CONTRIBUTORS

MJ. Alonso, Universidad de Santiago, Laboratorio de Farmacia Galenica, 15706 Santiago de Compostella, Spain

T.M. Allen, Department of Pharmacology, University of Alberta, Edmonton, Canada T6G 2H7

1. d'Angelo, URA CNRS 1843, Faculty of Pharmacy, University of Paris-Sud XI, France

LA.1.M. Bakker-Woudenberg, Department of Clinical Microbiology, Erasmus University, Rotterdam, The Netherlands;

Y. Barenholz, Department of Biochemistry, The Hebrew University-Hadassah Medical School, P.O.B. 12272, Jerusalem 91120, Israel

G.Barratt, URA CNRS 1218, Centre d'Etudes Pharmaceutiques, Universite Paris-Sud, Chatenay-Malabry, France

C.c. Benz, Division of Hematology and Oncology, Cancer Research Institute, Department of Cellular and Molecular Pharmacology, Liposome Research Laboratory, CPMCRl, San Francisco, CA, USA

O.c. Boerman, Department of Nuclear Medicine, University Hospital, Nijmegen, The Netherlands

K.D. Caldwell, Center for Biopolymers at Interfaces, Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA

F.H.M. Corstens, Department of Nuclear Medicine, University Hospital, Nijmegen, The Netherlands

P. Couvreur,URA CNRS 1218, Faculty of Pharmacy, University of Paris-Sud XI, France

DJ.A. Crommelin, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O.Box 80.082, 3508 TB Utrecht, The Netherlands

T. Daemen, Department of Physiological Chemistry, Groningen Institute for Drug Studies,University of Groningen, Medical Sciences, Antonius Deusinglaan 1,9713 AV Groningen, The Netherlands

289

E. Dellacherie, Laboratoire de Chimie Physique Macromoleculaire, ENSIC, 1, Rue Grandville bp 451, Nancy 54001, France

D. Desmaele, URA CNRS 1843, Faculty of Pharmacy, University of Paris-Sud XI, France

J.-P. Devissaguet, URA CNRS 1218, Centre d'Etudes Pharmaceutiques, Universite Paris-Sud, Chatenay-Malabry, France

R. Duncan, Centre for Polymer Therapeutics, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WCIN lAX, UK

E. Estey, Department of Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

E. Fattal, URA CNRS 1218, Faculty of Pharmacy, University of Paris-Sud XI, France

A. Fernandes, Centro de Tecnologia Farmaceutica, Inst Superior de Ciencias da Saude - Sul, Quinta da Granja, Travessa da Granja, 2825 Monte da Caparica, Portugal

P. Ferruti, Dipartimento di Chimica Organica e Industriale, Universita di Milano, Via Venezian 21,20133 Milano, Italy

A. Gabizon, Department of Oncology, Hadassah Hebrew University, Hospital, Jerusalem, Israel

J. Gittelman, SEQUUS Pharmaceuticals, Inc., 960 Hamilton Court, Menlo Park, California 94025, USA

S. Gordon, Sir William Dunn School of Pathology, University of Oxfor, South Parks Road, Oxford OXI 3RE, UK

D. Goren, Department of Oncology, Hadassah Hebrew University, Hospital, Jerusalem, Israel

R. Gref, Laboratoire de Chimie Physique Macromoleculaire, ENSIC, 1, Rue Grandville bp 451, Nancy 54001, France

G. Gregoriadis, Centre for Drug Delivery Research, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WCIN lAX, UK

C.B. Hansen, Department of Pharmacology, University of Alberta, Edmonton, Canada T6G 2H7

J.A. Harding, SEQUUS Pharmaceuticals, Inc., 960 Hamilton Court, Menlo Park, California 94025, USA

D. Hirsch-Lerner, Department of Biochemistry, The Hebrew University-Hadassah Medical School, PO Box 12272, Jerusalem, Israel;

K. Hong, Department of Cellular and Molecular Pharmacology, Liposome Research Laboratory, CPMCRI, San Francisco, CA, USA

290

A.T. Horowitz, Department of Oncology, Hadassah Hebrew University, Hospital, Jerusalem, Israel

J.A.A.M. Kamps, Department of Physiological Chemistry, Groningen Institute for Drug Studies,University of Groningen, Medical Sciences, Antonius Deusinglaan 1,9713 AV Groningen, The Netherlands

D. Kirpotin, Department of Cellular and Molecular Pharmacology, Liposome Research Laboratory, CPMCRI, San Francisco, CA, USA

G.A. Koning, Department of Physiological Chemistry, Groningen Institute for Drug Studies,University of Groningen, Medical Sciences, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands

K. Kostarelos, Farmeco Co., 32 Ag. Glykerias Str., Galatsi 11146, Athens, Greece

J. Kreuter, Institut fur Pharmazeutische Technologie, Biozentrum, J. W. Goethe-Universitat, D-60439 Frankfurt, Germany

R. Krishna, Department of Advanced Therapeutics, BC Cancer Agency, 600 West lOA venue, Vancouver, BC, V5Z 4E6, Canada

D. Labarre, URA CNRS 1218, Centre d'Etudes Pharmaceutiques, Universite Paris-Sud, Chatenay-Malabry, France

D. Lopes de Menezes, Department of Pharmacology, University of Alberta, Edmonton, AB, Canada T6G 2H7

G. Lopez-Berestein, Imrnunobiology and Drug Carriers Section, Department of Bioimrnunotherapy and Department of Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

M. Luck, Department of Pharmacy, Biopharmacy and Biotechnology, Freie University of Berlin, 12169 Berlin, Germany

M. Mital, Centre for Drug Delivery Research, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N lAX, UK

L.D. Mayer, Department of Advanced Therapeutics, BC Cancer Agency, 600 West 10 Avenue, Vancouver, BC, V5Z 4E6, Canada

B. McCormack, Centre for Drug Delivery Research, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WCIN lAX, UK

K. Mehta, Imrnunobiology and Drug Carriers Section, Department of Bioimmunotherapy and Department of Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

O. Meyer, Department of Cellular and Molecular Pharmacology, Liposome Research Laboratory, CPMCRI, San Francisco, CA, USA

291

E.H. Moase, Department of Ph anna co logy, University of Alberta, Edmonton, Canada T6G 2H7

S.M. Moghimi, Department ofPhannacy, University of Brighton, Brighton BN2 4GJ, UK

N. Mullah, SEQUUS Pharmaceuticals, Inc., 960 Hamilton Court, Menlo Park, California 94025, USA

R.H. Milller, Department of Pharmacy, Biopharmacy and Biotechnology, Freie University of Berlin, 12169 Berlin, Germany

W.J.G. Oyen, Dept of Nuclear Medicine, University Hospital, Nijmegen, The Netherlands

D. Papahadjopoulos, Department of Cellular and Molecular Phannacology, Liposome Research Laboratory, CPMCRI, San Francisco, CA, USA

lW. Park, Division of Hematology/Oncology, Cancer Research Inst, Department of Cellular and Molecular Phannacology, Liposome Research Laboratory, CPMCRI, San Francisco, CA, USA

C. Passirani, URA CNRS 1218, Centre d'Etudes Phannaceutiques, Universite Paris-Sud, Chatenay-Malabry, France

M.T. Peracchia,URA CNRS 1218, Faculty ofPhannacy, University of Paris-Sud XI, France

W.T. Phillips, Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284, USA

A. Priev, Department of Biochemistry, The Hebrew University-Hadassah Medical School, P.O.B. 12272, Jerusalem 91120, Israel

M.M. Qazen, SEQUUS Pharmaceuticals, Inc., 960 Hamilton Court, Menlo Park, California 94025, USA

P. Quellec, Laboratoire de Chimie Physique Macromoleculaire, ENSIC, 1, Rue Grandville bp 451, Nancy 54001, France

S. Richardson, Centre for Polymer Therapeutics, The School ofPhannacy, University of London, 29-39 Brunswick Square, London WC1N lAX, UK

A.M. Samuni, Department of Biochemistry, The Hebrew University-Hadassah Medical School, P.O.B. 12272, Jerusalem 91120, Israel

G.L. Scherphof, Department of Physiological Chemistry, Groningen Institute for Drug Studies,University of Groningen, Medical Sciences, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands

R.M. Schiffelers, Department of Phannaceutics, Utrecht Institute for Phannaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Y. Shao, Department of Cellular and Molecular Phannacology, Liposome Research Laboratory, CPMCRI, San Francisco, CA, USA

292

B. Sternberg, Research Institute and California Pacific Medical Center, 2340 Clay Street, San Francisco, CA 94115, USA

G. Storm, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.o.Box 80.082, 3508 TB Utrecht, The Netherlands

O. Tirosh, Department of Biochemistry, The Hebrew University-Hadassah Medical School, P.O.B. 12272, Jerusalem 91120, Israel

M. Tobio, Universidad de Santiago, Laboratorio de Farmacia Galenica, 15706 Santiago de Compostella, Spain

C. Vauthier, URA CNRS 1218, Faculty of Pharmacy, University of Paris-Sud XI, France

S. Zalipsky, SEQUUS Pharmaceuticals, Inc., 960 Hamilton Court, Menlo Park, California 94025, USA

X. Zhang, Centre for Drug Delivery Research, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WClN lAX, UK

W. Zheng, Department of Cellular and Molecular Pharmacology, Liposome Research Laboratory, CPMCRI, San Francisco, CA, USA

N.J. Zuidam, Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands

293

INDEX

Activated macrophages, 20 functions, 20

AII-trans-retinoic acid, see also retinoids, 88 Antibody-mediated targeting, 65

advantages, 65 disadvantages, 65

Artificial organs, 1 materials, suitable, I surface design, I

Artificial surfaces, I interaction with plasma proteins, I

Asparaginase, 30,198,199,200 enzyme kinetics, 200,201 polysialylated, 30 polysialylation of, 198

Azidothymidine, 255 nanoparticle-bound, 255

Catalase, 198, I 99 polysialylation of, 198,199

Cationic lipids, 169,171,178,186 composition, 169 DC-CHOL, 178,179 DDAB,Ig6 DOTAP, 171

Cationic Iiposome-DNA complexes, see also Lipoplexes, 185,186,187

hexagonal arrangements, 185 honeycomb-like structure, 185 fibrillar structures, 185 map-pin structures, 185 morphology, 187 multilayered arrays, 185 optimization, 186 pegylated, 186 pegylated, morphology of, 187,188 polymorphic structures, 185 spaghetti-like tubules, 185 stability, 185 steric stabilization, 185 strands, 185 structure, 185 transfection activity, 188, 189

Cationic liposomes, 171,172,173,174,177 electric properties, 174 elt'ctrostatic properties. 171

interaction with DNA, mechanisms of, 177 ionization, 172 stability, 172 surface potential, 172 titration curves, 173

Colloidal gold particles, 42 in liposomes, 42

Colloidal systems, 24 I limitations, 241 liposomes, 241 nanoparticles, 241 opsonization, 241

Colominic acid, see also Polysialic acids, 198,199 activation of, 199 structure, 198

Complement, 241,242 activation of, 242 alternative pathway, 241 function, 242 heparin, interaction with, 244

Complement activation, 242,243,245 alternative pathway, 243 classical pathway, 243 heparin, influence of, 245 heparin, modulation with, 242

Copolymers, 246 amphiphilic, 246 preparation of, 246

Dalargin, 256 nanoparticle-bound, 256

Dendritic cells, 19 surface receptors, 19

Dextran, 245 antibodies to, 245 composition, 245

Diagnostic imaging, 109,110,112 computed tomography, 109 with 11IIn-pentetreotide, 112 with liposomes, 109 magnetic resonance, 109 in metastatic breast cancer, 110 receptor-mediated, 112 scintigraphic nuclear, 109 targeted, 109 with technetium-99M, II 0

295

Dideoxycytidine, 255 nanoparticle-bound, 255

Doxil,82 clinical trials, 82 phannacokinetics, 82 phannacodynamics, 82 anti-tumor responses, 82

Doxorubicin, 77,78,258 cardiotoxicity, 77 liposomal formulation, 77 liposomes, entrapment in, 78 nanoparticles, bound to, 258

Doxorubicin-containing liposomes, 52 toxicity, 52,53

Drug carrier systems, 26 anatomical considerations, 27 cellular, 26 classification, 26 disposition in vivo, 26 macromolecular, 26 particulate, 26 pathological considerations, 27,28 physiological considerations, 26,27

Fibrinogen, 5,6 adsorption to surfaces, 5,6 polystyrene particles, adsorption to, 5

Ganglioside GM 1 ,242 in stealth liposomes, 242

Gentamicin, 128 in liposomes, 128

Gold particles, 265,266 lactosylated, 266 opsonization of, 265,266

Heparin, 242,243,244,245 anticoagulant activity, 244 biological activity, 244 biomaterials, grafting to, 242 composition, 244 molecular weight, 244 polymers, coupled to, 245 structure, 243 structure-activity relationship, 244 therapeutic uses, 244

Hexamethylpropylene oxine, 112 technetium-99M, complexed with, 112

High density lipoproteins, see also HDL, 36 effect on liposomal stability, 36 interaction with liposomes, 36

HIV,254 in macrophages, 254 mucosal transmission, 254

Human immunodeficiency virus, see also HIV,253

in lymphocytes, 253 in macrophages, 253

Imaging agents, 122 advantages, 122

296

disadvantages, 122 Gallium-67 citrate, 122 IIIIndium-IgG, 122 radiolabelled leukocytes, 122

Immunoliposomes,41,42,43,49,52,66,69,70,100 applications, 41 cancer therapy, barriers to, 70 in cancer treatment, 69 doxorubicin-containing, 43,44,69 hepatic endothelial cells, targeting to, 56 pegylated, 49,53,66 phannacokinetics, 43 plasma half-lives, 43 scavenger receptor-mediated targeting, 56 selective toxicity, 100 stability in vivo, 43 sterically stabilized, 41,43 in targeted drug delivery, 41

Implants, 2,3; see also Artificial surfaces biological response to, 2,3 cellular responses to, 2 colloidal gold particles in, 42 design of, 42 Fab' fragment in, 42 fibronogen, interaction with, 2,3 inflammatory response to, 2 interaction with cancer cells in vitro, 42 neutrophil attachment to, 3 opsonization of, 2 pegylated,42 polyethyleneglycol, interaction with, 3 targeting to HER2 receptor, 42

Ligand-bearing liposomes, 132 preparation, 132 in targeting, 132

Ligands, 134 pegylated liposomes, conjugated to, 134

Lipoplexes, 169,170,171,174,175,177,178,179,185 acyl chains, 175 aggregates, formation of, 179 characterization, 169,174 composition, 169 definition, 169 efficiency, 170 electrostatic properties, 171 formation, 170 in gene therapy, 169 honeycomb structure, 178 in lipofection, 170 lipofection efficiency, J 79 multilamellar structure, 178,179 polyamines, stabilization with, 185 size, effect of DNA to charge ratio on, J 78, 179 size distribution, 177 spaghetti structure, 178,179 stability, 170 sterk stabilization, 185 structure, 178 surface charge, effect of DNA on, 175 transfection, helper lipids in, 169

transfection activity, 185 transfection with, 169 vesicle size, 170 viral vectors, comparison with, 169

Liposomal doxorubicin, 78,82,103 i!iodistribution, 79,80 clinical trials, 82 against MDR, 103 pharmacokinetics in vivo, 79,80 therapeutic efficacy, 78 tumours, distribution in, 78

Liposomal retinoids, 89,91 anti-proliferative properties, 89,90 anti-tumor activity, 89 clinical studies, 91 clinical use, 89 distribution in vivo, 89 leukaemia cells, effect on, 89 pharmacokinetics in patients, 92 toxicity, 91 toxicity, reduction in, 89 retinoid resistance, circumvention of, 90,91

Liposomal stability, 36,143 homopolymers, effect of, 143 role of cholesterol, 36 role of phospholipid, 36

Liposome-based companies, 64 Liposome-coupled ligands, 65,66

antibody fragments, 65 carbohydrates, 65 chemistry,66 growth factors, 65 lipoproteins, 65 monoclonal antibodies, 65 peptides, 65 pharmacokinetics, 67 proteins, 65 vitamins, 65

Liposome-entrapped, 78,88,100,112 doxorubicin,64,78,100 epirubicin, 100 retinoids, 88 technetium-99M, 112 vincristine, 64

Liposome-entrapped drugs, 64 clinical use, approved for, 64

Liposome-entrapped gentamicin, 128 in lung infection, 128

Liposome-entrapped MDR modulators, 101 MDR-l ribozymes, 101

Liposomes, 31,35,36,37,49,62,63,64,65,66,77,99, 101,103,109,113,139,140,141,143,147,148, 149,150,152,241

acyl chain degradation, effect of PEG on, 152 bound water, assay of, 150 chemical stability, 140 clearance from blood, effect of vesicle stability

on,37 clearance from blood, effect of opsonins on, 37 in computed tomography, 113 coupling of ligands, 65

in diagnostic imaging, 109 doxorubicin-loaded, 49 drug entrapment in, 62 drug toxicity, reduction in, 77 electrostatic stabilization, 141 half-life in circulation, 37 as imaging agents, 113 interaction with block copolymers, 143-145 v-irradiation, exposure to, 147 v-irradiation, effect of freezing on, 149 ligand-mediated targeting, 64 lipid peroxidation, 147 long circulating, 35 in magnetic nuclear imaging, 113 MDR, in combination therapy against, 103,104 MDRmodulators, 101,102 MDR reversal, roles in, 99,100 oxidative damage, protection from, 147,151 passive targeting, 63 pegylated, 31,49,65 pharmacokinetics, 62 phospholipid content, assay of, 148 physical stability, 140 in scintigraphic nuclear imaging, 113 size, measurement of, 149 solute retention, 36 stability, 140,141,147 stability in plasma, 36 stabilization of, 140-142 steric stabilization, 141,143 sterically stabilized, 63,66,241 structure, optimization of, 140 tailoring of, 37,38 targeting of, 36 technetium-99M-labelled, 113 tumours, localization in, 63,64 in ultrasound contrast, 113 vesicle stability, effect on clearance, 37

Liposomes as drug carriers, 35 early work, 35 fate in vivo, 35

Liposomes in drug targeting, 62 prerequisites, 35-38, 62

Long circulating Iiposomes, 35,37,69 effect of vesicle size, 37 in cancer chemotherapy, 37 evolution of concept, 35 lipid composition, effect of, 37,38 RES avoidance, 37 targeting in vivo, 69

Long circulating nanobeads, 268 poloxamine 908-coated, 268

Macrophage function, 20 liposomes, manipulation with, 20,21

Macrophage system, 15,16 in vitro, 15,16 in vivo, 16

Macrophages, 15-20,254 activated, 18,20 alveolar, 18

297

biological function, 19 biosynthetic activity, 19 in bone marrow, 19 in dendritic cells, 16 in endocrine organs, 19 endothelial, 18 endocytic activity, 16 enveloped viruses, interaction with, 18 in epidermis, 19 function, 15 harvesting of, 16 HIV, vectors for, 254 interaction with liposomes, 20 Langerhans cells, 19 life-span, 19 lineage, 19 in liver, 19 in lymph nodes, 19 mannose receptors, 17 markers on, 18 membrane internalisation, 17 in microglia, 19 migration pathways, 18 modulation with cytokines, 16 monocytes, 16 mononuclear cell precursors, 19 opsonins, interaction with, 18 in Peyer's patches, 19 phagocytosis, mechanism of, 17,18 phagocytosis, receptor-dependent, 17 pinocytic, 17 plasma membrane receptors, 16,17 properties in vivo, 18,20 receptors, 15,16 secretory activity, 16 sinusoidal, 19 source of, 16 in spleen, 19 stromal, 19

Mannose receptor, 17 on macrophages, 17

MDR modulators, 101,102 delivery with liposomes, 101 second generation, 102

Microglia, 20 function of, 20 in tissue homeostasis, 20

Mitomycin,216 P~,bouodto,216

Mononuclear phagocyte system, see also reticuloendothelial system, 15

function, 15 interaction with liposomes, 15,16 macrophages in, 15

Multidrug resistance, 95,96,97,99; see also MDR acquired, 95 categories, 95 chemosensitized, 98 clinical significance, 96,97 definition, 95

298

inherent, 96 liposomes, a role for, 95 mechanisms, 95,96 modulators, 97 P-glycoprotein in, 95 reversal, a role for liposomes in, 99 reversing agents, 97 tumours, chemosensitization of, 98,99

Multilamellar vesicles, 36 clearance from blood, 36

Nanobeads, 264,265 poloxamine-coated, 264,265

Nanoparticle-bound dalargin, 257 analgesia effect, 257 pharmacological responses, 257

Nanoparticle-bound doxorubicin, 258,259 blood clearance, 258 brain, uptake by, 259 heart, uptake by, 258

Nanoparticles, 225,241,242,245,246,247,253,254, 255,256,257,258; see also Nanobeads, . or Nanospheres 275

amphiphilic, 245 azidothymidin bound to, 254,255 brain, targeting to, 256 characteristics, 246 dextran-coated, clearance of, 247,248 dideoxycytidine bound to, 254,255 distribution in tissues, 255 doxorubicin bound to, 258 fate in vivo, 253 fluorescent, 246,247 heparin-coated, clearance of, 247,248 hepatic uptake, 254 HIV, drug carriers for, 254 long circulating, 225 opsonin adsorption to, 225 oral administration, 255 pegylated, 225 pegylation of, 225 phagocytosis of, 254 poloxamer-184, coated with, 256 poloxamer-188, coated with, 256 poloxamer-407, coated with, 256 poly(butyl cyanoacrylate), made of, 254,255 poly(isobutylcyanoacrylate), made of, 242 poly lactic acid, made of, 242 polyoxyethylene-23-laurylether, coated with, 256 polysorbate, coated with, 256,257 preparation of, 245,246 size, determination of, 246 surfactants, coated with, 253 z-potential, 246

Non-opsonic receptors, 17 on macrophages, 17

Non-viral vectors, 185 advantages, 185 serum, instability in, 185 viral vectors, comparison with, 185

Opsonins,49,225 apolipoprotein E, 49,50 hepatocyte-specific, 49 nanoparticles, adsorption to, 225

Opsonization, 241 reduction of, 241

P AA -bound Triton-100 cell toxicity, 220 red blood cells, lysis of, 220 synthesis, 220

PAA-mitomycin conjugates, 216 antitumour activity in vivo, 217-219 cytotoxicity,216 synthesis, 217

Particles, 263 long-circulating, 263

PEG,3,276 interaction with surfaces, 3,4 multiblock polymers of, 276

PEG-coated nanospheres, 275,276,277,280,281 albumin entrapment, 281,282 cyclosporin A, encapsulation of, 276,280 effect of PEG on size, 277 hydrophobic drugs, encapsulation of, 276 lidocaine, encapsulation of, 276, 280 preparation, 275 protein adsorption, 277,278 protein adsorption, effect of PEG on, 276,278 protein entrapment, 281 size, effecrofpolymer content on, 281 size, effect of polymer type on, 281 surface composition, 275 surface optimization, 276 therapeutic applications, 275,280

PEG-peL polymers, 277 nanospheres made of, 277

PEG-PLA nanospheres, 279,282,283,284 entrapped albumin, release of, 282, 283 entrapped tetanus toxoid, release of, 284 gelatin entrapment, 283 preparation, 284 tetanus toxoid entrapment, 283,284 vaccine entrapment, 283 zeta-potential, effect of PEG on, 279,280,283

PEG-PLA polymers, 277 nanospherers made of, 277

PEG-PLGA polymers, 276 nanospheres made of, 276

PEG-polycyanoacrylate copolymer,233 characterization, 233 structure, 234 synthesis, 233

Pegylated drugs, 30 asparaginase, 30 doxorubicin, 30 interleukin-2, 30 proteins, 30

Pegylated immunoliposomes, 43,44,49,53 against.colon carcinoma, 53 anti-tumor efficacy, 44 in cancer treatment, 49

coupling techniques, 53 doxorubicin-loaded, 49 extravasation of, 45 in HER2-overexpressing breast cancers, 44 in human tumor xenografts, localization in, 43 intracellular localization, 43 intratumoural localization, 53,54 oligonucleotide delivery, 44,45 plasma half-lives, 43 plasmid delivery, 44 stability in vivo, 43

Pegylated lipids, 133 Pegylated liposomes, see also Stealth™ liposomes,

49,52,78,109,114,121,122,123,127,128, 131,132,134,147,148,152;156,157,161,163

acyl chain degradation, effect of PEG on, 152 antibiotic treatment, 127 attractive forces, 148 bilayer hydration, 163 blood pool imaging, 114 in cancer treatment, 49,78 conformational flexibility, 131 desferol, entrapment of, 122 in diagnostic imaging, 109,121 doxorubicin-containing, 49,52 freezing, effect of, 148, 149, 152 gentamicin-containing, 128 in imaging, 114 immunospecific delivery, 49 II I Indium, labelled with, 122 infection imaging, 121,123,124 inflammation imaging, 114,121 intrahepatic distribution, 50,51 y-irradiation, effect of, 148-153 ligand-bearing, 131,132 ligands coupled to, 134 ligand-coupling, method for, 132, 134-136 lipid bilayers, properties of, 161 lipid composition, 78 Iymphoscintigraphy, 114 optimal formulations, 131 oxidative damage, protection from, 147 PEG chain mobility, 131 PEG molecules, hydration number of, 156 PEG molecules, mobility of, 148 physical properties, 157-163 as platforms, 132 preparation, 132 repulsive forces, 148 scavenger receptor-mediated delivery, 49,56 stability, 147 stability, mechanism of, 148 tumour imaging, 114 technetium-99M, labelled with, 123

Pegylated nanoparticles, 225,226,232 structure, 226 synthesis, 225 synthesis from PEG-polycyanoacrylate

copolymer, 232 Pegylated nanospheres, see also PEG-coated

nanospheres,275 half-life in the circulation, 275

299

protein adsorption, effect of PEG on, 275 protein adsorption to, 275 surface properties, 275

Pegylated PACA nanoparticles, 226,228 complement consumption by, 230,231 PEG content, 227,228 preparation, 226,231 size, 226 structure, 226 synthesis, PEG effect on, 229,230

Pegylated PIBCA nanoparticles, 226,228 complement consumption by, 230,231 PEG content, 227,228 preparation, 226,231 size, 226 structure, 226 surface properties, 228 synthesis, PEG effect on, 229,230

Pegylation, 225,226 of PAC A nanoparticles, 226,227 ofPIBCA nanoparticles, 226

PLA-nanospheres, 282 entrapped albumin, release of, 282, 283

Plasma proteins, I interaction with surfaces, 1,2

Plasmids, 44 cationic liposomes, delivery with, 45 liposomes, delivery with, 44 oligonucleotides, delivery with, 44

Plasminogen, 32 in drug targeting, 32

Pluronic acid-coated particles, 6 blood clearance, 6 half-life in blood, 6 interaction with cells, 7

Pluronic acid-coated surfaces, 7 suppressed bacterial colonization,7

Pluronic acids, 4,6,8 fibrinogen adsorption, 5,6 ligand attachment, 8-10 protein adsorption, 5,6 protein repulsion, 4 surface coatings with, 4 surface protection with, 4 surfactants, 4

Pluronic-coated nanoparticles, 254 phagocytosis of, 254

Poloxamer-184, 256 nanoparticles coated with, 256

Poloxamer-188, 256 nanoparticles coated with, 256

Poloxamer-407,256 nanoparticles coated with, 256

Poloxamers, see also Pluronic acids, 4, 263,264 lipid emulsions coated with, 263 particle surface, adsorption to, 264 polymeric tri-block surfactants, 4 stoichiometries, 4

Poloxamine, 263,264 particles coated with, 263

300

particle surface, adsorption to, 264 poloxamine-908, 264

Poloxamine-coated beads, 268 fate in vivo, effect of bead size on, 268

Poloxamine-coated nanobeads, 265,269 fate in vivo, 265 fate in vivo, effect of repeated dosage on, 269 interaction with plasma proteins, 265 liver, reduced uptake by, 265 protein adsorption, 265

Poloxamine-908, 264 molecular weight, 264 polystyrene beads, adsorption to, 264 structure, 264

Poloxamine-908 coated beads, 267 lymphatic distribution, 267

Poloxamine-908 coated nanobeads, 270,271 fate in vivo, 271 liver, uptake by, 270 spleen, uptake by, 270 tissue distribution, 270,271 tissue distribution, effect of surfactants on,

271,272 Polyaikylcyanoacrylate, see alsoPACA, 225

nanoparticles made of, 225 Poly( amido-amines), see also P AA, 207,214,217,

219,221 analogues, 209-211 antitumour activity, 214 cytotoxicity, 215 degradation in aqueous media, 213,214 endocytosis, conformation changes during, 221 heparin, as carriers of, 207 in intracytoplasmic delivery, 217 maximum tolerated dose, 216 melanoma cells, toxicity to, 216 pH-responsive, 217,220 polycations, 207 as polyelectrolytes, 212,213 polymerization reaction, 208 preparation, 207,208 properties, 211,213 ,207 structure, 207 toxicity, 215 Triton X -100 bound to, 219

Poly €-caprolactone, see also PCL, 276 Polyethylene glycols, see also PEG, 3,28,78,143,

148,156,276 hydration of, 156, 159, 160 liposomes coated with, 78 liposomes, interaction with, 143 in stealth therapeutic systems, 28-30

Polyethylene oxide, see also poloxamers, 4 Polyisobutylcyanoacrylate, see also PIBCA, 226

nanoparticles made of, 226 Poly(lactic acid), see also PLA, 276 Poly(lactic-co-glycolic acid), see also PLGA, 276 Poly lactic acid particles, 242

fetuin, coated with, 242 polysialic acids, coated with, 242

Polymeric micelles, 28 polymeric drugs, 29 structure, 28

Poly(methylmethacrylate) particles, 242 dextran, coated with, 242 heparin, coated with, 242

Polymers, 143,207,245 block polymers, 143 dextran, coupled to, 245 heparin, coupled to, 245 liposomes, interaction with, 143 poly(amido-amines),207 tailored, 207

Polyoxyethy1en-23-1aury1ether, 256 nanoparticles coated with, 256

Polysialic acids, 30,193,194-196,198,204,242 antigenicity, 204 blood clearance, effect of chain length on,

196,197 blood clearance, factors influencing, 195 chain length, 194 clearance from the circulation, 194-196 colominic acid, 198 drug coupling to, 196 in drug delivery, 193,197 drug delivery systems, coupled to, 197 heteropolymers, 194 homopo1ymers, 194 hydrophilicity, 194 immunogenicity, 204 origin, 194 peptides, coupled to, 197,242 phospholipid content, 194 poly lactic acid particles, coupled to, 242 polysaccharide B, 194 polysaccharide K92, 194 proteins, coupled to, 197,242 serogroup B, 194 serogroup C, 194 in stealth therapeutic systems, 30 structure, 194

Polysialy1ated asparaginase, 200,201,202 clearance from the circulation, 202,203 enzyme activity, 202,203 enzyme kinetics, 200,201 pharmacokinetics, 202,203 stability in plasma, 201

Polysialylated catalase, 199 coupling procedure, 199 enzyme activity, 199

Polysialylated enzymes, 198,199 asparaginase, 198 catalase, 198,199

Polysialylated particles, 242 blood clearance, 242

Polysorbate-80, 256 nanoparticles coated with, 256

Polystyrene beads, 264,267 lymphatic distribution, 267 po10xamine adsorption to, 264

Protein adsorption, 9 activity, loss of, 9, JO

Receptors, IS on macrophages, 15.16

Reticulo-endothelial system, see also RES, or mononuclear phagocyte system, 15

Retinoids,87,89 clinical use, 87,88 in Iiposomes, 87 properties in vitro, 87 toxicity, 87 toxicity, mechanism of, 89

Small unilamellar vesicles, 36 clearance from blood, 36

Stealth ™ , see also sterically stabilized, 241 Stealth ™ liposomes, 29,61,63,65,67,77,78,82,142,

186; see also Pegylated Iiposomes, 148, or long circulating liposomes, 69

advantages over conventionalliposomes, 63 applications, 67 in cancer treatment, 69,82 coupling of ligands, 65 doxorubicin-containing, 69,77,78,82 drug retention by, 82,83 in drug targeting, 61 GM 1, role of, 29 morphology, 186 pegylated,29 pharmacodynamics, 82 pharmacokinetics, 63,82 surface conformations, 142,143 targeting, 82 targeting strategies, 68 therapeutic efficacy, 69 vesicle-polymer interaction, 142,143

Stealth™ therapeutic systems, 1,25,28,29,41,241 active targeting strategies, 25 approaches to, 29 as circulating microreservoirs, 32 hydrophilic surface, 241 immunoliposomes, 41 Iiposomal systems, 29 nanoparticles, 29 non-Iiposomal, 28 passive targeting strategies, 25 pegylated, 29 phosphatidylinositol, role of, 29 polysialic acids, role of, 30 polymeric micelles, 28 rationale, 25 sialic acids, role of, 29 stability,28 sterically stabilized, 4 J strategies, 1,25,28,241

Surface-adsorbed pluronic acids, 6 complex stability, 6

Surface-binding proteins, 2 albumin,2

301

fibronectin, 2 fibronogen, 2 immunoglobulin G, 2 kinetics of binding, 2 kininogen, 2

Surfactants, 253 nanoparticles coated with, 253

Surfactant-coated nanoparticles, 254

Targeting of drugs, 31,61 active, 31 with homing devices, 31 with plasminogen, 32 ligand-mediated, 61 passive, 61

302

Targeting of Iiposomes, 56 with poly-aconitylated albumin, 56,57

Targeting strategies, 27 carrier selection, 27 immunospecific, 27

Technetium-99M labelled Iiposomes, 113,123 biodistribution, 124 biodistribution, effect of size on, 123,127 in diagnostic imaging, 113,123 IgG-99M, comparison with, 123 in infection imaging, 113 in inflammation imaging, 113 in scintigraphic nuclear imaging, 113

Triton X-IOO, 219 PAA-bound,219