Phm Nh, Hong Sm, Nguyn Sn, L My

Phng php iu tr chnh

gip nhiu bnh nhn ung th ko di tui th1

Bun nnRng tcTiu chyChn nSuy ty xngRi lon huyt hcV sinhCu gtKh mingNhc uKhng th cha tr hon ton

Song, chng c nhiu tc dng ph v khng th cha tr hon ton -> thc y cc nh nghin cu ko ngng tm kim phng php mi2

Phm Hi Nh, Hong Th Sm, Nguyn Minh Sn, L Tr MyXin trn trng gii thiu

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Mt s phng php iu tr ung th mi

http://www.cancer.gov/about-cancer/treatment/types/surgery/lasers-fact-sheethttp://www.cancer.gov/about-cancer/treatment/types/surgery/photodynamic-fact-sheethttp://www.cancer.gov/about-cancer/treatment/types/surgery/hyperthermia-fact-sheet5

Cn ang th nghim

Min dch v iu tr ch l hai phng php t kt qu kh quan khi trong iu tr nhiu loi ung th6

Liu phpMIN DCH

Mt phng php cha tr khng au n v an ton.7

Liu phpMIN DCHLiu php min dch l g?Lch s pht trinBin php tc ngCc hng tip cn khi uTrin vng ca liu php min dchLiu php min dch l g?Lch s pht trinBin php tc ngCc hng tip cn khi uTrin vng ca liu php min dchTrastuzumabTrastuzumab

Trong phn ny chng ti s gii thiu v8

LCH S PHT TRINhttp://www.cancerresearch.org/our-strategy-impact/timeline-of-progress/timeline-detail

(lt)9

Hng lot pht hin v h min dch trong th k 20 l nn tng cho cc nghin cu v liu php min dch (lt)10

T nm 1997, thi ki hng thinh cua liu phap min dich m ra (lt)11

nh ngha khi qut nht, liu php min dch l . C cc c tnh trin vng: c hiu, p ng nhanh v tc dng lu bn12

X tr lm t bo ung th bin i nhanh hn. Ha tr th khng c hiu. iu tr ch tc ng ch tc ng vo 1 c ch ca TB ung th -> TB ung th bin i -> khng thuc; iu tr ch tc ng vo hormone, protein -> ko c hiu vs ch TB ung th13

Cng vi s sn sinh antigen mi,t bo T, t bo B, h thng b th cng c kch hot

Cc t bo T, t bo B tip cn antigen c kh nng bit ha thnh t bo nh

BIN PHP TC NGCh ngB ngBn chtKch thch h thng min dch ca bnh nhn t chng li khi uCc thnh phn ca h min dch c sn xut bn ngoi ri a vo c th bnh nhn chng li khi u V dVacxinCht kch thch min dchLiu php t boKhng th n dngChng bt hot phn ng min dchCytokineKh nngTo tr nh min dch -> duy tr nh hng lu bnKh nng to tr nh min dch thp hn

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CC HNG IU TR

Vc-xin

Liu php t boCht kch thch min dch

Khng th n dng

Chng bt hotphn ng min dch

Cytokine

Mt s hng iu tr chnh hin nay, ngoi ra, cn rt nhiu phng n kt hp vi cc liu php khc17

Vc-xina thnh phn v hi ca khi u vo c thKch thch h min dch to tr nh min dch

Khi u b bt hot, ch c kh nng sn sinh cht kch thch min dchPeptide t khi uOncoVAX, Reniale, GVAXKhi u b bt hot, ch c kh nng sn sinh cht kch thch min dchPeptide t khi u uChuyn trnh t m ha peptide antigen bng plasmidChuyn trnh t m ha peptide antigen bng plasmid DCs c ci bin nhn bit c hiu peptide antigenDCs c ci bin nhn bit c hiu peptide antigenChuyn trnh t m ha peptide antigen bng vector virtChuyn trnh t m ha peptide antigen bng vector virtOncophage, Stimuvax, GardasilProvengeMammaglobin-ADNA, rhPSA, VXM01Ad-sig-hMUC-1/ecdCD40L, alpha fetoprotein

C nhiu loi vc-xin:Examples: OncoVAX (vaccinogen) for colon cancer; Reniale (LipoNova) for renal cancer; GVAX for prostate cancerExamples: Oncophage for kidney cancer, melanoma and brain cancer; Stimuvax for lung cancer and breast cancer; Gardasil and Cervarix as preventive vaccines for cervical cancerExample: ProvengeExamples: Mammaglobin-A DNA vaccine for breast cancer; rhPSA for prostate cancer; human gp100 and gp75 DNA vaccine for melanoma; VXM01 for pancreatic cancer; many others for ovarian cancer, cervical cancer, liver cancer etc.Examples: Ad-sig-hMUC-1/ecdCD40L vaccine for metastatic breast cancer; alpha fetoprotein adenoviral vector vaccine for liver cancer18

Cht kch thch min dchThng l cc protein antigen qua x l, khng cn kh nng gy bnhMi ch c cht kch thch min dch Alum c chp nhn s dng trong iu tr ung th

Examples: BCG, KLH, IFA, QS21, Detox, DNP, GM-CSF19

Liu php t boT bo min dch ca ngi bnh c ci bin ngoi, ri a tr li c th

C rt nhiu ng dng, y l v d v ng dng ph bin nht hin nay anti-CD19 CAR c kh nng kch thch sn sinh t bo T, cytokine, phn ng vim.S dng vs cng th th CAR ny, ngi ta c nh vi CD3, 20

Khng th n dngLa nhng khang th c sinh ra t cac t bao min dich ging nhau.

Co ai lc lin kt vi cung mt epitope, c tnh c hiu vi antigen

ng dng trong tinh sch, iu tr ch

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Chng bt hotphn ng min dch

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ngi, tm thy 2 receptor m nhn chc nng ny l PD-1 v CTLA-4. Thuc Yervoy (Ipilimumab) thng c s dng vi ung th da23

CytokineCytokine (vi du nh IL-2 hay IFN-a) co ph ap ng min dich rng, trai ngc vi s ap ng khang nguyn c hiuCytokine khi kt hp vi thu th c hiu trn b mt t bao T se kich thich t bao T tng sinh, tip tuc san sinh ra cytokine va kich hoat hang loat cac t bao min dich khac

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Mt v d c th v ng dng ca liu php min dch

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TRASTUZUMAB

L khng th n dng c ngi ha Gip km hm s tng sinh khng kim sot ca t bo Do s biu hin qu mc receptor tng biu biu b HER2 (t bin HER2/neu) c FDA chp nhn trongiu tr ung th v, d dyL khng th n dng c ngi ha Gip km hm s tng sinh khng kim sot ca t bo Do s biu hin qu mc receptor tng biu biu b HER2 (t bin HER2/neu) c FDA chp nhn trongiu tr ung th v, d dy

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HER2HER2 cng vi HER1, HER3, HER4 l cc receptor tng trng biu b (Human Epidermal Growth Factor Receptors)

Hot ng khi c dimer ha vi receptor trong hKch thch t bo sinh trng thng qua con ng RAS-MAPK

Bt hot qu trnh cht t bo thng qua con ng mTOR

Kch thch to mch mu

N Engl J Med 2007;357:39-51.Copyright 2007 Massachusetts Medical Society.

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t bin HER2/neu

pht hin t bin ny

Hai k thut FISH (c lng DNA) v IHC (c lng protein biu hin) u c kh nng pht hin t bin ny. Song k thut FISH cho kt qu chun xc hn c

2 loi probe so snh31

nh hng ca t bin ny

Pht hin c 25-30% bnh nhn ung th vBnh nhn mang t bin ny khng th iu tr hiu qu bng cc bin php truyn thng.

C CH HOT NG CATRASTUZUMAB

Khi domain ngoi mng t bo b ct, p95 s c phospho ha

Dn n vic truyn tn hiu kch hot cc con ng (nh nu trn: tng sinh t bo, bt hot s cht t bo, tng mnh mu,)

S kt hp ca trastuzumab vi HER2 cn ngn chn s dimer ha ca n vi cc receptor cng h.

Dn n vic tn hiu kch hot cc con ng khng c truyn i.

Phn Fc (ca IgG) c kh nng thu ht cc t bo min dch.

Hot ha qu trnh c t bo ph thuc vo khng th

Trastuzumab cng c kh nng kch thch nhp bo, hn ch s lng HER2 c biu hin trn b mt t bo

Kt hp iu tr vi NK c ci bin (liu php t bo)

Ngoi ra, tng ADCC (antibody dependent cell-mediated cytotoxicity)ngi ta c th kt hp..39

Kt hp vi ha trJournal of the New Zealand Medical Association, 02-June-2006, Vol 119 No 1235

Kadcyla Trastuzumab ci bin

Nhiu phc iu tr kt hp c th nghim

Liu phpIU TR CH

Phng php cha tr c hiu cho tng bnh nhn46

Liu phpIU TR CHLiu php iu tr ch l g?Kh khn trong vic phn phi thucVt liu sinh hc nanoHng iu tr ca liu php chCarbon nanotubeLiu php iu tr ch l g?Hng iu tr ca liu php chKh khn trong vic phn phi thucVt liu sinh hc nanoCarbon nanotube

Trong phn ny chng ti s gii thiu v47

Mc tiu ca liu php iu tr ch l ph v qu trnh hnh thnh khi uCarcinogenesisbng cc loi thuc nhm vo cc b phn ca t bo v cc tn hiu cn thit cho qu trnh khi pht ung th cng nh pht trin khi u

Mt s yu t cn thit trong qu trnh pht trin khi u

Gii thch cc yu t ny: http://ozradonc.wikidot.com/rb:hallmark-self-sufficiency49

V cht c ch chng

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Bi vic a thuc n ng ch thng gp nhiu ro cn sinh hc

http://www.nature.com/nbt/journal/v33/n9/fig_tab/nbt.3330_F1.html51

Carbon Nano Tube

Trong , mng carbon thu ht c s ch ln nh tnh ng dng cao (xy dng hnh nh t bo ung th, vn chuyn thuc, t b khi u,)52

IntroductionCc vt liu sinh hc nano c pht trin nh: quantum dots, dendrimers, carbon nanotubes (CNTs), gold and silver nanoparticles, liposomes, micelles.

IntroductionHnh dng ca CNT s cho php cc vt liu i vo t bo thng qua cc phng php khc nhau, nh khuch tn th ng qua lp kp lipid, hoc endocytosis, theo CNT gn vo b mt ca t bo v sau c nhn chm bi mng t boChng c th bin i tan nhiu hn trong nc v huyt thanh, vi mc c gim i

Single Wall Carbon Nano TubeMutiple Wall Carbon Nano TubeMt lp: 0.4 -2nmNhiu lp: 1-3nm (trong); 2-100nm (ngoi)

Cu trc c bn ca Carbon Nanotubes

S dng nhiu hn bi cu trc n ginS dng trong ct b khi u

Yu u tin phi k n l cu trc c bn ca mng cacbon56

Thng dng ngun cacbon l cc hidrocacbon (CH4, C2H2) hoc kh CO v s dng ngun nng lng nhit/plasma/lazer phn ly cc phn t kh thnh phn t cc bon hot ha.

Cc nguyn t ny khuch tn xung v lng ng ln cc ht kim loi xc tc ( Fe, Ni, Co) v CNT c to thnhTng hp Carbon NanotubesPhng php lng ng pha hi ha hc (to c SWCNT v MWCNT)

Phng php phng h quang in

Hi cc-bon c to ra bng phng 1 lung h quang in gia 2 in cc lm bng cc bon v CNT t mc ln t hi cc-bon

Mt chm lazer nng lng cao lm bay hi 1 bia graphit trong l nhit 1200 C. Trong l c kh He v Ne m bo p sut v lm cht kh mang a cc bon v pha lng ng

Tia laser (ch yu to SWCNT)

Dng bnh thp khng r vi cng cao cha cc bi thp khng r. graphit tinh khit vo v thi kh Argon cho ln p sut 300kPa. Quay bnh nghin graphit trong nhiu gi.

Ch to bng nghin bi v nhit( to MWCNT)

Cht c t boCht c ch cc thnh phn cn cho pht trin khi uHunh quangAnti-sense

lm cho CNT t c hi hn, d p ng sinh hc, tng tnh tan trong nc (tun hon lu hn) cn thm...61

K thut chc nng ha Carbon Nano TubeS dng lin kt yuKhng c hiu qu trong phn phi thucS dng lin kt ha trHiu qu hn cho vic phn phi thuc nhng cng c 1 s hn ch nh trong vic chp nh

S dng .62

K thut chc nng ha Carbon Nano TubeS dng lin kt yu( non-covalent): t hiu qu khng cao trong vic vn chuyn thuc so vi dng lin kt ha tr

S dng .63

S dng lin kt ha tr ( covalent):Thng l oxi ha CNT bng cc axit mnhGn gc COOH vo b mt CNT tng kh nng tan trong nc v i lc sinh hcCc nhm chc COOH s phn ng tip hnh thnh mui nano carbon tan

K thut chc nng ha Carbon Nano Tube

S dng .64

K thut chc nng ha Carbon Nano Tube

S dng .65

CNTs trong vic phn phi thucGn thuc vi CNT bng lin kt ha tr: Cc nh nghin cu H Stanford phn phi paclitaxel bng lin kt n vi SWNCT.Palitaxel c x l vi sucsinic anhydrite, gn thm 1 gc COOH bn ngoi m khng lm thay i hot tnh. SWNCT c lk ha tr vi PEG-NH2 sau c trn vi Palataxel qua x l.V hiu qu khi nghin cu in vitro cho thy rng Palitixel-SWNCT gip c ch khi u tt hn hn

CNTs trong vic phn phi thuc

CNTs trong vic phn phi thucGn thuc vi CNT bng lin kt yu: Vic gn thuc vo CNT bng lin kt ha trc th nh hng n hot tnh ca thuc. Lin kt yu c s dng y thng l cc lin kt vt l: -, lin kt k nc, lin kt tnh in

CNTs trong vic phn phi thucGn thuc vi CNT bng lin kt yu: Tuy nhin, gn bng cc lin kt yu th s vn ti km hiu qu, c th gii phng thuc khi cha n chNghin cu v tng tc yu gia doxorubicin v SWCNT:

CNTs trong vic phn phi thuchttp://www.ncbi.nlm.nih.gov/pubmed/19760685

Ti thuc vo trong cc CNTMt CNT vi ng knh 80 nm c th ti c 5 triu phn t thucMt s chin lc ti thuc vo CNT:Phng php ng lc hc phn t: s dng lc tng tc phn t a thuc vo CNTK thut ha t: cc dung dch cha CNT c m 2 u v cc loi thuc c trn vi nhau, nh tc dng ca nhit vo p sut s to ra CNT cha thuc

Ti thuc vo trong cc CNT

S hng m v hp th ca CNTsS hng mGn ln b mt CNT nhng khng th c i lc c bit vi cc t bo m ung thCc khng th thng c s dng hng m ung th thng l IgGCc nghin cu cng cho thy rng vic gn khng th ln b mt CNT khng lm mt i tnh i lc c hiu ca khng th

S hng m v hp th ca CNTsS hp th ca CNTCn nhiu tranh ci trong vic nhp bo ca CNT, tuy nhin c 2 con ng chnh c m t: khuch tn th ng qua lp kp lipid hoc c s h tr ca nng lng nh thc bo

Di chuyn vo t bo

http://www.hindawi.com/journals/jdd/2014/670815/75

S hng m v hp th ca CNTsS hp th ca CNT

C ch chnh xc ca s hp ph CNT ph thuc vo nhiu yu t khc nhau: knh thc, hnh dng, phn tn, loi phc CNT SWCNT v MWCNT khc nhau v c ch i vo t bo

S hp th ca CNT

S hng m v hp th ca CNTs

tng ti thuc vo trong cc CNT c bt 2 u bi cc phn t c th d dng loi b trong mi trng ni bo:

Thc t quan st cho thy rng mi trg acid, doxorubicin c gii phng nhiu hn phc mang n, cn pH 5,5 th ch t 40% . Mt th nghim tng t, siRNA c gn vi CNT bng lin kt disulfide. Sau khi vo t bo ch, cc lin kt disulfide c ct ra v gii phng siRNA, qu trnh ny c h tr bi mi trng acid trong lysosomeGii phng thuc khi CNT

Gii phng thuc khi CNT

Phi sng vi tia lazer c th t chy khi u, tuy nhin c 1 s hn ch l s phn b nhit khng ng u trn khi u v c nguy c nht nh nh hng n cc t bo lnh xung quanhCc th nghim cho thy rng vic x l nhit trung gian qua cc CNT hn ch c nhng vn trn, tng hiu qu cho vic t

CNT trong ng dng t b cc t bo ung th

CNT trong ng dng t b cc t bo ung thNgoi CNT, cc ht nano t tnh cng c ng dng trong liu php nhit

CNT trong liu php genTrong liu php gen quan trng nht l a c on gen ti ng v tr. Nu s dng vector virut th c th gy vim, p ng min dch, cn nu s dng vector phi-virut nh liposome th hiu qu dc l li km hn.CNT c th s dng nh 1 vector phi virut hiu qu.

http://www.sciencedirect.com/science/article/pii/S0169409X1300237882

c tnh ca CNTKch thc ht cng nh, cng lm tng din tch tip xc, tc l cng tng din tch vng tng tc ha hc , tng tnh c

B mt CNT d b nhim bn bi kim loi, cacbon v nh hnh. Nh 1 nghin cu ch ra b mt CNT nhim st tng cng hot ng ca yu t phin m AP1

c tnh ca CNTDo c kch thc rt nh nn n c th d dng b pht tn vo khng kh.Cc nghin cu chng minh vic ht phi CNT gy ra triu chngnh ht phi Amiang( tn gi chung ca khong silicat): vim, so, u phi

c tnh ca CNTMt s nghin cu khc cho thy rng CNT khi c thm vo t bo in vivo lm tng hot ng ca vic cht theo chu trnh bng cch gy c cho cc t bo

c tnh ca CNThttp://www.sciencedirect.com/science/article/pii/S1383571811000647

SWCNT c tnh c cao hn MWCNT cng 1 lng

c tnh ca CNTCNT qu di s khng th b thc bo, tnh c s cao hn, chng tch t gy ra u ht.

Ti liu tham khohttp://www.thelancet.com/http://www.sciencedirect.com/https://www.google.com.vn/http://www.ncbi.nlm.nih.gov/