Bài Nghiên Cứu Về Thuốc Điều Trị Ung Thư Vú POLYCEFIN

7/23/2019 Bi Nghin Cu V Thuc iu Tr Ung Th V POLYCEFIN

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MC LC

1. TNH HNH UNG TH V HIN NAY ....................................................................... 1

2. NGUYN NHN UNG TH V................................................................................... 2

3. THUC IU TRCHO UNG TH V ...................................................................... 4

3.1. Thuc iu trhin nay ............................................................................................. 4

3.2. Thuc thng minh Polycefin iu trung th v................................................... 4

4. QUY TRNH TNG HP THUC THNG MINH POLYCEFIN7........................ 6

4.1. Chun bha cht ..................................................................................................... 6

4.2. Quy trnh tng hp .................................................................................................... 7

5. NH GI HIU QUCA THUC....................................................................... 135.1. Xc nh kch thc ca cc mu PMLA mang cc gc thuc khc nhau9....... 13

5.2. Thnghim in vitro................................................................................................. 13

5.2.1. Dng tbo v iu kin nui cy9 ................................................................. 13

5.2.2. Sng lc khnng sng ca tbo9 ................................................................ 13

5.3. Thnghim in vivo.................................................................................................. 15

5.3.1. nh gi khnng tp trung ca thuc tbo ung th v dng tnh viHER2/neu9 ....................................................................................................................... 15

5.3.2. nh gi khnng c chspht trin tbo ung th ca thuc trnchut9 17

TI LIU THAM KHO


2/19

NGHIN CU TNG HP V THNGHIM HOT

TNH POLYCEFIN, THUC IU TRUNG TH V

C KHUNG MANG THUC NANOBIOPOLYMER,POLYMALIC ACID

1.

TNH HNH UNG TH V HIN NAY

Theo GS Phm Thy Lin, nguyn Gim c BV Ung th Quc gia, ung th

Vit Nam giy phbin n mc hu nh bt cai tthnh thn nng thn, nukhng phi l bn thn mnh, u c t nht mt ngi thn hoc quen mc ung th.

Bo co chnh thc vtnh hnh mc v tvong do ung th nc ta (thng k nm

2006):mi nm nc ta c khong 150.000 ngi mc ung thv 100.000 ngi cht.

V nguy c mc cn bnh nan y ny ngy cng gia tng mnh m.

Vit nam c khong 86 triu dn, n gii chim 51%. Ung th v l mt loi

ung th ph bin nht ph n, Thnh ph H Ch Minh v H Ni l nhng ni c t

l ung th v caonht nc. C 100.000 ph n H Ni th c 30 ngi ung th v,

ti Tp.HCM l 20ngi. Hng nm c thm 14.000 ph n b ung th v.

Hnh 1. Tlngii cht do ung th M, nm 2010.
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2. NGUYN NHN UNG TH V

Vphng din sinh hc, ung th v c nhng nguyn nhn chnh l: cc vn

do hoocmon (cthl estrogen),v cc vn lin quan n gen HER-2/neu. Cc

ri lon sinh hc, t bin, hoc cc tc nhn mi trng khc lm thay i mt cch

bt bnh thng cc yu ttrn, dn n nguy c gy ung th.12

HER-2 l ththtrn mng tbo thuc nhm ththca yu ttng trng

thng b- gi l EGFR (epidermal growth factor receptor). Hin nay ththny c

quan tm nhiu trong bnhung th vv nhiu nghin cu cho thy ththny lin

quan n sinh bnh hc, cng nh din tin, tin lng v p ng iu trca bnhung

th v.2

EGFRl mtglycoproteinxuyn mng, phn nm bn trong mng t bo ca

th th ny gn vi mttyrosine kinaze.Tyrosine kinaze c hot ha khi EGF n

gn vi th th EGFR. Th th EGFR do mtgenenm trong t bo quy nh, l

mttin-gene sinh ung.S t bin, thay i trong khi hon i gene, hoc s khuch

i ca gene ny s lm thay i th th, s lng th th tng ln v c th gy gia

tng nguy cung th vt th nghim v ngi.2

Hnh 2. Cc loi HER
https://vi.wikipedia.org/wiki/Ung_th%C6%B0_v%C3%BAhttps://vi.wikipedia.org/wiki/Ung_th%C6%B0_v%C3%BAhttps://vi.wikipedia.org/wiki/Ung_th%C6%B0_v%C3%BAhttps://vi.wikipedia.org/wiki/Ung_th%C6%B0_v%C3%BAhttps://vi.wikipedia.org/wiki/Ung_th%C6%B0_v%C3%BAhttps://vi.wikipedia.org/wiki/Ung_th%C6%B0_v%C3%BAhttps://vi.wikipedia.org/w/index.php?title=Glycoprotein&action=edit&redlink=1https://vi.wikipedia.org/w/index.php?title=Glycoprotein&action=edit&redlink=1https://vi.wikipedia.org/w/index.php?title=Glycoprotein&action=edit&redlink=1https://vi.wikipedia.org/w/index.php?title=Tyrosine_kinaze&action=edit&redlink=1https://vi.wikipedia.org/w/index.php?title=Tyrosine_kinaze&action=edit&redlink=1https://vi.wikipedia.org/w/index.php?title=Tyrosine_kinaze&action=edit&redlink=1https://vi.wikipedia.org/wiki/Genhttps://vi.wikipedia.org/wiki/Genhttps://vi.wikipedia.org/wiki/Genhttps://vi.wikipedia.org/wiki/Gene_sinh_ung#Ch.E1.BB.A9c_n.C4.83ng_c.E1.BB.A7a_ti.E1.BB.81n-gene_sinh_unghttps://vi.wikipedia.org/wiki/Gene_sinh_ung#Ch.E1.BB.A9c_n.C4.83ng_c.E1.BB.A7a_ti.E1.BB.81n-gene_sinh_unghttps://vi.wikipedia.org/wiki/Gene_sinh_ung#Ch.E1.BB.A9c_n.C4.83ng_c.E1.BB.A7a_ti.E1.BB.81n-gene_sinh_unghttps://vi.wikipedia.org/wiki/Gene_sinh_ung#Ch.E1.BB.A9c_n.C4.83ng_c.E1.BB.A7a_ti.E1.BB.81n-gene_sinh_unghttps://vi.wikipedia.org/wiki/Gene_sinh_ung#Ch.E1.BB.A9c_n.C4.83ng_c.E1.BB.A7a_ti.E1.BB.81n-gene_sinh_unghttps://vi.wikipedia.org/wiki/Ung_th%C6%B0https://vi.wikipedia.org/wiki/Ung_th%C6%B0https://vi.wikipedia.org/wiki/Ung_th%C6%B0https://vi.wikipedia.org/wiki/Ung_th%C6%B0https://vi.wikipedia.org/wiki/Gene_sinh_ung#Ch.E1.BB.A9c_n.C4.83ng_c.E1.BB.A7a_ti.E1.BB.81n-gene_sinh_unghttps://vi.wikipedia.org/wiki/Genhttps://vi.wikipedia.org/w/index.php?title=Tyrosine_kinaze&action=edit&redlink=1https://vi.wikipedia.org/w/index.php?title=Glycoprotein&action=edit&redlink=1https://vi.wikipedia.org/wiki/Ung_th%C6%B0_v%C3%BAhttps://vi.wikipedia.org/wiki/Ung_th%C6%B0_v%C3%BAhttps://vi.wikipedia.org/wiki/Ung_th%C6%B0_v%C3%BA


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Cc receptor HER2 c m ha bi cc gen HER2. Cc receptor HER2 gip

iu khin qu trnh pht trin, phn chia, sa cha t bo. C khong 20-30% cc

trng hp ung th v c biu hin qu l th th HER-2(hay cn c gi lHER-

2/neu) ny trn b mt mng t bo.Vic qu nhiu ththHER-2 lm tbo phn chiamt cch nhanh chng mt cch mt kim sot, iu ny sdn n ung th.Cc th th

HER-3, HER-4 khng thng gp ung th ngi.2

Hnh 3. M tvai tr ca cc nhn tpht tr in trong nhn i tbo.


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Hnh 4. ThthHER2 bnh thng vbt thng.

3. THUC IU TRCHO UNG TH V

3.1. Thuc iu trhin nay

Hin nay, Trastuzumab khng th n dng khng HER2/neu ngi

(Humanized anti-HER2/neu monoclonal antibody (mAb) trastuzumab) cn gi l

Herceptin ang c sdng ring lhoc kt hp vi ha trliu (chemotherapy)

iu trcho nhng bnh nhn ung th v do biu hin qu mc ca HER2/neu. Chng

sgip kha bmt ca nhng ththHER2/neu, khng cho tbo khi u pht trin

thm na.3

Mc d nhng hiu qukhng ung bu ng kca Herceptin, chng li gy

ra nhiu nh hng c hi n tbo bnh thng. Hn na, nhiu bnh nhn cn cho

du hiu ln Herceptin trong mt nm iu tr. V vy nhng thhthuc mi vi cc

tnh nng nh vo mc tiu khi u cth, v khnng tp trung cao trong tbo khi

u, t tc dng phang l yu cu cp thit cho iu trung th v.4

3.2. Thuc thng minh Polycefin iu trung th v

Morpholino Antisense oligonucleotides (MORPH-AON) lin kt c trng

vi mARN v kha cc qu trnh tng hp protein, l cng chu dng cho sc ch


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gen/protein. Nhng nghin cu tin lm sng gn y ca AON iu trung th v

cho nhng kt quy ha hn, sbn vng ca AON trong huyt tng (plasma)

khin n l mt thuc tim nng.AON c chsxut hin mi ca HER2/neu, trong

khi Herceptin chc chnhng ththHER2/neu tn ti sn trn tbo, v vyAON c chsnhn i ca tbo ung th tt hn Herceptin.5

Nu nh kt hp cAON v Herceptin trn cng mt cht mang thuc, hiu qu

iu trca thuc sc tng lnng k. PMLA [poly(b-L-malic acid)] l pht hin

mi vcht mang thuc. Trn phn tca PMLA c rt nhiu nhmCOOH, c th

gn cc gc thuc cn thit y. Ngoi ra, PMLA l mt bionanopolymer, c thphn

hy sinh hc, khng c hi v khng gy knh ng min dch, bn vng trong mu v

c ha tan cao trong nc. Nhiu nghin cu cng chng minh PMLA l mt

cht mang thuc hiu qu, gip iu trbnh ung th.6

Hnh 5. Cu tr c ca PMLA.

Polycefin, l mt thuc c khung cht mang thuc l PMLA, trn kt hp c

AON v Herceptin, ngoi ra cn c mt sthnh phn khc. CthPolycefin bao gm

5 hoc 6 thnh phn cha kha chnh nh sau:7

+ PMLA l khung chnh, mang nhiu nhm carboxylic, chng c thphn hy

sinh hc hon ton to ra CO2v H2O, skhng gy hi cho c thv tbo. Ti v

trCOOH ny, c thgn lin hp cc gc thuc vi cc chc nng, vai trkhc nhau

to nn mt phn tthuc ti u nht.8

+ Morpholino antisense oligonucleotides (MORPH-AON): gip c chstng

hp mi protein HER2/neu, y l thuc chnh iu trung th v . MORPH-AON

khng li chui 4 v 1 ca protein laminin-411, y l proteinchuyn bit ca mch


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mu khi u, dn n mch mu ca khi u khng c hnh thnh nn khi u skhng

c hnh thnh v tng trng c, lm gim nguy c ung th v.9

+ Herceptin : Vai tr ging MORPH-AON, nhng Herceptin sc chshot

ng ca cc ththHER2/neu tn ti trn mng tbo bng cch skha cc b

mt hot ng ca ththHER2/neu.3

+ Transferrin receptor (TfR) monoclonal antibody(mAb): Khng thn dng

ca ththtransferrin: y l tc nhn nhm trc ch, gip PMLA i n ng tbo

ung th v. Cc mAb sgn vo cc ththreceptor transferrin c trn mng tbo

ung th v, lm thuc neo u v tp trung c tbo khi u.7

+Leucine ethyl ester (LOEt): gip vn chuyn AON trong tbo cht. Thuc

xm nhp vo tbo bng cch thc m bo, v vy sau khi vo tbo, thuc sc

bao quanh bi mng tbo. LOEt c nhim vph vmng tbo bao quanh thuc,

gip thuc gii phng ra v thc hin chc nng.7

+EG5000 (polyethylene glycol, M=5,000): tng tnh bn ca thuc trong mu.7

+Alexa Fluor 680 C2-maleimide (Invitrogen): cht nh giu quan st vtr

ca thuc.7

Hnh 6. Cc gc thuc trn khung PMLA.

4. QUY TRNH TNG HP THUC THNG MINH POLYCEFIN7

4.1. Chun bha cht


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2 mu morpholino-3-NH2 AONs iu trHER2/neu, c iu chnh bi cng c

Gen Tool.

Mu 1: 5-AGGGAGCCGCAGCTTCATGTCTGTG-3

Mu 2: 5-CATGGTGCTCACTGCGGCTCCGGC-3

+ Khng thn dng(mAb) ca ththtransferrin (CD71) c ly c ly

tChemicon International (Temecula, CA).

+-Poly(L-malic acid) (PMLA) l polymer tnhin, Mw=50000, phn tn l

1.3, c ly tdch mi trng nui cy caPhysarum polycephalum.

+ mPEG5000-amine v maleimide-PEG3400-maleimide c ly t Nektar

Therapeutics (San Carlos, CA).

+3-(2-Pyridyldithio)-propionate (PDP).

+ Fluorescein-5-maleimide c ly t Molecular Probes (Leiden, The

Netherlands).

+ Alexa Fluor 680 C2-maleimide ly tMolecular Probes-Invitrogen (Karlsruhe,

Germany).

+Endosomal marker FM 4-64 c mua t Molecular Probes.

+ V tt ccc hp cht sch v tinh khit khc c mua tMerck (Darmstadt,

Germany), SigmaAldrich (Munich, Germany), v Pierce (Rockford, IL).

4.2. Quy trnh tng hp

4.2.1.

PMLA-N-hydroxysuccinimidyl Ester (PMLA-NHS) (2)

Mc ch ca tng hp bc ny l bin cc gcOH (l nhm xut km) ti

cc gcCOOH thnh nhm dxut lNHS. Qua to iu kin gn cc gc

thuc cn thit ln PMLA.


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Mt hn hp ca 10mmol khan PMLA (1), N-hydroxysuccinimide (NHS) v

dicyclohexylcarbodiimide (DCC) c ha tan trong DMF, sau c nhit phng. Sn phm c kt ta trong ethyl acetate (P1), diethyl ether (P2), v n-hexane

(P3), sau c ha tan trong DMF, tinh chv lm sch bng sc k gel Sexphadex

LH 20,sn phm thu c bo qun nhit -20oC. .

Ester PMLA-NHS thu c c kim tra li bng cch cho phn ng hon ton

vi n-butylamine to cc NHS tdo, NHS tdo ny c kim tra bng sc k lng

pha o RP-HLPC. Sau khi kim tra xong, P3 c sdng i tng hp polycefin(v hiu sut P3 t c t50-60%).

4.2.2. (2-Pyridyldithio)propionyl Morpholino Antisense Oligonucleotides

(PDP-MORPH-AONs) (6-4 v 6-1)

Mc ch ca bc ny l gn thm nhm PDB ((2-Pyridyldithio)propionyl) vo

MORPH-AON, gip MORPH-AON c thgn ln c nanopolymer mang PMLA

mt cch ddng hn.


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Morpholino-3-NH2 oligonucleotide c ghp cp vi N-succinimidyl-3-(2-

pyridyldithio)-propionate (SPDP) trong dung mi DMF 10%.(lng SPDP vt gp hai

ln MORPH-AONs, 20oC).

Phng trnh: MORPH-AONs + SPDP PDP-MORPH-AONs

Sn phm thu c cho qua ct sc k gel microspin Sephadex G-25, vi 0.1M m

gm Na3PO4 (pH=6.5), 0.15M NaCl v 10mM EDTA (m A), sau sn phm c

lm sch bng TLC.

4.2.3. mAb-(S-succinimidyl-PEG3400-maleimide)3(4)

Mc ch bc ny l gn thm nhm cn thit ln mAb, gip mAb gn cln khung PLMA.

mAb (20-30 nmol) c khtrong sc mt ca 53 mol 2-MEA hydrochloride

(2-mercaptoethylamine hydrochloride) trong m A ( nu trn), phn ng xy ra

khong 90 pht 37oC.

Sn phm thu c c lc qua blc siu li tm Sigma Ultrafree-CL,mc ich

lc ny l loi b cc 2-MEA d tha (c thnh tnh 2-MEA bng thuc th

Ellman).


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Cc gc sulfhydryls tdo c trn sn phm trn sc phn ng vi maleimide-

PEG3400-maleimide ( lng ny gp 50 ln mAb), thu c (4), lng maleimide-

PEG3400-maleimide d tha sc loi bbng diafiltration.

4.2.4. PMLA/mPEG5000-NH2(5%)/2- MEA (10%)/Valine (49%) (3)

K hiu / biu thcho cc gc thuc gn ln PMLA.

Ester PMLA-NHS (2)hon tan trong DMF c gn theo thtvi mPEG5000-NH2, 2-MEA, v L-valine (c thdng gylcine hoc L-alanine) bng cch to cc lin

kt amide.

Phn trm(%) y chnh l phn trm m cc gc thuc lin kt so vi tng

ton bcc gcCOOH c trn mch PMLA.

Vi 1mmol PMLA-NHS (P3)lin kt c vi phn trm tng ng trn

th cn 50mol mPEG5000-NH2, 100mol of 2-MEA.

1mmol L-valine (hoc glycine, L-alanine) c gn ln PMLA trong hn hp

dung dch DMF/PBS (lng bng nhau), trong 1h v 20oC

Lu l sn phm thu c khng xut hin kt ta.

Sn phm c chuyn vo hm A ( nu trn), sau c lm sch trong

ct sc k gel Sephadex G25

4.2.6. Tng hp Dye-Polycefin (7)


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(4) c thm vo tng git to lin kt vi (3), pha trong hm A, 4oC.

Nhmthiol (3) phi nhiu gp 50 ln snhm maleimido c (4).

Tip , cho 2.5 mol of fluorescein-5-maleimide (hay Alexa Fluor 680 C2-

maleimide) (5), 5 mol of PDP-MORPH-AON1 (6-4), v 5 mol of PDP-Morph-

AON2 (6-1) vo (3) qua m phn ng ghp cp xy ra.

Cc nhm sulfhydryl t do khng phn ng s c kha li bng 3-(2-

pyridyldithio)propionate (PDP).

Vic gn Herceptin cng thc hin tng tnh i vi mAb.


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Hnh 7. Ton bquy t rnh tng hp Polycefin


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5. NH GI HIU QUCA THUC

5.1. Xc nh kch thc ca cc mu PMLA mang cc gc thuc khc nhau9

Bng cch sdng hthng nano Zetasizer ZS90 (Malvern Instruments) o

kch thc ca cc PMLA c gn cc gc thuc, nhm chc khc nhau. Cc thng s

vkch thc thu c cho thy thuc c kch thc dng nano.

Ngoi ra cng c tho kch thc ca cc nano thuc ny bng knh hin vi

in tTEM, SEM.

Bng 1. Kch thc cc PM LA mang cc gc thuc khc nhau .

Sau khi tng hp c Dye-Polycefin l nanopolymer PLMA c gn cc gc

thuc ln, tin hnh i kim tra hiu quca thuc ctrong in vitro v in vivo

5.2.

Thnghim in vitro5.2.1. Dng tbo v iu kin nui cy9

Cc dng tbo ung th v ngi c thnghim l BT-474, SKBR-3,

MDA-MB-231, MDA-MB-435, MDA-MB-468 v MCF-7.

BT-474, MDA-MB-231, MDA-MB-435, MDA-MB-468 v MCF-7 c nui

trong DMEM vi 10% FBS v thuc khng sinh.

SKBR-3 c nui cy trong mi trng trung tnh 5A ca McCoy vi 10%

FBS v thuc khng sinh.

5.2.2. Sng lc khnng sng ca tbo9

BT-474, SKBR-3, MDA-MB-231, MDA-MB-435 c cho vo a 6 ging

(3x105tbo trn mt ging).

Ngy tip theo, cc tbo c xl vi :


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+ PBS (mu control), hoc Endoporter (4mmol/L; mucontrol),

+ Herceptin (40mg/mL),

+ P/mPEG/LOEt/Herceptin (40mg/mL),

+ Endoporter (4mmol/L) thm AON (4mmol/L),

+ P/mPEG/LOEt/AON/TfR (40mg/mL)

+ P/mPEG/LOEt/AON/Herceptin/TfR (40mg/mL)

Sau 72h, em nhum mu tbo bng xanh trypan (trypan blue) v m cc t

bo cn sng.

Hnh 8. Khnng sng ca tbo ng vi cc PMLA khc nhau.

Kt quthu c c ththy khi khung PMLA c mang cHerceptin v AON

cho hiu quc chspht trin ca cc dng tbo ung th cao nht. iu chng


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t rng, so vi cc loi thuc hin ti, vic kt hp cHerceptin v AON trn mt

nanopolymer mang PMLA to ra c thuc chng ung th v dng tnh vi

HER2/neu rt hu hiu.

5.3.

Thnghim in vivo

5.3.1. nhgi khnng tp trung ca thuc tbo ung th v dng tnh

vi HER2/neu9

Hnh 9. Khnng tp trung ca cc PMLA trong cc c quan ca chut.

Cc nhn nh du Alexa Fluor 680 gn trn PMLA gip quan st c ng

i ca thuc cng nh khu vc m thuc tp trung.

Thnghim c tin hnh sau khi chut c tim thuc 24h. C ththy, vi

P/mPEG/LOEt/IgG (mu thuc i chng), sau 24h tim chng tp trung chyu gan

v thn, cn khi u, lng thuc tp trung y rt thp. P/mPEG/LOEt/Herceptin


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(c Herceptin), sau 24h thuc cng c tp trung cc khi u, nhng vi slng cng

cn rt nh. Cn vi hP/mPEG/LOEt/AON/Herceptin/TfR lng thuc tp trung

khi u tng ln rt nhiu.

Sdng knh hin vi cng tiu (confocal microscopy) quan st k hnmc

tp trung ca thuc tbo khi u sau 24h tim thuc. Mu l mu ca Alexa

Fluor 680 quan st di knh hin vi. C th thy rng, vi h

P/mPEG/LOEt/AON/Herceptin/TfR mt mu rt nhiu, chng trng slng

thuc tp trung khi u tng ln.

Hnh 10. Khnng tp trung thuc khi u ng vi cc PMLA khc nhau.


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Vic tng ln ny l do thuc c gn thm gcTfR mAb, y l tc nhn dn

thuc n ch. V vy vi cc thhthuc thng minh, tc nhn dn thuc n ch

ng mt vai tr quan trng n hiu quca thuc.

5.3.2.

nh gi khnng c chspht trin tbo ung th ca thuc trn

chut9

Hnh 11. Kch thc khi u chut ng vi cc PM LA khc nhau.

Hnh 12. Biu kch thc khi u theo thi gian iu trbng cc PM LA khc nhau.


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Thnh (A) v (B) cho thy, vi hP/mPEG/LOEt/AON/Herceptin/TfR lm

gim kch thuc khi u mt cch ng ktcc ngy iu trtip theo. Chnh do skt

hp gia AON v Herceptin tng hiu quca thuc (hiu quhip ng).

TI LIU THAM KHO

1. Jeffrey S. Rossa, J. A. F., Gerald P. Linetteb, James Stec, Edward Clark, Mark Ayers, W. Fraser

Symmans, Lajos Pusztaie and Kenneth J. Bloom, The HER-2/neu Gene and Protein in Breast Cancer

2003: Biomarker and Target of Therapy. The Oncologist February 5, 2003,8(4), 307-325.

2. Ross, J. S.; Fletcher, J. A., The HER-2/neu Oncogene in Breast Cancer: Prognostic Factor,

Predictive Factor, and Target for Therapy. STEM CELLS 1998,16(6), 413-428.

3. Keefe, D. L., Trastuzumab-associated cardiotoxicity. Cancer 2002,95(7), 1592-1600.

4. Tseng, P.-H.; Wang, Y.-C.; Weng, S.-C.; Weng, J.-R.; Chen, C.-S.; Brueggemeier, R. W.;

Shapiro, C. L.; Chen, C.-Y.; Dunn, S. E.; Pollak, M., Overcoming trastuzumab resistance in HER2-

overexpressing breast cancer cells by using a novel celecoxib-derived phosphoinositide-dependent

kinase-1 inhibitor.Molecular pharmacology 2006,70(5), 1534-1541.

5. Roh, H.; Pippin, J.; Drebin, J. A., Down-regulation of HER2/neu expression induces apoptosis

in human cancer cells that overexpress HER2/neu. Cancer research 2000,60(3), 560-565.

6. Lee, B. S.; Vert, M.; Holler, E., Watersoluble Aliphatic Polyesters: Poly (malic acid) s.

Biopolymers Online 2002.

7. Lee, B.-S.; Fujita, M.; Khazenzon, N. M.; Wawrowsky, K. A.; Wachsmann-Hogiu, S.; Farkas,

D. L.; Black, K. L.; Ljubimova, J. Y.; Holler, E., Polycefin, a new prototype of a multifunctional

nanoconjugate based on poly (-L-malic acid) for drug delivery.Bioconjugate chemistry 2006,17(2),

317-326.

8. Inoue, S.; Ding, H.; Portilla-Arias, J.; Hu, J.; Konda, B.; Fujita, M.; Espinoza, A.; Suhane, S.;

Riley, M.; Gates, M., Polymalic AcidBased Nanobiopolymer Provides Efficient Systemic Breast

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Bài Nghiên Cứu Về Thuốc Điều Trị Ung Thư Vú POLYCEFIN