-confined polymer brushes [4]. Combining sugar-based ligands with such versatile polymer chemistry is attractive for drug-delivery applications because of their low-molecular weight, enormous structural diversity and the potential to selectively target various receptors from any cell types via receptor-mediated endocytosis (RME). In particular, galactose residues have been widely used as glycan ligands for RME. Indeed, the first report on such glycotargeting was in the early 1970s, when Ashwell and Morrell described selective targeting of hepatocytes by removal of terminal sialic acid residues from native mammalian serum glycoproteins, thereby exposing the galactose terminal residues [5]. Subsequently, the asialoglycoprotein receptor was isolated, characterized and demonstrated to be responsible for such cell targeting. The specificity of this process stems from the terminal galactose, as shown by modification of this residue with b-galactosidase or galactose oxidase, as well as by enzymatic resialylation [5]. This high affinity of the hepatocyte asialoglycoprotein receptor (ASGPR) towards galactose ligands has been evaluated by the drugdelivery community. For example, chitosan has been functionalized with galactose residues to improve liver targeting [6]. Similarly, the nontoxic and nonimmunogenic properties of biocompatible synthetic polymers such as poly(2-hydroxypropyl) methacrylamide [or poly(HPMA)] have also led to encouraging preclinical studies [7]. In particular, HPMA-based copolymers bearing terminal N-acylatedgalactosamine and a conjugated
10.4155/TDE.13.141 © 2014 Future Science Ltd
Ther. Deliv. (2014) 5(2), 105–107
Irene Canton Author for correspondence: Department of Biomedical Sciences, University of Sheffield, Sheffield, South Yorkshire, S10 2TN, UK E-mail: [email protected]
Burcin Ustbas Department of Biomedical Sciences, University of Sheffield, Sheffield, South Yorkshire, S10 2TN, UK
Steven P Armes Department of Chemistry, University of Sheffield, Sheffield, South Yorkshire, S3 7HF, UK
ISSN 2041-5990
105
Editorial | Canton, Ustbas & Armes anticancer drug [8] or protein have been reported to allow ASGPR targeting in the liver [9]. In fact, the first Phase I trial to examine a synthetic polymer drug conjugate for the treatment of liver cancer was based on HPMA copolymer-Gly-Phe-LeuGly-doxorubicin modified with a galactosamine ligand [8]. Strong evidence for galactose-mediated targeting has been demonstrated since the doxorubicin–polymer conjugate without galactosamine showed no targeting and the concentration of drug in the hepatoma cells was 12- to 50-fold higher than that during administration of the free drug. However, the proportion of drug delivered to the tumor tissue was only approximately 20% of that localized to normal hepatic parenchyma [8]. This is presumably because normal hepatocytes also express the ASGPR on their cell surface. Furthermore, there are also reports suggesting that expression of ASGPR can be suppressed by the malignant differentiation of hepatomas, as well as by proliferative, premature hepatocytes [10], which could potentially prohibit the use of galactosylated polymers for the treatment of liver disease. In this context, it is clear that further detailed molecular studies of receptor–ligand specificity in diseased versus healthy tissue are highly desirable. Similarly, there have been few attempts to design new monovalent ligands with high binding affinities towards ASGPR as a possible replacement for N-acylatedgalactosamine [11]. More potent ligands that are highly selective towards specific liver cells are essential for improving galactose ligand-mediated hepatic delivery of therapeutic agents.
“Combining sugar-based ligands with such versatile polymer chemistry is attractive for drug-delivery applications because of their low-molecular weight, enormous structural diversity and the potential to selectively target various receptors…” Nevertheless, galactosylated ligands are not exclusively intended for the targeting of the liver-specific C-type lectin, ASGPR. Recently, researchers have begun to realise that galectins may offer therapeutic potential for galactosylated-ligand drugs. Minko reviewed the use of galectins as targets in colon cancer therapy [12] and Belardi and co-workers created a new methodology to investigate the biological significance of galectin lattices on live cell membranes using fluorescently-labeled synthetic glycopolymers [13]. Very recently, our group has demonstrated 106
Ther. Deliv. (2014) 5(2)
the avid uptake of galactosylated diblock copolymer vesicles by primary human dermal fibroblast cells that express galectin-3, with subsequent intracellular release of a model payload [14]. Indeed, galectins are over-expressed in many diseases, including HIV infection, inflammation, arthritis, various cancers, asthma, diabetes, neural degeneration and atherosclerosis [15,16]. Galectins, or S-type lectins, are highly conserved throughout eukaryotic species. Approximately 15 members of the galectin family have been identified in mammals based on structural similarities in the carbohydrate binding domains. They are often located on the cell surface, as well as in the cytoplasm and in the nucleus of various cells, performing key roles in cellular homeostasis processes such as cell adhesion, apoptosis and receptor turnover and endocytosis. In mammals, galectins exhibit strong affinity for specific b-galactose-containing glycoconjugates through the presence of a highly conserved core [15]. This core is a sequence of approximately 130 amino acids known as the carbohydrate recognition domain and is responsible for the binding of specific sugars. The biological implications of the preference of individual galectins for specific glycoproteins are as yet unknown but specificity in targeting may be implied. Recently, Klyosov described galectins as ‘cellular antennae’ that specialize in the control of many cellular processes via ligand binding, acting either as blockers or enhancers as required [16]. In principle, unraveling such codes should allow the development of synthetic ligand mimics that enable stopping, enhancing or correcting specific messages for therapeutic purposes. However, the complexity of the technical challenge should not be underestimated. Galectins exhibit complex biology, because they are both ubiquitous and highly mobile inside the cell. They have specific functions within the nuclear region, the cytosol and the cell surface. Such multifunctionality is in part achieved via the multiplicity of available galectins [15,16]. Furthermore, galectin-mediated cellular receptor internalization and recycling processes can be very rapid. Once internalized via endocytosis, many galectins, together with their cargoes, have been identified in rab11-positive recycling endosomes, which are traversed in the forward pathway of apical cargo molecules [17]. Although the detailed internalization and recycling mechanism has not yet been established, they seem to be able to avoid lysosomal compartments [17]. Thus it seems plausible that, on entering the cell future science group
Galactosylated block copolymers from the extracellular milieu, galectins can modulate the transport and sorting of cargoes inside the cell. If this hypothesis is correct, it suggests new therapeutic targets for nanomedicine. Future perspective In conclusion, galactosylated doligosaccharide ligands contain encoded biological information in their sequences and conformations. However, this does not necessarily translate into maximum specificity for a particular cell type. The cellular glyco-code must be further deciphered and interpreted in order to create the desired highly specific delivery systems that are likely to underpin important future advances in nanomedicine. It is well worth bearing in mind that many pathogens (e.g., viruses, bacteria and protozoa) have evolved to colonize the host organism while avoiding attack by the host’s immune system. Some of these pathogens mimick the cell’s sugar codes and then rely on the host’s self-recognition molecules (such as galectins) for infection in a dual purpose ‘Trojan horse’ approach. Thus, they evade destruction by the immune system and are simultaneously granted cell entry via galectin-driven RME mechanisms [18]. The design of new synthetic ligands with even greater binding affinity than current
| Editorial
naturally-occurring ligands, combined with the use of stealthy polymers (i.e. PEGylated polymers), is expected to be invaluable for the development of much more target-effective galactosylated drug carriers. In addition to the ubiquitous problems of selectivity and affinity, the optimization of biocompatibility, biodegradability and immunogenicity (as well as the precise intracellular fate) are likely to complicate the designs of successful carriers. The judicious design of appropriate delivery systems that can escape the degradative lysosomal environment and/or direct the cargo to specific subcellular compartments (i.e., cytosolic or nuclear compartments) is essential if the maximum therapeutic potential of many drugs (including proteins and nucleic acids) is to be achieved. Financial & competing interests disclosure The authors acknowledge financial support from EPSRC funding I Canton (Grant NO. EP/I001967/1) and YCR (SPP062) for funding B Ustbas. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
References 1
2
3
4
5
6
7
Avila-Olias M, Pegoraro C, Battaglia G, Canton I. Inspired by nature: fundamentals in nanotechnology design to overcome biological barriers. Ther. Deliv. 4(1), 27–43 (2013). Muro S. Challenges in design and characterization of ligand-targeted drug delivery systems. J. Control. Release 164(2), 125–137 (2012). Davis BG, Robinson MA. Drug delivery systems based on sugar-macromolecule conjugates. Curr. Opin. Drug Discov. Devel. 5(2), 279–288 (2002). Vazquez-Dorbatt V, Lee J, Lin EW, Maynard HD. Synthesis of glycopolymers by controlled radical polymerization techniques and their applications. Chembiochem 13(17), 2478–2487 (2012). Ashwell G, Harford J. Carbohydrate-specific receptors of the liver. Annu. Rev. Biochem. 51(1), 531–554 (1982). Gao S, Chen J, Xu X et al. Galactosylated low molecular weight chitosan as DNA carrier for hepatocyte-targeting. Int. J. Pharm. 255(1–2), 57–68 (2003). Ulbrich K, Subr V. Structural and chemical aspects of HPMA copolymers as drug
future science group
carriers. Adv. Drug Deliv. Rev. 62(2), 150–166 (2010). 8
Seymour LW, Ferry DR, Anderson D et al. Hepatic drug targeting: Phase I evaluation of polymer-bound doxorubicin. J. Clin. Oncol. 20(6), 1668–1676 (2002).
9
Wang X, Sun H, Meng F, Cheng R, Deng C, Zhong Z. Galactose-decorated reductionsensitive degradable chimaeric polymersomes as a multifunctional nanocarrier to efficiently chaperone apoptotic proteins into hepatoma cells. Biomacromolecules 14(8), 2873–2882 (2013).
10 Yura H, Ishihara M, Kanatani Y et al.
Interaction study between synthetic glycoconjugate ligands and endocytic receptors using flow cytometry. J. Biochem. 139(4), 637–643 (2006). 11 Mamidyala SK, Dutta S, Chrunyk BA et al.
Glycomimetic ligands for the human asialoglycoprotein receptor. J. Am. Chem. Soc. 134(4), 1978–1981 (2012). 12 Minko T. Drug targeting to the colon with
lectins and neoglycoconjugates. Adv. Drug Deliv. Rev. 56(4), 491–509 (2004).
www.future-science.com
13 Belardi B, O’Donoghue GP, Smith AW,
Groves JT, Bertozzi CR. Investigating cell surface galectin-mediated cross-linking on glycoengineered cells. J. Am. Chem. Soc. 134(23), 9549–9552 (2012). 14 Ladmiral V, Semsarilar M, Canton I, Armes
SP. Polymerization-induced self-assembly of galactose-functionalized biocompatible diblock copolymers for intracellular delivery. J. Am. Chem. Soc.135(36), 13574–13581 (2013). 15 Yang RY, Rabinovich GA, Liu FT. Galectins:
structure, function and therapeutic potential. Expert Rev. Mol. Med. 10, e17 (2008). 16 Klyosov A, Traber PG. Galectins and disease
implications for targeted therapeutics (Chapter 1). American Chemical Society, Washington, DC, USA, 3–43 (2012). 17 Straube T, von Mach T, Honig E, Greb C,
Schneider D, Jacob R. pH-dependent recycling of galectin-3 at the apical membrane of epithelial cells. Traffic 14(9), 1014–1027 (2013). 18 Vasta GR. Roles of galectins in infection. Nat.
Rev. Microbiol. 7(6), 424–438 (2009).
107
