This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 8123–8125 8123 Cite this: Chem. Commun., 2012, 48, 8123–8125 Selective non-covalent triggered release from liposomesw Adam J. Plaunt, Meghan B. Courbanou, Katrina D. Cuison, Kara M. Harmatys and Bradley D. Smith* Received 25th April 2012, Accepted 27th June 2012 DOI: 10.1039/c2cc32962j A zinc(II)-dipicolylamine coordination complex selectively associates with anionic liposomes, including sterically protected PEGylated liposomes, and causes rapid leakage of encapsulated contents. Encapsulating drugs inside liposomes is a well-known method of reducing drug toxicity and improving therapeutic efficacy. 1 The current generation of government approved liposome/ drug formulations use passive diffusion processes to release the drug, which makes it hard to regulate the delivery. 2 One of the goals of nanomedicine is to improve liposome-based formulations by developing strategies to trigger drug release with spatiotemporal control. 3 The literature on triggered release liposomes includes systems that leak their encapsulated aqueous contents upon changes in local environmental factors such as temperature, 4 pH, 5 light, 6 and ultrasound. 7 There are also liposome systems that become leaky after selective chemical bond cleavage. 8 Although many chemicals are known to disrupt bilayer membranes, the concept of selective non-covalent triggered release from lipo- somes is surprisingly underdeveloped. 9 A likely reason for this situation is the challenge to find a liposome composition that can be selectively lysed by an exogenously added chemical that otherwise has little affinity for the host cell membranes. Previously, we have reported that zinc(II)-dipicolylamine (ZnDPA) coordination com- plexes have a remarkable ability to selectively associate with anionic bilayer membranes and not associate with zwitterionic membranes that are characteristic of healthy mammalian cells. 10 We have utilized this membrane selectivity to develop in vivo imaging probes that target localized populations of anionic cells, such as apoptotic mammalian cells or bacteria, within living animal models. 11 Here, we propose a new application using ZnDPA complexes; that is, a novel method of non-covalent triggered drug delivery (Scheme 1). We envision a two-step dosing strategy. The mammalian subject is treated intravenously first with appropriately functionalized, anionic liposomes that are filled with drugs. After time to allow liposome accumulation at the site of disease, a subsequent dose of ZnDPA complex targets the liposomes and induces leakage of the encapsulated drugs. A strategic advantage with this method of triggered liposome release is that it does not require any knowledge of the anatomical location of the site of disease. Herein, we describe in vitro liposome studies that demonstrate proof of the general concept. The liposomes used in this study incorporated different ratios of three polar lipids, phosphatidylcholine (PC, zwitterionic head group), cholesterol (uncharged head group), and phosphatidyl- serine (PS, anionic head group). PS was chosen as the anionic target phospholipid for several reasons. It is typically the most common anionic phospholipid in the plasma membrane of healthy cells (5–15% of total phospholipid), 12 but it is sequestered almost exclusively in the inner leaflet of the plasma membrane and not available for targeting by a hypothetical intravenous dose of ZnDPA complex 1. In comparison, a perfused disease-site containing a population of exogenous, PS-rich liposomes is expected to be a distinctive and biocompatible binding target for 1. Furthermore, it is known that association of metal cations or Scheme 1 Triggered release from liposomes. Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN, USA. E-mail: [email protected]; Tel: +1 574-631-8632 w Electronic supplementary information (ESI) available: methods and spectral data. See DOI: 10.1039/c2cc32962j ChemComm Dynamic Article Links www.rsc.org/chemcomm COMMUNICATION Downloaded by University of Notre Dame on 02 October 2012 Published on 28 June 2012 on http://pubs.rsc.org | doi:10.1039/C2CC32962J View Online / Journal Homepage / Table of Contents for this issue
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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 8123–8125 8123
Cite this: Chem. Commun., 2012, 48, 8123–8125
Selective non-covalent triggered release from liposomesw
Adam J. Plaunt, Meghan B. Courbanou, Katrina D. Cuison, Kara M. Harmatys and
Bradley D. Smith*
Received 25th April 2012, Accepted 27th June 2012
DOI: 10.1039/c2cc32962j
A zinc(II)-dipicolylamine coordination complex selectively associates
with anionic liposomes, including sterically protected PEGylated
liposomes, and causes rapid leakage of encapsulated contents.
Encapsulating drugs inside liposomes is a well-known method
of reducing drug toxicity and improving therapeutic efficacy.1
The current generation of government approved liposome/
drug formulations use passive diffusion processes to release the
drug, which makes it hard to regulate the delivery.2 One of the
goals of nanomedicine is to improve liposome-based formulations
by developing strategies to trigger drug release with spatiotemporal
control.3 The literature on triggered release liposomes includes
systems that leak their encapsulated aqueous contents upon
changes in local environmental factors such as temperature,4
pH,5 light,6 and ultrasound.7 There are also liposome systems
that become leaky after selective chemical bond cleavage.8
Althoughmany chemicals are known to disrupt bilayermembranes,
the concept of selective non-covalent triggered release from lipo-
somes is surprisingly underdeveloped.9 A likely reason for this
situation is the challenge to find a liposome composition that can be
selectively lysed by an exogenously added chemical that otherwise
has little affinity for the host cell membranes. Previously, we have
reported that zinc(II)-dipicolylamine (ZnDPA) coordination com-
plexes have a remarkable ability to selectively associate with anionic
bilayer membranes and not associate with zwitterionic membranes
that are characteristic of healthy mammalian cells.10 We have
utilized this membrane selectivity to develop in vivo imaging probes
that target localized populations of anionic cells, such as apoptotic
mammalian cells or bacteria, within living animal models.11 Here,
we propose a new application using ZnDPA complexes; that is, a
novel method of non-covalent triggered drug delivery (Scheme 1).
We envision a two-step dosing strategy. The mammalian subject is
treated intravenously first with appropriately functionalized,
anionic liposomes that are filled with drugs. After time to allow
liposome accumulation at the site of disease, a subsequent dose of
ZnDPA complex targets the liposomes and induces leakage of the
encapsulated drugs. A strategic advantage with this method of
triggered liposome release is that it does not require any
knowledge of the anatomical location of the site of disease.
Herein, we describe in vitro liposome studies that demonstrate
proof of the general concept.
The liposomes used in this study incorporated different ratios
of three polar lipids, phosphatidylcholine (PC, zwitterionic head
group), cholesterol (uncharged head group), and phosphatidyl-
serine (PS, anionic head group). PS was chosen as the anionic
target phospholipid for several reasons. It is typically the most
common anionic phospholipid in the plasma membrane of
healthy cells (5–15% of total phospholipid),12 but it is sequestered
almost exclusively in the inner leaflet of the plasma membrane
and not available for targeting by a hypothetical intravenous dose
of ZnDPA complex 1. In comparison, a perfused disease-site
containing a population of exogenous, PS-rich liposomes is expected
to be a distinctive and biocompatible binding target for 1.
Furthermore, it is known that association of metal cations or
Scheme 1 Triggered release from liposomes.
Department of Chemistry and Biochemistry, 236 Nieuwland ScienceHall, University of Notre Dame, Notre Dame, IN, USA.E-mail: [email protected]; Tel: +1 574-631-8632w Electronic supplementary information (ESI) available: methods andspectral data. See DOI: 10.1039/c2cc32962j
ChemComm Dynamic Article Links
www.rsc.org/chemcomm COMMUNICATION
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2JView Online / Journal Homepage / Table of Contents for this issue
1 (a) P. Milla, F. Dosio and L. Cattel, Curr. Drug Metab., 2012,13, 105; (b) J. Szebeni, F. Muggia, A. Gabizon and Y. Barenholz,Adv. Drug Delivery Rev., 2011, 63, 1020.
2 Y. Malam, M. Loizidou and A. M. Seifalian, Trends Pharmacol.Sci., 2009, 30, 592.
3 (a) A. M. Alaouie and S. Sofou, J. Biomed. Nanotechnol., 2008,4, 234; (b) D. C. Drummond, C. O. Noble, M. E. Hayes, J. W. Parkand D. B. Kirpotin, J. Pharm. Sci., 2008, 97, 4696; (c) L. H. Lindnerand M. Hossman, Curr. Opin. Drug Discovery Dev., 2010, 13, 113.
4 L. Li, T. L. M. ten Hagen, D. Schipper, T. M. Wijnberg, G. C. vanRhoon, A. M. M. Eggermont, L. H. Lindner and G. A. Koning,J. Controlled Release, 2010, 143, 274.
5 E. Torres, F. Mainini, R. Napolitano, F. Fedeli, R. Cavalli,S. Aime and E. Terreno, J. Controlled Release, 2011, 154, 196.
6 (a) J. A. Zasadzinski, B. Wong, N. Forbes, G. Braun and G. Wu,Curr. Opin. Colloid Interface Sci., 2011, 16, 203; (b) G. Qin, Z. Li,R. Xia, F. Li, B. E. O’Neill, J. T. Goodwin, H. A. Khant, W. Chiuand K. C. Li, Nanotechnology, 2011, 22, 155605.
7 (a) A. L. Klibanov, T. I. Shevchenko, B. I. Raju, R. Seip andC. T. Chin, J. Controlled Release, 2010, 148, 13; (b) B. Geers,I. Lentacker, N. N. Sanders, J. Demeester, S. Meairs and S. C. DeSmedt, J. Controlled Release, 2011, 152, 249.
8 (a) T. L. Andresen, D. H. Thompson and T. Kaasgaard,Mol. Membr.Biol., 2010, 27, 353; (b) X. Li and Y. Zhao, Langmuir, 2012, 28, 4152;(c) B. Goldenbogen, N. Brodersen, A. Gramatica, M. Loew,J. Liebscher, A. Herrmann, H. Egger, B. Budde and A. Arbuzova,Langmuir, 2011, 27, 10820; (d) J. Banerjee, A. J. Hanson, B. Gadam,A. I. Elegbede, S. Tobwala, B. Ganguly, A. V.Wagh,W.W.Muhonen,B. Law, J. B. Shabb, D. K. Srivastava and S. Mallik, BioconjugateChem., 2009, 20, 1332; (e) W. Ong, Y. Yang, A. C. Cruciano andR. L. McCarley, J. Am. Chem. Soc., 2008, 130, 14739; (f) B. Romberg,W. E. Hennink and G. Storm, Pharm. Res., 2007, 25, 55; (g) X. Guoand F. C. Szoka Jr., Acc. Chem. Res., 2003, 36, 335.
9 (a) D. Pornpattananangkul, L. Zhang, S. Olson, S. Aryal, M. Obonyo,K. Vecchio, C. M. Huang and L. Zhang, J. Am. Chem. Soc., 2011,133, 4132; (b) I. Cheong, X. Huang, K. Thornton, L. A. Diaz Jr. andS. Zhou, Cancer Res., 2007, 67, 9605; (c) D. Volodkin, H. Mohwald,J. C. Voegel and V. Ball, J. Controlled Release, 2007, 117, 111;(d) B. A. McNally, W. M. Leevy and B. D. Smith, Supramol. Chem.,2007, 19, 29.
10 (a) C. Lakshmi, R. G. Hanshaw and B. D. Smith, Tetrahedron, 2004,60, 11307; (b) R. G. Hanshaw, E. J. O’Neil, M. Foley,R. T. Carpenter and B. D. Smith, J. Mater. Chem., 2005, 15, 2707;(c) E. J. O’Neil and B. D. Smith, Coord. Chem. Rev., 2006, 250, 3068.
11 (a) B. A. Smith, S. Xiao, W. Wolter, J. Wheeler, M. A. Suckow andB. D. Smith, Apoptosis, 2011, 16, 722; (b) B. A. Smith, W. J. Akers,W. M. Leevy, A. J. Lampkins, S. Xiao, W. Wolter, M. A. Suckow,S. Achilefu and B. D. Smith, J. Am. Chem. Soc., 2010, 132, 67;(c) A. G. White, N. Fu, W. M. Leevy, J. J. Lee, M. A. Blasco andB. D. Smith, Bioconjugate Chem., 2010, 21, 1297; (d) W. M. Leevy,J. R. Johnson, C. Lakshmi, J. Morris, M. Marquez and B. D. Smith,Chem. Commun., 2006, 1595; (e) K. M. Divittorio, J. R. Johnson,E. Johansson, A. J. Reynolds, K. A. Jolliffe and B. D. Smith, Org.Biomol. Chem., 2006, 4, 1966.
12 J. M. Boon and B. D. Smith, Med. Res. Rev., 2002, 22, 251.13 (a) S. Ohnishi and T. Ito, Biochemistry, 1974, 13, 881; (b) G. Denisov,
S. Wanaski, P. Luan, M. Glaser and S. McLaughlin, Biophys. J.,1998, 74, 731; (c) A. J. Bradley, E. Maurer-Spurej, D. E. Brooks andD. V. Devine, Biochemistry, 1999, 38, 8112.
14 S. G. Clerc and T. E. Thompson, Biophys. J., 1995, 68, 2333.15 K. M. DiVittorio, W. M. Leevy, E. J. O’Neil, J. R. Johnson,
S. Vakulenko, J. D. Morris, K. D. Rosek, N. Serazin, S. Hilkert,S. Hurley, M.Marquez and B. D. Smith,ChemBioChem, 2008, 9, 286.
16 The glucose leakage experiment employed a standard coupled enzymeassay that consumes NADH and produces a change in absorbance.For further details, see the ESIw and also: P. R. Westmark andB. D. Smith, J. Am. Chem. Soc., 1994, 116, 9343.
17 C. Allen, N. Dos Santos, R. Gallagher, G. N. C. Chiu, Y. Shu,W. M. Li, S. A. Johnstone, A. S. Janoff, L. D. Mayer, M. S. Webband M. B. Bally, Biosci. Rep., 2002, 22, 225.
18 G. N. C. Chiu, M. B. Bally and L. D. Mayer, Biochim. Biophys.Acta, Biomembr., 2002, 1560, 37.
19 J. W. Holland, C. Hui, P. R. Cullis and T. D. Madden, Biochemistry,1996, 35, 2618.
20 (a) S. L. Veatch and S. L. Keller, Biophys. J., 2003, 85, 3074;(b) T. Baumgart, S. T. Hess and W. W. Webb, Nature, 2003,425, 821; (c) D. Y. Sasaki, Cell Biochem. Biophys., 2003, 39, 145.
21 N. Shimokawa, M. Hishida, H. Seto and K. Yoshikawa, Chem.Phys. Lett., 2010, 496, 59.