Liposome - H chuyn thuc tiờn tin cụng ngh dc phm Trn Th Hi Yn Trng i hc Dc H Ni SUM M ARY Lip o so m e s - m ic ro sc o p ic a n d n a n o sco p ic p h o s p h o lip id b u b b le s w ith a b ila y ered m em b n e stru c tu re - h a v e re ceiv ed a lo t o f a tte n tio n d u rin g th e p a s t y e a rs a s p h a rm a c e u tica l carriers o f g re a t p o te n tia l O riginal a p p ro a ch e s to im p ro v e sp e c ific ity fo r th e ta rg e t a n d to c o n tro l th e stru c tu l resp o sive n ess o f lip o so m es, d e p e n d in g o n th e ir im m e d ia te en v iro m en t, w ith th e aim o f en h a n cin g th e d e liv e re d th e p eu tic ses, a re su m m a rized T h is re v ie w a im s to d e scrib e m a jo r d ire ctio n s o f d e sig n s a n d stra teg ie s o f lip o so m es stru ctu re s o v e r re c e n t yea rs T khúa: Lip o so m e , c ụ n g n g h d c p h m K t nhng nm 60 ca th k trc, bỏc s b hng nghỡn cụng trỡnh nghiờn cu cng nh huyt hc ngi Anh A D Bangham phỏt hin cỏc bng phỏt minh liờn quan n liposome phospholipid cú kh nng hp t phỏt to thnh vũng 10 nm tr li õy Liposome cú rt nhiu hỡnh cu khộp kớn mụi trng nc thỡ thut u im, ú l: tng thớch sinh hc, cú th mang ng liposome i Cho n liposome c dc cht thõn nc khoang nc, dc nghiờn cu rt nhiu nh mt h mang thuc cụng ngh dc phm Liposome l h phõn tỏn dng nang, cu to bi mt hoc nhiu lp mng kộp ca cỏc phõn t lng tớnh phospholipid, bao quanh mt lừi cha nc (hỡnh ) Cỏc tiu phõn ny phõn tỏn pha nc vi kớch thc thay i t 20 nm n vi um Trờn th gii ó cụng cht thõn du v, l tiu phõn nht cú th mang dc cht n t bo ớch cng nh bo quan ni bo; kớch thc, in tớch, b mt cú th thay i d dng bng cỏch thờm mt s thnh phn vo v Ngy trờn th gii nhiu ch phm liposome ó c ng dng lõm sng (bng ) Phospholipid cú mch carbon 'iinh Cu to liposome Mng phospholipid kộp Liposome Dc cht Bit dc Ch nh Daunorubicin Daunosomeđ Kaposi's sarcoma Doxorubicin Lipodoxđ, Myocetđ, Doxilđ, Cealyxđ,ThermoDoxđ Ungthgan, ungthvỳ Cisplatin Lipoplatin Ungthty Amphotericin B AmBisomeđ Nhim nỏm Paclitaxel Lipusuđ Ung thvỳ, ung th phi Veteporfirin Visudyneđ Bnh mt (thoỏi húa im vng, cti th bnh lý) Thuc dựng quang tr liu (photodynamk therapy) Buvipacain Exparel Gim au tỏc dng kộo di Morphin DepoDurđ Gim au tỏc dng kộo di Cytarabin DepoCyteđ Bnh bch cỏu cp th ty, ung th mng nóo Liposome qui c (conventional liposome); l nhng liposome cu to t phospholipid (thng l phosphatidylcholine) v cholesterol Cholesterol cú tỏc dng lm vng chỏc lp v lipid, gim tớnh thm ca lp v, ú hn ch s rũ d dc cht bờn liposome ngoi, m bo n nh cho liposome iu kin bo qun Liposome qui c khụng c bin i b mt cng nh lp v nờn chỳng ch cú chc nng nang húa, bo v dc cht bờn trong, nu ng dựng l tiờm ti ch thỡ liposome cú tỏc dng gii phúng dc cht kộo di Hn na nhng liposome ny h tun hon chung d dng b opsonin húa v b bt gi bi dũng t bo bch cu nờn dc cht s trung nhiu ti gan, lỏ lỏch v ty xng Mt dng bin i ca liposome qui c cú th lit kờ õy l cu trỳc DepoFoamđ ca hóng dc phm Pacira (M) [17] DepoFoamđ bn cht l liposome nhiu khoang (MVL- Multilvesicular Liposome) cú cu trỳc t ong (hỡnh 2), giam gi dc cht bờn cỏc khoang, cu trỳc t ong ca liposome c hỡnh thnh nh thờm vo thnh phn triolein to cỏc ngó r ca mng V trớ Triolein Hỡnh Cỏu trỳc liposome nhiờu khoang DepoFoỷiv đ Liposome bin i: l nhng liposome c bin i thnh phn v hoc b mt cú nhng c tớnh mi Vớ d bin i thnh phn v liposome bng cỏch s dng cỏc loi phospholipid phospholipid kộp DepoFoamđ khụng c tiờm khỏc s nhn c nhng liposome nhy cm vi cỏc tỏc nhõn bờn ngoi nh nhit , ỏnh tnh mch vỡ kớch thc rt ln (khong vi chc sỏng, t tớnh Khi nhn cỏc kớch thớch t bờn ngoi um), tiờm ti ch cỏc cu trỳc ny s c phỏ vựng cú mt liposome, lp v lipid s bin i v dn dn v gii phúng dc cht t t Cỏc ch dn n tng tớnh thm i vi dc cht v ú phm Exparel [22], DepoDur v DepoCte u l dc cht gii phúng nhanh liposome Do nhng liposome cu trỳc DepoFoamđ cú tỏc dng vy nhng liposome ny c gi l liposome kim gii phúng kộo di dc cht bupivacain, morphin soỏt gii phúng (trigger release) Cũn bin i b mt liposome bng cỏc phõn t khỏc s c v cytarabin ti ni tiờm liposome tun hon lõu hay liposome chuyn ch ng n ớch tỏc dng Cỏc cht hay c s Lso-phospholipid l phospholipid cú cha mt uụi thõn dỏu hydrocarbon (Vớ d: mon dng lm ligand gn lờn b mt liposome opalmitoylphosphatidylcholine chuyn ch ng l nhng cht cú s lng th cm monostearoylphosphatidylcholine (receptor) ln ti mụ ớch kt hp lyso-phospholipid MPPC v MSPC vo (MPPC) (MSPC) hoc Khi mng phospholipid ca DPPC thỡ gim nhit chuyn pha t 41,9c tng ng xung 40,5c v Liposome bin i thnh phn v 41,3c, v hn 80% dc cht c gii phúng Liposome nhy cm nhit (thermo-sensitive liposome) ó c nghiờn cu t 30 nm trc t ý tng ca nh khoa hc Yatvin v cụng s [11] Gii phúng thuc liposome da trờn nguyờn tc c bn: s dng nhit nõng cao nhit xung quanh liposome lờn nhit chuyn pha gel - tinh th lng (T ), nhit vt qua T thỡ tớnh lysoliposome vũng vi giõy nhit 41 42C Trong ú liposome ch cha DPPC thỡ ch 20% DC c gii phúng liposome vũng phỳt nhit chuyn pha Ti thi im hin cụng ty Celsion Corporation (USA) ó bo ch thnh cụng thuc tiờm liposome thm ca mng tng lờn rt nhiu, ú thuc doxorubicin nhy cm nhit (ThermoDoxđ) v ang th nghim lõm sng pha III trờn bnh ung th c nang húa s gii phúng nhanh cht gan v pha II trờn bnh ung th vỳ (www.celsion mang [3] Phospholipid cú nhit chuyn pha com) ThermoDoxđ c cu to t cỏc thnh phn cao hn nhit c th mt ớt nh dipalmitoyl phosphatidylcholin (DPPC - nhit chuyn pha DPPC/MSPC/DSPE-PEG-2000 (t l mol 86/10/4) 41,4 0,5C) v dipalmitoyl phosphatidylglycerol [2];[21];[5], cũn c gi l lyso-liposome nhy cm (DPPG) c s dng bo ch liposome nhy nhit ThermoDoxđ c cụng b si m u lờn 42C thỡ ton b lng DOX c bao cm nhit Liposome nhy cm nhit khỏc liposome gii phúng nhanh chúng vũng 30 vi liposome PEG húa l khụng ph thuc vo giõy [8] ThermoDoxđ c nghiờn cu lõm sng trờn hiu ng tng tớnh thm v thi gian lu (EPR ung thgan (hepatocellular carcinoma - HCC) kt hp effect - enhance Permeability an Retention effect) Liposome nhy cm nhit c tiờm vo c th vi súng vụ tuyn (Radiofrequency ablation - RFA) lm m m ụ ớch (khi u) v th u c c nang húa liposom e lp tc c gii phúng mch mỏu ca u, to chờnh lch nng thuc ln dn n s khuch tỏn thuc t mch mỏu vo u Núi cỏch khỏc, liposome nhy cm nhit khụng ũi hi tớch ly liposome lm m u RFA tng t nh siờu õm, s dng mt u dũ t vo v trớ u Khi kớch hot súng vụ tuyn hot ng tn s 460 - 480 kHz thỡ kớch ng ion v ma sỏt nhit xy mụ xung quanh gõy cht v hoi t t bo ThermoDoxđ c nghiờn cu lõm u nh vo cỏc l hng thnh mch, m quỏ trỡnh ny ph thuc rt nhiu vo loi ung sng trờn ung th vỳ tỏi phỏt kt hp s dng vi súng (microwave) lm m u n gin húa cụng thc v tng hiu qu iu tr ca lyso-liposome nhy cm nhit , Tatsuaki th [6] Tuy nhiờn, giai on nghiờn cu ban u Tagami (2011) v cng s ó nghiờn cu bo ch ca liposome nhy cm nhit gp phi : liposome nhy cm nhit cha doxorubucin bao th nht l nhit chuyn pha tng i rng, gm cỏc thnh phn DPPC: Brij 78 (96:4, t l mol) Brij th hai l dc cht gii phúng liposome 78 l mt cht din hot khụng ion húa cú bn cht chm [7]; [10] m nguyờn nhõn l s cú mt ca l poloxyethylen stearyl ether Do ú, nú cú mt cholesterol mng liposome T ú, Needham mch cacbon gn lp phospholipid kộp ca v cng s ó a gii phỏp cho bi toỏn ny ú liposome, thay th cho vai trũ ca lyso-phospholipid, l vic kt hp lyso-phospholipid v phospholipid v nú cũn cú chui polyoxethylen (20 n v) nờn cú gn PEG vi dipalmitoylphosphatidylcholine thay th cho phospholipid cú gn PEG (DSPE- (DPPC) PEG-2000) Thuc gii phúng liposome to thnh lsoliposome [1];[4] lm m u nhanh hn ỏng k ( 100% thuc gii phúng vũng - phỳt) vi mc thm ca mng liposome gp - ln so vi ThermoDoxđ C hai cụng thc (liposome mi v ThermoDoxđ) cú bn huyt tng tng i tt (10 - 20% gii khong 630 - 820 nm, v kt qu l tng tớnh thm dc cht ca lp mng lipid kộp, gii phúng dc cht liposome [12], Cú hai loi liposome phúng 30 phỳt) nhng liposome c bo ch nhy sỏng l: liposome nhy sỏng theo c ch húa tng tớch ly ca thuc u lờn 1,4 ln so vi ThermoDoxđ Cũn so sỏnh vi Doxorubicin hc v vt lý Nhng liposome nhy sỏng theo c liposome) cha loi lipid, s b thay i di tỏc ng ca ỏnh sỏng cú bc súng nm t thỡ liposome ny tng tớch ly thuc mụ ch húa hc l-nhng liposome b phõn hy húa hc lp v lipid bng nhng phn ng xỳc tỏc ung th hn 5,2 ln v gim lng thuc n tim bi ỏnh sỏng Do ú ũi hi nghiờn cu tng hp hn 15 ln [9], nhng lipid cú tớnh cht nhy sỏng mi Thụng Liposome nhy cm pH (pH-sensitive liposome): liposome nhy cm pH c cu to t nhng thnh thng nhng liposome nhy sỏng c chiu phn nhy cm vi pH, di tỏc ng pH acid mi nhy ỏnh sỏng ph nhỡn thy v hng ni bo hoc u s gii phúng dc cht liposome Nghiờn cu liposome nhy cm pH ngoi l cn thit Cũn liposome nhy sỏng theo c ch vt lý s hp th nng lng ỏnh sỏng v l phỏt trin lipid mi hay bin i liposome bng cỏc polyme nhy pH hoc phi hp liposome nhy xy quỏ trỡnh bin i nhit hoc c hc lp v lipid ca liposome [23], pH vi liposome tun hon lõu hoc liposome chuyn ch ng [15] Cỏc liposome nhy cm pH Mt vớ d v h liposome nhy cm ỏnh sỏng theo c ch húa hc l liposome b phõn hy bng thng cha phosphatidylethanolamine (PE) nh mt phospholipid ph tr bt buc Thụng thng trờn c s phn ng quang - oxy húa plasmalogen liposome nhy cm pH c thit k b phõn hy ỏnh sỏng ph t ngoi, nờn vic tng hp lipid phn ng quang - oxy húa plasmenylcholine da khong pH - 6,3 Nhng liposome ny s gii mng sinh hc í tng ny da trờn sthay i pha trờn mng hoc tng tớnh thm ca mng phúng dc cht ni bo cng nh u phõn hy plasmenylcholine thnh cht din m pH nhng ni ny gim so vi pH ca dch hot cú mch carbon xy phn ng quang - sinh lý bỡnh thng Vớ d nh cht s dng oxy húa liờn kt vinyl - etherca plasmenylcholine liu phỏp iu tr gen (antisense oligonucleotides) (hỡnh 3) di tỏc ng ca ỏnh sỏng bc súng c chuyn vo ni bo nh phospholipid 630 - 820 nm Di tỏc ng ca ỏnh sỏng, tớnh anion nhy pH l phosphatidylethanolamine (PE), liposome ny bn huyt tng cú pH 7,4 nhng ni bo, pH gim, thỡ PE chuyn pha to lp v lng lo, tng tớnh thm dc cht [14], Hay tng s tớch ly t bo cht ca thm ca mng liposome vi dc cht tng lờn, ú tng s khuch tỏn dc cht qua mng Vai trũ quyt nh ca plasmenylcholine c dc cht nhy sỏng (photosensibilitizer) 9-acetoxytetra-n-propylporphyrence, ngi ta gn dc cht vo liposome nhy cm pH cu to bi phosphatidyl chng minh bng cỏch chiu sỏng liposome qui c cu to t phosphotidlcholine trng cú cha calcein khoang nc v liposome nhy sỏng cng cha calcein khoang nc ethanolamine v cholesteryl hemisuccinate pH Phosphatidylcholine trng cú cha nhiu acid bộo khụng no nhng khụng cú liờn kt vinyl - ether Kt 7,4 cholesteryl ester tớch in õm nhng pH v qu cho thy tc v mc gii phúng calcein mụi trng acid thỡ nú khụng tớch in na, ú liposome qui c thp hn ln so vi liposome lc y tnh in gia cỏc liposome khụng cũn, nhy cm ỏnh sỏng S tỏc ng lờn liờn kt vinyl ú cỏc liposome s kt hp vi nhau, phỏ v cu trỳc - ether ca plasmenylcholinebng phn ng oxy liposome, to thnh cu trỳc hỡnh tr di, gii phúng húa xỳc tỏc bi ỏnh sỏng bin plasm enylcholine dc cht [13], thnh cht din hot cú cha mch cacbon, ging lsolipid Do ú lm tng tớnh thm dc Liposome nhy cm ỏnh sỏng (light-sensitive ầH2< ặ ^ R ' I R-COO-CH liờn kt vinyl-ether hon ca liposome v tớnh thm cao ca thnh mch mụ ung th Liposome chuyn ch ng (active targeted liposome) Liposome chuyn ch ng c chc nng C H -O -P -O -C H H 1H ' húa b mt bng cỏc ligand m c nhn bit bi cỏc th cm (receptor) trờn b mt t bo mụ ớch (hỡnh Hỡnh Cỏu toPlasmeỡkholine B, D, E) Nhng liposome ny c nghiờn cỳu cht qua mng liposome v tc chy dc cht t khoang nc ngoi ln hn nhiu ln so vi chuyn ch ng n mụ ung th t bo ung th sn sinh rt nhiu cỏc protein, hormon, enzym nh liposome cu to t cỏc loi lipid khỏc [28], l nhng khỏng nguyờn V nhng khỏng nguyờn ny Nhng nghiờn cu v liposome nhy sỏng s s c nhn bit bi cỏc khỏng th tng ng Trờn b dng dn cht ca coumarin, mt cht nhy sỏng mt t bo ung th khụng cú cỏc khỏng nguyờn cng theo c ch húa hc cng cho kt qu gii phúng dc cht khỏ tt Liposome cu to t proteinoid nh th cm (receptor) c hiu nhng li cú cha gp nhiu ln khỏng nguyờn cng nhth cm so vi cỏc mụ ca courmarin vi cỏc acid amin Asp, Ser, Leu kt lnh Vớ d nh cỏc th cm ca cỏc yu t tng trng hp vi phosphatidylcholine trng theo t l t (folat receptor, transferrin receptor), khỏng nguyờn ung 1:100 n 20:100 (kl/kl) thỡ gii phúng dc cht bt th bo thai (cardnoembryonic antigen CEA); protein u t l 5:200 sau 30 phỳt chiu ỏnh sỏng bc trờn b mt t bo ni mụ ung th (intergrins) [26], súng 254 nm, gii phúng c 30% vũng 180 phỳt Liposome khụng c chiu sỏng thỡ Cỏc ligand s dng chuyn ch ng: khụng gii phúng dc cht [24], Liposome cha cng cho kt qu gii phúng dc cht nhanh hn Khỏng th:lmmunoliposome l tờn t cho nhng liposome c gn khỏng th lờn b mt Khỏng c chiu sỏng bc súng 254 nm so vi th n dũng Immunoglobulin ca lp IgG c s liposome khụng cha dn cht coumarin [25] dng rng rói nht vỡ nú cú th gỏn vo liposome m khụng nh hng n tớnh ton ca liposome cng nh tớnh cht ca khỏng th Imumnoglobulin c gn vo liposome bng liờn kt cng húa tr lờn phosphatidylcholine trng v 7-acetoxy coumarin Liposome bin i b mt Liposome tuõn hon lõu (long-circulating liposome, Stealth liposome) l liposome ó c bao b mt bng cỏc phõn t thõn nc nh PEG Vỡ vy liposome cú cu trỳc khụng gian cng knh nờn khụng b opsonin húa v khụng b bt gi bi t bo b mt lp v hoc bng cỏch cy mt mch cacbon vo lp v ca liposome sau khỏng th ó c bin i vi mch hydrocacbon thõn du (hỡnh 4B) Mc dự ó c gn khỏng th c hiu nhng phn bch cu, ú nhng liposome ny cú thi gian ln immunoliposome tớch ly gan bi khụng thi gian chỳng tng tỏc vi t bo v mụ lu trỳ lõu h tun hon Hn na thnh mch ớch Do ú tng hiu qu tớch iy ch ng mụ ung th cú cu trỳc ln xn v khong k gia mụ ớch immunoliposome bao gi cng kt hp vi cỏc t bo thnh mch ln hn mụ lnh ( mụ ung gn PEG b mt (immunoliposome tun hon lõu) th khong 30 - 700 nm (tựy loi ung th), mụ lnh tng thi gian lu thụng h tun hon, m khong nm) Vỡ vy, vi kớch thc nh (100 - 200 bo thi gian liposome gp c mụ ớch nm) liposome d dng xõm nhp vo mụ ung th t c hiu qu tớch ly tt hn ligand khỏng th m khụng qua c thnh mch ca mụ lnh õy c gn vo cỏnh tay ca PEG, ú ligand s c gi l hiu ng tng tớnh thm v thi gian phớa bờn ngoi rng PEG dy c [20];[29] Doxil l lu õy l c chờ' tớch ly thuc th ng (passive liposome tun hon lõu cha doxorubicin, c gn target) da trờn thi gian lu trỳ lõu h tun khỏng th n dũng 2C5 thnh immunoliposome 150 Nghiờn cu ducThng tin th u c S 4/2013 y ? mngmựngeoooc),mangwecomQCfỡnyựrocawonmanựoumrrongmpnospnoi) L:UposomeWnmnluỳ:moipolmetmnffcnmFtbnngoõi(e), nhng polyme nũy ngon cn quỏ trỡnh opsonin húo(fỡ D: imiiunolèXSome tuõn hon lõu cú khỏng th gỏn vo b mt liposome (gj hoc gỏn vo õu poớyme bo \/ (h) E: liposome thộ h m cú mt c chc nong húa bng polyme bo W (i) hoc polyme kột hp khúng th (j), gõn chút ỏnh du chn oỏn (k), cú phospholipid tớch in dng (I) v too phc vi ADN {m gỏn lipiỏ nhcm (n), gõn polmenhcm (o), gỏn protein xuờn mng (pl gn thựnlỡ phõn ca virus (q) Ngoũira lipom e cú thgn tiuphỏn mang t tớnh (rl b bỏt bi by t, hoc gỏn tiuphụn vng hoc bc 50i di kớnh hin vi in t(s) chuyn ch ng dc cht Kt qu in vivo trờn chut cho thy immunoliposome tng tớch ly dc ngy ó gn transferrin vo PEG ca liposome PEG húa liposome va tun hon lõu va cht u v lng u ch cũn 25% so vi 40 % s dng Doxil [27], chuyn n mụ ung th (solid tumor) Folat Liposome c chc nng húa b mt Kt lun vi folat c nghiờn cu nhiu bi th cm folat cú rt nhiu t bo ung th Sau nhng Nh vy liposome l giỏ mang thuc thụng nghiờn cu ban u chng minh rng cú th minh cú tim nng ng dng dc phm chuyn nhng phõn t cú lng ln v sau ú l liposome n t bo sng nh th cm chuyn thuc n tn mụ ớch cng nh t bo ớch Hng ngn cỏc nghiờn cu trờn th gii folat ni nhp bo (endocytosis) [16], Liposome c thc hin tỡm nhng dng liposome mi Daunorubicin v Doxorubicin chuyn n ớch mang cỏc c tớnh mi phự hp vi tng loi dc cht m nú chuyn Ch cn thay i thnh phn nh recceptor folat ó c chng minh c tớnh t bo tng [18];[19] Tranferin Th cm transferin cú trờn b mt ca rt nhiu t bo ung th, ú khỏng th ca transferrin cng nh chớnh transferrin l ligand ph bin cho liposome chuyn ch ng n mụ ung th cng nh t bo ung th Nhiu nghiờn cu phospholipid v lipid ca liposome cú th to cỏc liposome nhy cm vi cỏc tỏc nhõn t bờn ngoi, hay gn cỏc ligand trờn b mt liposome d dng to cỏc liposome n (liposome tun hon lõu), hay liposome chuyn ch ng TI LIU THAM KHO A nyaram bhatla GR, N eedham D (1999), "E nh an cem ent o f the phase transition perm eability o f DPPC liposom es by incorporation of M PPC: A n ew tem perature-sensitive liposom e for use w ith m ild hypertherm ia.", J Liposom es Res, (9), pp 491 - 506 Banno B , Ickenstein L.M., Chiu G.N et al (2010), 'T h e functional roles o f poly(ethylene glycol)-lipid and lysolipid in th e drug retention and release from lysolipid-containing therm osen sitive liposom es in vitro and in vivo", J P h a m Sci., (99), pp 2295 - 2308 Blok M C, van d er Neut-Kok EC, van D eenen LL et al (1975), 'T h e effect o f chain length and lipid phase transitions on th e selective perm eability properties o f liposom es", Biochim Bioph ysA cta, (406), pp 187 -1 David N eedham , Gopal A nyaram bhatla, Garheng Kong et al., (2000), "A N ew Tem perature-sensitive Liposom e for Use w ith Mild Hypertherm ia: Characterization and Testing in a Hum an Tu m or Xenograft Model", Cancer research, (60), pp 1197 -1201 5 Dromi S , Frenkel V , Luk A et al., (2007), "ulsed-high in ten sity focused ultrasound and lo w tem perature-sensitive liposom es for enhanced targeted drug d e live ry and an titu m or effect", Clin C ancer Res., (13), pp 2722 - 2727 M aeda H (2010), 'Tu m o r-se le ctive delivery o f m acrom olecular d rugs via the EPR effect: background and futu re prospects", Bioconjug Chem, (21), pp 797 -8 M aruyam a K., Unezaki S ,T akah ash i N e t al., (1993), "Enhanced delivery o f doxo rub icin to tu m or by long-circulating th erm osensitive liposom es and local hypertherm ia", Biochim Bioph ysA cta, (1149), pp 209 - 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Anticancer Res., (22), pp -2 19 Pan X Q., W ang H ,Lee R J (2003), " A ntitu m or activity o f folate receptor-targeted liposom al doxo rub icin in a KB oral carcinom a m urine xenograft m odel", Pharm Res., (20), pp 417 - 422 20 Paszko E ,Senge M.O (2012), "Im m unoliposom es ", Current M edicinal Chemistry, 19(31), pp 5239 - 5277 21 Poon R.T ,Borys N (2009), "Lyso-therm osensitive liposom al d oxo rub icin: a novel approach to enhance efficacy o f therm al ablation o f liver cancer" Expert Opin Pharm acother, (10), pp 333 - 343 22 Praveen Chahar ,K enn eth C C u m m in g s III (2012), "Liposom al bu pivacain e: a review o f a n e w b u pivacain e form ulation", Jo u rn o /o f Pain Research, 5pp 257 - 264 23 Sarah J Leung ,M arek Rom anow ski (2012), "Light-A ctivated Content Release from Liposom es ", Theranostics, 2(10), pp 1020 -1 24 Seo H J ,Kim J.C (2012), "Light-sensitive liposom es containing coum arin-proteinoid conjugate.", J N a n o sd N anotechnol., 12(5), pp 4 -5 25 Seo H J ,Kim J.C (2011), "C h ararteristics and photo-responsive release property o f liposom e containing 7-acetoxy coum arin.", J N an o sd N anotechnol, 11 (11 )pp 10262 - 70 26 Sofou Stavroula (2007), "Surface - active liposom es for targeted cancer th erap y ", Nanom edicine, 2(5), pp 711 - 724 27 Tam e A ElBa you m i, V ladim ir P Torchilin (2009), 'Tum or-Targ eted N anom edicines: Enhanced A ntitu m o r Efficacy In vivo of Doxorubicin-Loaded, Long-Circulating Liposom es M odified w ith Cancer-SpecificM onoclonal A n tib o d y, C ancer Therapy: PrecTinical, 15(6), pp -1 28 Thom pson D.H., G erasim ov O V , W heeler J J et al., (1996), 'Trig g erab le plasm alogen liposom es: im p rovem en t o f system efficiency", Biochim Biophys A a a , (1279) 29 Torchilin V P (2005), "Recent ad van ces w ith liposom es as pharm aceutical carriers ", Nature reviews, 4p p 145 -1 ... pH hoc phi hp liposome nhy xy quỏ trỡnh bin i nhit hoc c hc lp v lipid ca liposome [23], pH vi liposome tun hon lõu hoc liposome chuyn ch ng [15] Cỏc liposome nhy cm pH Mt vớ d v h liposome nhy... v 7-acetoxy coumarin Liposome bin i b mt Liposome tuõn hon lõu (long-circulating liposome, Stealth liposome) l liposome ó c bao b mt bng cỏc phõn t thõn nc nh PEG Vỡ vy liposome cú cu trỳc khụng... bờn liposome ngoi, m bo n nh cho liposome iu kin bo qun Liposome qui c khụng c bin i b mt cng nh lp v nờn chỳng ch cú chc nng nang húa, bo v dc cht bờn trong, nu ng dựng l tiờm ti ch thỡ liposome