KHOA HQC CONG NGHE
TOIXIG OUAIM CAC PHUOIMG P H A P TOIXIG H O P IXIAIXIO CHITOSAIXI V A IJIXIG DIJIXIG TROIVG D I E U T R ! KHOI U
Nguyin Xuan Hoan^ Dinh H€ru DongS Duong Hong Qu^S Pham van Thinh^ Nguyin Thi Phugng', Hoang Thdi HaS Dang Xuan Cu6ng^, Lam lh6 Hai' T6MTAT
Nano chitosan la val lieu tir nhien dugc che tao tir chitosan co ngu6n gdc tir vo giap xac nhir cua. lorn,... va kich thiroc phan tii cua chung tir 1 toi 100 nm. Chiing co hoat tinh sinh hpc rat phong phii nhu: chM chdng oxy hoa, khang khuan, chong ung thir va h6 tro suih hoc nham tang cuong hieu qua di^u tri benh. Bai bao tap trung trinh bay phuong phap dieu che nano chitosan va iing dung chiing trong difiu tri khdi u. Nano chitosan dugc dieu che theo 5 phuong phap nhir: phuong phap lien k^t cheo; nhu tuong-giot; ion hda;
micelles dao va phuong phap sang. Chuan bi nano chitosan bang phuang phap lien ket cheo va ion hda deu dira tren sir tirong tac giiia nhdm amino tu do cua chitosan va cac polyanion, nhung khong sii dung dung rnoi de kdt tiia nano chitosan trong qua trinh ion hda. Phirong phap micelles dao la nhung hat nano chitosan trong dung moi hiiu co' va nhirng chat hoai dgng be mat. Dau ira nuoc ciia chat hoat dpng be mat lien k^t vdi nuac va duoi ciia chung liSn kel vdi dung moi. Phirong phap sang dira vao kich Ihudc phan tir cua hat nanochitosan. Hat nanochitosan dugc diSu che bang cac phuang phap tren deu the hien hoat tinh khang u tdt va tiem nang iing dung trong thuc pham chiic nang va duoc pham.
TiJT khoi Cbdng ung thu, chitosan, giap xac, keo hoa ion, nana.
I.GIDITHlEUVECHrrOSAN
Nano chitosan la vat lieu thifen nhi^n voi cac hoat tinh sinh hpc tdt, than thien moi trucmg, clirpc sii dung trong nhieu linh vuc nhu y hpc, thuc pham, nong nghiep, cong nghiep,... Ngay 18/10/2011 Uy ban chau Au da quyet dmh vat heu nano duo'c coi la vat lieu tu nhien hoac san pham vol kich thuoc hat tir 1 nm - 100 nm va cac hat co hon 50% mdi vat lieu tong. Trong cac truong hpp cu the, cac hat co the it hon 50% tong sd hat. Vi vay, kich thuoi:: cua vat lieu ciia nano chitosan la tir 1 nm - 100 nm.
Nano chitosan co cac hoat tinh sinh hpc doi dao va da dang nhu khang khuan, chdng nam, chdng virus va chdng ung thu. Hat nano cung co chiic nang nhu mpt chat mang mam benh (khang khuan, chdng virus, chdng nam va chong ky sinh triing). Tac dung di^u tri cua thudc cho nam la thap, tudi thp cua cac loai thudc chdng virus thap va kha nang xam nhap cua thudc khang sinh vao noi bao ciia cac td bao bj nhidm dupx: gioi han.
Cac hat nano chitosan dong vai tro van chuyen, giiip van chuyen cac chat hoat tinh sinh hpc vao mdi td bao cua ca the con ngtroi. Chitosan co the tao ra
' Tnimig Dai hoc Cdng nghiep Th^rc pham TP. HCM
• Tnrcmg Dai hpc NguySn lk Thilnh ' Vien Nghien ciru U'ng dimg Cdng nghe Nha Trang
bd mat tu do cho cac mdi lien ket, vi vay chiing cai thien kha nang tham thau dac biet cua mang td bao cho cac loai thudc phan cue nhu peptide va protein (Luessen H. L va cong su, 1996) va kich thuoc ciia te bao mau do la tir 2.000 den 5.000 nm. Vi vay, img dung nano chitosan vao thuc pham, thuc pham chiic nang va thudc se mang lai gia tri cao vd site khde va kinh te cho con nguoi. Ngay nay, cd rat nhieu nghien ciiu vd chd tao nano chitosan va cac img dung ctia chiing tren thd gidi. Tuy nhien, chi co mot sd xuat ban ve nano chitosan.
Bai viet nay tap trung gidi thieu cac phuong phap tong hop nano chitosan va iing dung vao chdng ung thu.
2. TOniG HOP NANO CHITOSAN
Ngay nay, cd bdn phuong phap phd bien dimg de tdng hop nano chitosan tren the gidi. Mdi phuong phap duoc tdng hop theo cac tinh chat tu nhien cua phan tti hoat dpng va/hoac theo su chuyen hda cua nd.
2.1. Phmmg phap lien kdt ch6o trong nhu tuong Phuong phap nay, cac hat nano chitosan da dune chuan bi theo cac nguyen tdc cua nhO tuong chitosan trong dau. Cac chat dn dinh be mat se lam bdn nhu tuong nay. Cac hat nano chitosan da duoc lam cung boi cac chat nhu glutaraldehyde, tripolyphotphate voi CO chd hinh thanh lien ket cheo giiia cac chat nay va chitosan. Cac hat nano chitiosan duoc lam day va rua
NONG NGHIEP VA PHAT TRIEN NONG THON - KY 1 - THANG 7/2020 11
KHOA HOC C 6 N G NGHE sach nhieu lan vol n-hexan, sau khi ethanol dupc sir
dung de loai bo du lugng dung moi va cac hat nano kho. Kich thudc cua cac hat nano chitiosan phu thupc vao miic dp lien ket cheo va khuay dpng trong qua trinh hinh thanh cac he thdng nhu tuong (Pi- ping LV va cpng su, 2009). Tuy nhien, theo Pi-ping LV va cpng su (2009) n-hexan khong duoc su dung de lira. Ether dau hoa, acetone va ethanol dugc su dung de riia va ly tam 8000 rpm (Hinh 1).
Dung dich Chitosan
n
I Pha dauYeu to lien ket
Nhu tuone tuidc/dau
T T
Cac hat cmp hem IWA
^
Tach hat
Nano chitosan
Hinh 1. Quy trinh tdng hop hat nano chitosan b4ng phuang phap Udn kdt chdo
Cac yeu td dup^ sir dung de hinh thanh cac lien ket cheo nhu tripolyphotphat hoac glutaraldehyde da dupc loai bd bang each sir dung CaCl2 tao tua va ly tam. Sau khi ly tam, dung dich da duac dong kho (Krishna va cong su, 2010).
(B); tao ra hd thdng nhii tuong dn dinh tir he thdng A va B; ly tam nia sach de thu thap cac hat nanochitosan (Hinh 3). Trong che bien chuan bi he thdng nhu tuong dn dinh voi tdc do khuay cao, mdi gipt nhu tuong se va cham va ket hop ngau nhien. Tir dd, cac hat chitosan ket tua duoc hinh thanh. Kich thudc hat phu thupc vao tdc dp khuay. Kich thuoc hat bl giam khi tdc do khuay dupc tang len. O muc cd nghia la, kich thudc hat va tdc dp khuSy tuong tac voi nhau va tuan theo mo hinh phi tuyen tinh bac hai (2.1)
(2.1) y = AX^2-HBX + C
Diem nay la diem chung giua phuong phap ket hgp gipt nhu tuong va phuong phap hen kdt cheo trong nhu tuong. Trong thuc te, cd rat nhidu nghien cim tdng hgp hat nano chitosan theo phuong phap nay (M. Dasha va cong su, 2011).
Hinh 2. Hinh SEM ciia cac hat nano chitosan da duac chuan bi bang dich sii dving phtrong phap lien kdt
cheo trong hd thdng nhii tuong 2.2. Phirong phip kdt hgp gipt nhu tuong Phuong phap nay ldn dau tien dugc phat trien bdi Tokumitsu et. al. (1999). Phuong phap nay duac thuc hien theo 4 budc: chuan bi 2 he thdng nhu tuang dn dinh, chitosan trong dung giai dau Parafin long (A) va NaOH trong dung giai dau Parafin long
• M O I
m
Hinh 3. Ki thdng hat nano oia nano chitos in t6ng hop bSng phuong phap kAh(ip gipt nhu mg
KHOA HOC C 6 N G NGHl
2.3. Phtrong phap hda ion Dung i c h Chitosan
Toe do khuay eao
r l ^ V '
iuugdicliPolyaiiionie
at uauo chitosan
Hinh 4. H^ thdng chuan bi h^t chitosan b4ng phuong phap gel hda ion
Phuang phap gel hda ion dya tren nguyen tic tuong tac giiia cac phan tu tich dien trai dau de chuan bi hat nano chitosan va tuong tac giiia cac phan tu ve ban chat la tuong tac vat ly. Sir tuong tac vat ly nay cd uu diem de phuc hdi va tranh duoc nhiing phan ling khong mong mudn. Tuy nhien, hat nano cd dp chac vat Iy rat yeu nen hi ban che su dung trong y dugc. Trong phuang phap gel hda ion
Bd sung chitosan, thudc
nay, cation chitosan duac hda tan trong dung dich acid loang. Dung dich nay duac nhd gigt vao dung dich tripolyphotphat (TPP) dudi didu kien khuay trpn. Sau dd tien hanh Iy tam, rua sach d^ thu hat (Natasha va cgng su, 2012). Hinh 4 the hien chi tiet luan giai tren. Phuong phap.
2.4. Phuong phap micelles pha dao
Phuang phap nay cung bi anh hudng rat ldn bdi tdc do khuay.
Micelles pha dao la hdn hop dung dich nuac, dau va chat hoat dpng be mat dn dinh ve nhiet dpng hpc. Vd tdng the, chung dong nhat va dang hudng, quy mo cau tnic dpng hgc trong nude va ddu duac phan rieng bdi mang giau chat hoat dpng be mat
Mpt trong nhimg khia canh quan trong nhat cua he thdng chu micelle pha dao la phan iing dpng hpc ciia chiing. Khi nay nhiing gipt micellar tuan theo chuyen dpng Brown va chiing cii the chuydn ddng den khi tai phan rieng theo thai gian giiia milli giay va micro giay (Luisi va cpng su, 1988). ICich thudc, su phan bd va on dinh ve nhiet dong lyc hpc cua nhirng gigt nay dupc duy tri trong he thdng nhanh chdng thong qua can blng dpng (A. Maitra va cpng sy, 1984) va hinh 5 se minh hoa ro rang hon.
Micelle pha dao (chat hoat dong be mat hoa tan trong dung moi huu ca)
Bd sung nhan td lien kdt ngang va
khuay qua dem
mm
Co quay de loai bd dung moiChat kho
Hat nano chitosan trong dem Chat boat dpng be mat
Hinh 5. Su c h u ^ bi hat nano chitosan Trong phuong phap nay, chat hoat ddng bd mat duoc hda tan trong dung moi hiiu ca dd dieu chd micelles pha dao. Dung dich bao hda ciia chitosan va nhan td lien ket ngang (vi du: tripolyphotphat CTPF)) dupc them vao vdi ty le nhat dinh cd khuay trdn tranh tao due va de qua dem cho phan ung hoan toan. Dung moi dugc loai bo bang phuong phap co quay. Chat kho thu duac hoa tan trong dem (vi du:
b^ng phuong phap micelles pha dao
Tris- CI pH 7,4), sau dd bd sung CaCl^ hoac NaOH de Ioai bo chat hen ket ngang nhu diethylhexyl sulfosuccinate hay TPP hoac glutaraldehyde. Tiep theo Iy tam loai tua va thu dich chiia hat nano chitosan. Phuong phap nay khac vdi 2 phuang phap duac md ta d tren la khdng bi anh hudng nhieu bdi tdc do khuay.
NONG NGHIEP VA PHAT TRIEN NONG THON - KY 1 - THANG 7/2020
KHOA HOC CbNG NGHE
2.5. Phirong phap lpc qua ray
Gan day, S. A. Agnihotri va cong sy (2004) da phat trien mgt phuong phap rat truyen thdng va don gian de san xuat hat nano chitosan. Trong phuang phap nay, mgt lugng chitosan phii hpp duoc hda tan trong dung dich acid acetic 4% de hinh thanh khdi luong gel day, gel nay dugc thyc hien phan ung hen ket ngang vdi glutaraldehyde, sau do cho di qua ray
phan tu kich thudc mong mudn. Luong hat nano di qua ray duoc rua voi dung dich NaOH 0,1N de loai bo glutaraldehyde du va say qua dem d 40"C de thu hat nano chitosan. Phuong phap nay cung dupc trinh bay bdi M. Dasha va cpng su, 2011, don gian dd lam, tuy nhien cdn phai cd ap Iuc cao trong qua trinh thuc hien. Phuang phap nay cung khong bi anh hudng boi tdc dd khuay.
Ray
Gel chitosan
c h i i a [ • . • . • . • - • . • . • . • . • . • - • . • - • . • l ^
thudc
Gel da kdt Hinh 6. Sy chuan bi hat nano 3 . UNG DUIUB NANO CHITOSAN TRONG KHANG KHOI U Hoat tinh va tinh nang cua nano chitosan dupc cai thien ro ret khi ket hgp voi cac loai thuoc khang u khac nhau. Nhimg kdt qua thu nghiem ve sy kdt hgp nano chitosan va thudc da dugc nhieu nha khoa hoc minh chiing. Li-Feng Qi va cpng su (2005) cho thay hat nano chitosan cd kich thudc 65 nm vdi be mat tich dien cao tdi 52 mV da the hien hidu qua lie che su gia tang te bao ung thu MGC803 trong bieu mo da day ngudi d quy mo phdng thi nghiem. Dau hieu khang u ciia nano chitosan tren te bao Sarcoma480 va hepatoma H22 dugc cay trfin chuot, ddng thdi ciing chi ra kich thudc hat nano chitosan cang nhd thi hieu qua khang u cang cao (Lifeng Qi va cgng sy, 2006). Phan tii nano the hien sy hieu qua trong viec phan phdi vaccme ke tir khi chiing cd hoat tinh khang te bao ac tinh (Kreuter, 1995). Kich thudc sieu nhd ciia hat nano cho phep chiing tan cong vao dugc te bao M, loai te bao cd trong niem mac va lien quan den te bao lymphoid (MALT), vi du: td bao lympho rupt, miii va phe quan (Ilium va cpng su, 2001).
Immunoglobulin A (IgA) tdn tai d be mat nifim mac va te bao B thiic day IgA thuc hifin phan ung co ban tai MALT. Sau dd te bao B rdi khdi MALT va tidp tuc thiic day IgA thuc hifin phan iing co ban. Vi vay nano chitosan khong chi bao ve IgA ma cdn bao ve he thdng mifin dich. Phan phdi hat nano chitosan mang Doxorubicin theo dudng truyen cung chi ra su hdi
<^^ S^ .
Hat nano chitosan dan thudc
C3 O O O
^ <=> <^
ngang i chitosan bang phirong phap ra.y
quy trong sy phat trien khdi u va duy tri ty 16 song cua chuot dugc cay khdi u.
Kim JH va cpng su (2008) thong bao rang hat nano chitosan glycol ky nude chiia thudc khang ung thu khong hda tan cisplatin cd hoat tinh khang u cao va it doc tinh, boat tinh khang u the hien tren sy thay ddi the tich khdi u, khdi lugng co the va ty le sdng sdt. Hat nano chitosan glycol ky nude chiia thudc khang ung thu docetaxel cho hieu qua cao trong vific khang u, thong qua vific giam the tich khdi u va tang ty le sdng sdt ciia chuot mang td bao img thu phoi A549 cung duoc trinh bay bdi Hwang HY va cpng sii (2008). G. Saravanakumar va cpng sy (2009) da kham pha ra hat nano (HO-GC) chitosan glycol lien hgp cd dac tinh quan trgng la loi ben trong ua nude cua chiing. Su ua nude nay dam bao su Ufin ket lugng ldn PTX ciia chung. Hat nano HO-GC-FTX the hifin sy on dinh nhifit dong lyc hoc trong didu kien nude.
Ddng thdi, hat nano HO-GC-FTX phan ra thudc deu va duoc hap thu vao te bao nhanh. Cudi ciing, hat nano HO-GC dSn FIX dn dinh va tuong thich vk mat smh hpc da cd tinh dac hieu trfin khdi u ciia chupt mang khdi u. Nhu vay HO-GC nhu chat mang co tidm nang cao trong dieu tri ung thu.
Nam 2010, Milena G. Ignatova v;i, .-A,^ SU (2010) cong bd hieu qua khang u ciia ,lung dich DOX/polyO-lactide-co-d,l-Iactide) (coI'L\) va DOX/quatemized chitosan (QCW/coPL-X i, c gj^; ^
KHOA HOC CONG NGHE
cao hon (doxorubicin hydrochloride) DOX ty do.
Nhiing quan sat bang kinh hien vi dien tir, SEM, TEM cho thay hifiu qua khang u ciia sgi chiia DOX va spi dya tren QCh chu yeu the hien trfin cac te bao HeLa. Hat nano dan DOX gay ddc ldn hon ddi voi te bao QGY-7703 va ndng dp lie che 50% (IC50) ddi voi doxorubicin.HCI (DOX.HCI) va hat nano CTS/PEG- GA (acid chitosan/poly (ethylene glycol) eglycyrrhetinic dSn DOO tuong iing la 47 va 79 ng/mL Hon nua, hat nano CTS/PEGeGA dan DOX cd the lie chfi hifiu qua ddi vdi su phat tnen khdi u d te bao H22 trfin chuot ciing dugc thong bao bdi Qm Tian va cpng sy (2010). Parisa Youse^our va cpng sy (2011) chi ra hat nano lien hgp (chitosan-doxorubin) CS-DOX cd hinh cau va be mat tron vdi su phan bd kich thudc hep vdi c^u tnic vd loi. Tang ty lfi doxorubicin trong Ufin hop doxorubicin va chitosan se lam hifiu qua ben hop giam. Hat nano dinh Trastuzumab (CS-DOX-mAb) chiia 47 |ig/mg doxorubicin va 33,5 [.ig/mg trastuzumab. Ufin ke't cua trastuzumab ddi vdi hat nano dugc nghifin ciiu sau ban ve nhiet dgng hgc bdi phep do chuan ve dang nhiet. Kinh hien vi huynh quang giai thich su tang cudng va hap thu chgn lgc cua CS-DOX-mAb tren tfi bao ung thu Her2+ la cao hon so vdi hat nano CS-DOX va thudc.
Theo Hanafi N. (2012) cho thay hat nano chitosan (CNPs), mot loai chat mang thudc duac sii dung rong rai, cd kha nang gay dgc tren nhimg ddng te bao khdi u khac nhau d phdng thi nghifim va trfin lam sang. Nghien ciiu nay da tim each danh gia anh hucmg khang u ciia CNPs va hat nano chitosan dan 5- Flourouracil (F-CNPs) trfin ung thu bieu mo Ehrlich.
Trong nghien cuu lam sang, chuot cai duac cay te bao ung thu bieu mo Ehrlich trong ca de hinh thanh td bao ung thu bieu mo Ehrlich dang ran. Huyet thanh chitosan (5 mg/kg the trgng), CNPs va F- CNPs (0,5 mg/kg the trpng) duac phan phdi theo dudng udng. Kich thudc va khdi lupng klidi u dugc theo doi, dau hieu stress do bi oxi hda la dugc kiem ha, sy thay ddi mo benh hgc cua khdi u va nhung te bap than da dugc nghien cuu dudi kinh hien vi anh sang. Ddng thdi su hiiy hoai va hoai tu dugc kiem tra dudi dieu kien anh sang huynh quang. Trong phdng thi nghiem, CNPs the hifin hoat hnh kliang u cao va F-CNPs cd hoat Iuc cao hon. Nghien ciiu lam sang cho thay CNPs va F-CNPs lam cham su phat trien cua khdi u tuong iing la 7 ngay va 6 ngay. Kiem tra
mo benh hgc cho thay CNPs gay su pha buy ldn ddi vdi mo khdi u hay F-CNPs gay chet va hiiy hoai mo bao khdi u. Khi mo than dugc didu tri vdi CNPs thi cac td bao khdi u di can bien mat. Mat khac khi mo than duac difiu tri vdi F-CNPs, te bao khdi u di can bien mat nhifiu hon va it xay ra trudng hop tieu ciu bl thoai hda. Trang thai ty hiiy hoai cham ddi vdi te bao tieu cau than va te bao dng xoan dugc chi ra trong mo than cua chuot mang khdi u ung thu bieu mo EhrUch khi dugc difiu tn vdi CNPs hoac F-CNPs.
Sy oxi hda trong mo khdi u the hien trfin sy gia tang dang ke miic (malondialdehyde) MDA, su thay doi khong dang ke d ROS, sy giam dang ke d miic (ndng do Glutathione) GSH va khong dang ke d boat tinh CAT khi ddng vat thyc nghifim dugc dieu tri vdi CS, CNPs hoac F-CNPs. Trong nhdm chuot mang khdi u, bieu hifin mo than bi oxy hda the hifin trfin sy gia tang muc MDA va ROS va su giam dang ke miic GSH va hoat tinh CAT. Khi khdi u dugc dieu tri voi CS thi miic do MDA va ROS trong than giam di, gia tang dang ke miic do GSH va khong cd tac dung dang ke trong boat tinh (Catalase) CAT, Khi khdi u dugc difiu tn vdi CNPs va F-CNPs thi miic MDA va ROS trong than binh thudng. Tuy nhifin miic GSH gia tang dang ke va boat tinh CAT khong thay doi dang ke so vdi nhdm mang khdi u. Tdm lai, hat nano chitosan cd mdt vai tro trong vific lam giam te bao ung thu dl can va suy thoai su phat tnen khdi u.
Nhieu tac gia khac cung da chi ra rang hat nano chitosan glycol the hien sy keo dai tudn hoan mau d ngudi va phan phdi thudc khang ung thu dac hieu cho khdi u (]. H. Kim va cpng sy, 2008; H. Y. Hwang va cong sy, 2008). Chuan bi nano chitosan cho cac nghifin ciiu vd khang u dugc trinh bay d tren ddu dua vao 1 trong 4 phuang phap da duac chi ra.
4. KET LOAN
Da gidi tliifiu 5 phuang phap difiu che nano chitosan nhir phuang phap lifin ket cheo; nhu tuong- gipt; ion hda; micelles dao va phuang phap sang.
Nano chitosan duac difiu che kha cong phu va su ling dung trong didu tri khdi u cung dat hieu qua hon so vdi cac loai thudc khang u thong dung. Nano chitosan mang thudc sir dung trong dieu tn khdi u cd the duac phan phdi theo 2 con dudng truyfin va udng theo nhiing minh chiing d tren.
TAI UEU THAM KHAO
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NONG NGHIEP VA PHAT TRIEN NONG THON - KY 1 - THANG 7/2020
KHOA HOC CONG tiCMfc
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A SYSTEMATIC REVIEW THE PREPARATION OF NANO CHITOSAN AND ITS FURTHER APPUCATION IN ANTI-TUMOR
Nguyen Xuan Hoan, Dinh Huu Dong, Duong Hong Quan, Pham Van Thinh, Nguyen Thi Phuong, Hoang Thai Ha, Dang Xuan Cuong, Lam Tbe Hai Summary
Nano-chitosan is the natural matenal prepared from chitosan that extracted from crustacean ceUs such as crab, shrimp,... and their molecular size from i to 100 nm. They possess bioachve-value, for example, antioxidant, antibactenal, antitumor, anticancer and useful for the biological support increasing the disease freatment capacity. The study focused on the prepanng method of nano-chitosan and their application into the tumour freatment. There are five methods for nano-chitosan, for example, cross-linking, emuision- drops, ionic, reversed-micelles, and sieving. Nano-chitosan preparation is by using the ionic method and the cross-linking method basing on the reachon between free amino groups of chitosan and polyanions, but not use the solvent for precipitatmg nano-chitosan in the ionic process. The reverse micelles method is nano- chitosan droplets m organic solvents and the surfactant. Their polar heads of the surfactants link the water and their tails link to the organic phase. The sieving method is base on the molecular size of nano chitosan.
Nano chitosan particles preparing by over methods exhibit the good tumour activity and potential the apply into functional food and pharmaceutics.
Keywords: Antitumor, cbitosan, crustacean, ionic gelation, nano.
Ngudi phan bifin: GS.TS. Nguyfin Cong Khan Ngdy nhin bai: 3/4/2020
Ngiy thong qua phan bifin: 4/5/2020 Ngiy duyet dang: 11/5/2020
NONG NGHIEP VA PHAT TRIEN NONG THON - KY 1 - THANG 7/2020
