Influence of formulation parameters of doxorubicin-poly(butyl cyanoacrylate) nanoparticles on the treatment of glioblastomas and evaluation of the body distribution of labelled nanoparticles in healthy and glioblastoma-bearing rats [Elektronische Ressource] / by Alessandra Ambruosi

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• Publié par: goethe_universitat_frankfurt_am_main
• Publié le: 01 janvier 2006
• Nombre de lectures: 13
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Inf luenc e of For mulation Par am eters of Doxo rubic in - Po ly(butyl
Cyanoa cryl ate) Nanopa rticles on the Tr eatment of Gliob lastomas and
Evaluat ion of the Body Dist ribution of Labelled Nanopa rticles in Healthy
and Gliob lastoma - Bearing Rats
A Th esis
Subm itted to th e Faculty
of
Th e Dep artment of
Pha rmac eut ical Technolo gy
at
Th e Johann W olf gan g Go eth e Univ ersity
Frankfurt am Main, Germa ny
by
Ale ssan dr a Amb ruosi
(Bari, I taly)
In Partiall Fu lfil lment of th e
Requi rem ents fo r the Degree
of
Do cto r of Philosoph y
(Pharmac eutics)
Frankfurt am Main, 2005Ai miei genitoriT able of Content s
1 Z usammenfassung......................................................................................................1
2 Introduction................................................................................................................6
2. 1 G lioblastoma mu ltiforme...............................................................................................6
2.1.1 Background6
2.1.2 Pathoph ysiology.........................................................................................................7
2.1.3 Treatment st rategies fo r brain g liomas .......................................................................7
2.2 B lood-brain bar rier9
2.2.1 Structu re of th e Blood -Brain Ba rrier..........................................................................9
2.2.2 An atom y and ph ysiology of th e cerebral capillary endoth elia ................................10
2.2.3 Trans port at th e blood -b rain barrier 13
2.2.3.1 Cell mig ration ...................................................................................................13
2.2.3.2 Passiv e diffus ion...............................................................................................13
2.2.3.3 Carrier-mediat ed efflux ....................................................................................13
2.2.3.4 Facil itated diffusion .........................................................................................13
2.2.3.5 Vesicul ar tran sport............................................................................................14
2.2.3.5.1 Recepto r-me diated tran sc ytosis (RMT ) ....................................................14
2.2.3.5.2 Abs orptive -medi ated trancytosis (AM T ) ..................................................14
2.2.3.6 Tig ht jun ction m odul ation.................................................................................15
2.3 Drug targeting...............................................................................................................16
2.3.1 Background .............................................................................................................16
2.3.2 Strat eg ies for d rug targe ting.....................................................................................16
2.3.3 Drug targeting applies to t umour ............................................................................18
2.3.4 Enhan ced permea bility and r etent ion e ffect (EPR effect )........................................19
2.4 Nanoparticles ................................................................................................................21
2.4.1 Background ..............................................................................................................21
2.4.2 Nanopa rticles as deliv ery system for CNS-targeting...............................................21
2.4.3 M ech anism of nanopa rticl es-medi ated d rug transport to th e brain .........................22
2.4.4 Pol y alkyl(butyl cyanoacr ylate) nanop articl es .........................................................24
2.5 B ody dist ribution of nan oparticles aft er i ntravenous inje ction................................26
2.5.1 Reticuloendot heli al system upt ak e...........................................................................26
2.5.2 Modifi cation of bod y distribut ion by coatin g wi th s urf actants26
2.5.3 M ech anism of th e redu ction of the RES upt ak e.......................................................27
2.6 Nanoparticles drug re lease...........................................................................................28
- I -T able of Content s
2.6.1 Background ..............................................................................................................28
2.6.2 Release M ech anisms................................................................................................28
2.6.2.1 Diffusion ..........................................................................................................29
2.6.2.2 Nanopa rticl es matrix erosion............................................................................29
2.6.2.3 Desorption of sur face-bound d rug.....................................................................29
2.6.3 Stud y of drug release in vit ro ..................................................................................29
2.7 I sotope and devi ces detecting radioactivity ...............................................................31
2.7.1 Carbon -14.................................................................................................................31
2.7.2 Liquid s cintillation c ounting....................................................................................31
3 M aterials a nd M ethods............................................................................................33
3.1 Nanoparticles33
3.1.1 M aterials ...................................................................................................................33
3.1.1.1 Chemicals ..........................................................................................................33
3.1.1.2 Instruments ........................................................................................................33
3.2 Nanoparticles pr eparation ...........................................................................................33
3.2.1 Pol y(butyl cyanoacrylate) nanopa rtic les ..................................................................33
3.2.2 Doxorubi cin pol y(butyl cyanoacrylate) nanopa rticles .............................................34
3.2.3 Diff erent formulations of doxor ubi cin pol y(butyl cyanoacr ylate) nanopa rticl es.....34
3.3 Nanoparticles cha racterization....................................................................................35
3.3.1. Size..........................................................................................................................35
3.3.1.1 Prin ciple............................................................................................................35
3.3.1.2 Equipment ........................................................................................................35
3.3.1.3 W orking p aramet ers .........................................................................................35
3.3.1.4 Size determination .............................................................................................36
3.3.2 Doxorubi cin ass ay....................................................................................................36
3.3.2.1 Prin ciple36
3.3.2.2 Equipment .........................................................................................................36
3.3.2.3 Proc edu re...........................................................................................................36
3.3.2.3.1 C alibrati on cu rve........................................................................................36
3.3.2.3.2 Sam ple pr eparation.....................................................................................36
3.3.3 D rug lo adin g.............................................................................................................37
3.3.3.1 Prin ciple............................................................................................................37
3.3.3.2 D eterminati on by sp ectr ophotometer ................................................................37
- II -T able of Content s
3.3.3.2.1 Equi pment .................................................................................................37
3.3.3.2.2. C alibrati on C urve ......................................................................................37
3.3.3.2.3 Sam ple pr eparation.....................................................................................38
3.3.4.2 Determinati on by HPLC....................................................................................39
3.3.4.2.1 Equi pment ..................................................................................................39
3.3.4.2.2 W orking pa ramet ers...................................................................................39
3.3.4.2.3 C alibrati on cu rve........................................................................................39
3.3.4.2.4 Sam ple pr eparation39
3.3.5 Yi eld (gas chromato graph y) 40
3.3.5.1 Equipment .........................................................................................................40
3.3.5.2 W orking p aramet ers..........................................................................................40
3.3.5.3 Proc edu re...........................................................................................................40
3.4