Triggered release of liposome contents by the divalent anion B_1tn1_1tn2H_1tn1_1tn1SH(2-) [Elektronische Ressource] : biochemical studies / von Doaa Elsayed Mohammed Osman Awad

Renate Kühn

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• Gesundheit

Informations

• Publié par: universitat_bremen
• Publié le: 01 janvier 2006
• Nombre de lectures: 39
• Langue: English
• Poids de l'ouvrage: 14 Mo

Extrait

Triggered release of liposome contents
by the divalent anion B H SH(2-):12 11
Biochemical studies
Dissertation
zur Erlangung des Doktorgrades der Naturwissenschaften
- Dr. rer. nat. -
vorgelegt dem Promotionsausschuss
des Fachbereichs 2 (Biologie/Chemie) der Universität Bremen
von
Doaa Elsayed Mohammed Osman Awad
Universität Bremen 2006Tag des öffentlichen Kolloqiums
05.12.2006
Gutachter der Dissertation
1. Gutachter: Prof. Dr. Detlef Gabel
2. Gutachter: Prof. Dr. Mathias WinterhalterAcknowledgements
My deepest gratitude goes to my supervisor Prof. Detlef Gabel for his help and
support. The long discussions with him have made great impact on me.
I am grateful to Prof. Mathias Winterhalter, Prof. Manfred Radmacher and Dr. Monika
Fritz for reviewing the thesis.
I wish to express my gratitude to Renate and Ulfert Alberts who took me under their
wings on my arrival at Bremen.
My parents are warmly thanked. Without their support, this work would have been
much harder.
It has been a great pleasure to work with the whole working group. They are all great
people. I thank all of them.
iList of abbreviations
APr Acryloylpyrrolidine
B-6-14 S-(N,N-(2-dimyristoyloxyethyl)-acetamido)-thioundecahydro-
closo-dodecaborate
B-6-16 S-(N,N-(2-dipalmitoyloxyethyl
closo-dodecaborate
BChl Bacteriochlorophyll
BNCT Boron neutron capture therapy
BSH Mercaptoundecahydrododecaborate (Na B H SH)2 12 11
CPP cell-penetrating peptide
Cryo-TEM Cryo-transmission electron microscopy
DSC Differential scanning calorimetry
DHC Dihydrocholesterol
DLPC Dilauroylphosphatidylcholine
DMPC Dimyristoylphosphatidylcholine
DODAB Dioctadecyldimethylammonium bromide
DOPC Dioleoylphosphatidylcholine
DOPE Dioleoylphosphatidylethanolamine
1,2-di-O-SPC 1,2-di-O-stearoylphosphocholine
DPPC Dipalmitoylphosphatidylcholine
DPPE Dipalmitoylphosphatidylethanolamine
DPP1sCho Diplasmenylcholine
ECM Extracellular matrix
EGF Epidermal growth factor
FA Folic acid
FR Folate receptor
FRET Fluorescence resonance energy transfer
FTL folate-targeted liposome
GdDTPA Gadolinium diethyltriamine penta-acetic acid
H Inverted hexagonal phaseII
HA Hyaluronic acid
HAL Hyaluronic acid-modified liposome
iiILA Interlamellar attachment
ITC Isothermal titration calorimetry
L Lamellar phaseα
LCST Lower critical solution temperature
LysoPPC Palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine
MMCA Macromolecular contrast agent
MPPC Monopalmitoylphosphatidylcholine
NIPAM N-isopropylacrylamide
NTL Nontargeted liposome
PA Palmitic acid
PC Phosphatidylcholine
PLA Phospholipase A2 2
PE Phosphatidylethanolamine
PS Phosphatidylserine
PEG Poly-(ethylene glycol)
Q Cubic phaseII
TAT trans-activating transcriptional activator
TMC Transmonolayer contact
WSA Water soluble acridine
iii1. INTRODUCTION .................................................................................................... 1
1.1. Boron neutron capture therapy (BNCT).......................................................................................1
1.2. Mercaptoundecahydrododecaborate (BSH: Na B H SH) ........................................................ 22 12 11
1.2.1. Administration of BSH 2
1.2.2. Binding and distribution of BSH in tumor tissue 3
1.2.3. Interaction of BSH with phosphatidylcholine 4
1.2.4. Pharmacokinetics of BSH 5
1.3. Liposomes....................................................................................................................................... 6
1.3.1. Phospholipids 6
1.3.2. Preparation of liposomes 8
1.3.3. Physical properties of lipid-bilayer membranes 9
1.3.3.1. Geometric packing constraints in egg phosphatidylcholine vesicles............................. 9
1.3.3.2. Induction of fusion in phospholipid membranes .......................................................... 10
1.3.3.2.1. Stalk mechanism of membrane fusion ....................................................................... 12
1.3.3.2.2. The modified stalk theory of membrane fusion and inverted phase formation .......... 13
1.3.3.3. Phase behavior of lipid bilayers................................................................................... 15
1.3.4. Liposomal drug formulations 16
1.3.5. Steric stabilization of liposomes 16
1.3.6. Accumulation of liposomes in tumors (The concept of enhanced permeability and retention
EPR) 21
1.3.6.1. Tumor vascular permeability, accumulation and penetration of macromolecular drug
carriers ......................................................................................................................... 21
1.3.6.2. Characterizing extravascular fluid transport of macromolecules in the tumor
interstitium....................................................................................................................22
1.3.7. Liposome-encapsulated doxorubicin 23
1.3.8. Targeted delivery of liposomes 27
1.3.8.1. Development of epidermal growth factor-conjugated liposomes................................. 27
1.3.8.2. Folate-targeted liposomes ........................................................................................... 28
1.3.8.3. Liposomes targeted to CD44 receptors....................................................................... 28
1.3.8.4. Antibody targeting of liposomes (immunoliposomes).................................................. 29
1.3.8.5. Translocation of liposomes into cancer cells by cell-penetrating peptides.................. 29
1.3.9. Liposome cell interactions 30
1.3.10. Liposome content release 30
1.3.11. Distribution and uptake of liposomal doxorubicin 31
1.3.12. Penetration of doxorubicin into solid tumors 31
1.3.13. Triggered release of liposomal contents 32
1.3.13.1. Influence of liposomes composition on drug release characteristics .......................... 32
iv1.3.13.2. Drug release from temperature-sensitive liposomes................................................... 33
1.3.13.3. Thermosensitive polymer-modified liposomes ............................................................ 34
1.3.13.4. The effect of pH on content release of non-pH-sensitive liposomes........................... 36
1.3.13.5. pH-sensitive liposomes................................................................................................ 36
1.3.13.6. Liposomal drug release by phospholipase A (PLA ).................................................. 372 2
2+1.3.13.7. Light-induced calcium ions (Ca ) release from diplasmenylcholine liposomes.......... 38
1.3.13.8. Mechanical disruption of liposomes (ultrasound-triggered release)............................ 38
1.3.14. Liposomes as drug delivery vehicles for boron agents 39
1.4. Experimental techniques............................................................................................................. 41
1.4.1. Differential scanning calorimetry (DSC) 41
1.4.2. Isothermal titration calorimetry (ITC) 42
1.4.3. Fluorescence resonance energy transfer (FRET) 43
1.4.4. Cryo-transmission electron microscopy (Cryo-TEM) 44
1.4.5. Assessment of cell cytotoxicity 46
2. AIM OF THE WORK............................................................................................. 48
3. RESULTS............................................................................................................. 50
3.1. Interaction of BSH with cationic liposomes (Appendix I) ........................................................ 50
3.2. Interaction of BSH with neutral liposomes prepared from DMPC (Appendix III)................... 50
3.2.1. Cryo-TEM 50
3.2.2. Effect of choline 54
3.2.3. DSC 55
3.2.4. Leakage 59
3.2.5. Lipid mixing 60
3.3. Interaction of BSH with neutral liposomes composed of DPPC (Appendix II) ...................... 61
3.4. Interaction of BSH with DPPC:DSPE-PEG (98:2 mol%) liposomes (Appendix II).................. 62
3.5. Synthesis and liposomal preparation of two dodecaborate cluster lipids for BNCT
(Appendix IV) ....................................................................................................................................... 64
4. DISCUSSION ....................................................................................................... 66
4.1. Interaction of BSH with cationic liposomes (Appendix I) ........................................................ 66
4.2. Interaction of BSH with neutral liposomes prepared from DMPC (Appendix III)................... 66
4.3. Interaction of BSH wifrom DPPC (Appendix II) .................... 68
v4.4. Interaction of BSH with DPPC:DSPE-PEG (98:2 mol%) liposomes (Appendix II).................. 69
5. CONCLUSIONS AND OUTLOOK ....................................................................... 70
6. SUMMARY........................................................................................................... 71
6.1. Interaction of BSH with various liposomal formulations ......................................................... 71
6.2. Synthesis and liposomal preparation of two dodecaborate cluster lipids for BNCT............ 71
7. ZUSAMMENFASSUNG ....................................................................................... 73
7.1. Wechselwirkung von BSH mit verschiedenen Liposomen...................................................... 73
7.2. Synthese und Liposomenpräparati