Methoxypolyethylene glycol(MPEG) yog dav suav hais tias yog ib qho chaw nyab xeeb nrog ntau hom kev siv. Ib hom polymer pom kev siv dav hauv kev lag luam xws li khoom noj khoom haus, khoom siv kho kom zoo nkauj, tshuaj, thiab lwm yam. MPEG paub txog nws qhov xwm txheej tsis muaj tshuaj lom thiab muaj peev xwm ua kom khaus qis, ua rau nws tsim nyog rau kev koom ua ke rau hauv ntau yam kev saib xyuas tus kheej thiab cov khoom kom zoo nkauj. Tsis tas li ntawd, nws kuj yog siv rau hauv cov khoom noj thiab tshuaj formulations.
Txhawm rau kom ntseeg tau tias nws muaj kev nyab xeeb siv, nws yog ib qho tseem ceeb uas yuav tsum ua raws li cov lus pom zoo txwv kev txwv thiab ua raws li cov txheej txheem kev cai. Ua raws li kev tuav tswj kom raug thiab kev siv cov txheej txheem yog qhov tseem ceeb kom muaj kev nyab xeeb ntawm kev ua haujlwm. Ua qhov kev ntsuam xyuas txaus ntshai kuj tseem pom zoo kom txo qis cov kev phom sij uas cuam tshuam nrog kev siv MPEG lossis lwm yam tshuaj lom neeg. Zuag qhia tag nrho, thaum siv lub luag haujlwm thiab ua raws li cov lus qhia kev nyab xeeb, MPEG tuaj yeem siv tau zoo thiab nyab xeeb hauv ntau daim ntawv thov.
Cov tshuaj toxicity ntawm methoxypolyethylene glycol soj ntsuam li cas?
Kev nyab xeeb thiab toxicity ntawmmethoxypolyethylene glycol(mPEG) raug soj ntsuam los ntawm ntau yam kev xeem thiab ntsuas:
Cov kev tshawb fawb tsiaj - mob mPEG raug kuaj hauv nas, dev, thiab qee zaum primates los nrhiav cov tsos mob ntawm toxicity. Cov txiaj ntsig ntawm lub cev, cov ntaub so ntswg, lub cev hnyav, kev noj zaub mov, thiab lwm yam raug soj ntsuam.
Cytotoxicity - Cell kab lis kev cai raug cuam tshuam rau mPEG ntau yam los txiav txim siab qib uas ua rau 50% cell tuag (IC50). Qhov no txheeb xyuas qhov kev nyab xeeb ntau npaum li cas.
Immunogenicity - Muaj peev xwm ua rau lub cev tiv thaiv kab mob yog kuaj los ntawm kev nrhiav tshuaj tiv thaiv kab mob hauv cov qauv tsiaj. Tsis muaj immunogenicity yog xav tau.
Pharmacokinetics - Kev nqus, kev faib tawm, cov metabolism thiab tso tawm raug ntsuas tom qab kev tswj hwm mPEG. Cov ntaub ntawv no yuav pab txiav txim siab txog kev noj tshuaj thiab kev pheej hmoo.
Carcinogenicity thiab genotoxicity - Kev ntsuam xyuas rau qhov muaj peev xwm ua rau mob qog noj ntshav lossis DNA puas tsuaj los ntawm ob qho tib si luv thiab ntev mPEG raug.
Rov ua dua cov kev tshawb fawb tshuaj - Ntau qhov ntau npaum li cas tau muab rau lub sijhawm txuas ntxiv los ntsuas qhov cuam tshuam ntawm mPEG raug mob.
Cov khoom lag luam degradation - Txhua qhov sib txuas tau los ntawm mPEG rhuav tshem yog ntsuas kev nyab xeeb.
Cov khoom sib xyaw ua ke - Yog tias mPEG yog ib feem ntawm kev tsim nrog lwm cov khoom xyaw, lawv cov kev sib cuam tshuam raug soj ntsuam.Los ntawm kev ntsuam xyuas mPEG nrog ntau qhov kev ntsuam xyuas no, cov kws tshawb fawb tuaj yeem ua tus yam ntxwv ntawm nws cov toxicity profile txhawm rau txheeb xyuas cov kev pheej hmoo thiab teeb tsa kev nyab xeeb.
Puas yog methoxypolyethylene glycol bioaccumulate hauv lub cev?
Tsis yog,methoxypolyethylene glycol(mPEG) tsis zoo bioaccumulate nyob rau hauv lub cev vim nws cov tshuaj thiab pharmacokinetic zog:
1.High dej solubility - mPEG yog cov dej soluble heev uas tiv thaiv cia hauv cov ntaub so ntswg rog. Cov tshuaj uas bioaccumulate feem ntau yog rog soluble.
2.Molecular hnyav - Tsawg molecular hnyav mPEGs qis dua 20,000 Da tau yooj yim tshem tawm los ntawm ob lub raum es tsis tsim.
3.Metabolism - mPEG tsis yog feem ntau metabolized thiab tawg mus rau lwm cov tebchaw. Nws tseem muaj tshuaj lom neeg thaum tso tawm.
4.Excretion - mPEGs feem ntau yog tshem tawm tsis hloov pauv hauv cov zis nrog ib nrab ntawm lub neej nyob ib ncig ntawm 24 teev lossis tsawg dua. Qhov no tiv thaiv lub cev tuav.
5.Low protein binding - mPEG nthuav tawm cov protein tsawg tsawg hauv cov ntshav thiab cov ntaub so ntswg. Nws tsis tau txais sequestered ntawm cov proteins.
6.Dosing - Cov koob tshuaj ntev ntev ntau lub hlis lossis xyoo yuav tsum tau muaj rau bioaccumululation tseem ceeb ntawm mPEG, uas tsis tshwm sim kho.
Thaum me me nyob rau hauv daim tawv nqaij thiab cov pob txha matrix tuaj yeem tshwm sim tom qab cov koob tshuaj ntau duamethoxypolyethylene glycol(mPEG), Nws yog ib qho tseem ceeb kom nco ntsoov tias qhov kev txhawj xeeb no tshwm sim nyob rau hauv cov xwm txheej hnyav. Hauv cov tshuaj pharmacological ib txwm muaj, mPEG tau pom tias tsis muaj kev kho mob txog kev tsim tawm hauv lub cev. Cov kev tshawb fawb tau pom tias mPEG tau nkag tau yooj yim thiab tshem tawm ntawm lub cev los ntawm cov txheej txheem metabolic. Yog li ntawd, thaum siv cov koob tshuaj uas tsim nyog, mPEG raug suav hais tias muaj kev nyab xeeb rau ntau yam kev siv hauv kev lag luam xws li tshuaj, tshuaj pleev ib ce, thiab zaub mov. Nws yog ib qho tseem ceeb uas yuav tau ua raws li cov lus pom zoo thiab ua raws li cov txheej txheem tswj xyuas kom muaj kev nyab xeeb ntawm kev siv mPEG hauv cov kev lag luam no.
FDA kev soj ntsuam ntawm methoxypolyethylene glycol kev nyab xeeb yog dab tsi?
US Food and Drug Administration (FDA) txiav txim siab methoxypolyethylene glycol (mPEG) raws li feem ntau muaj kev nyab xeeb rau kev siv tshuaj thiab kev kho mob raws li cov ntaub ntawv tam sim no:
(1) GRAS kev faib tawm - mPEGs tau Pom Zoo Raws Li Kev Nyab Xeeb (GRAS) rau kev siv hauv cov khoom noj txog li 1g / hnub.
(2) Pom zoo formulations - Ntau tshaj 20 mPEG-muaj cov tshuaj txhaj thiab qhov ncauj formulations tau raug pom zoo los ntawm FDA, qhia tau hais tias muaj toxicity profiles.
(3) Kev paub txog kev kho mob - Ntau xyoo ntawm kev siv tshuaj kho mob thiab kev sim tsis tau qhia txog teeb meem kev nyab xeeb tseem ceeb nrog mPEGs thoob plaws ntau qhov hnyav molecular.
(4) txwv metabolism - mPEG tsis yog feem ntau tawg mus rau hauv metabolites, txo cov kev pheej hmoo ntawm cov tshuaj lom derivatives.
(5) Kev tso tawm - mPEGs tau tshem tawm sai sai ntawm lub cev los ntawm cov zis yam tsis muaj kev tsim kho lub sijhawm.
(6) Tsawg toxicity - Tsiaj toxicity test qhia tau hais tias tsawg kawg nkaus systemic toxicity, neurotoxicity, immunogenicity txaus ntshai nrog mPEGs.
(7) Biocompatibility - mPEGs pom muaj kev cuam tshuam tsawg heev thiab cuam tshuam nrog cov khoom lom lom.
Nws txhais tau tias ntau yuav tsum nco ntsoov tias kev ruaj ntseg ntawmmethoxypolyethylene glycol(mPEG) tuaj yeem hloov pauv ntawm ntau lub ntsiab lus ntawm cov khoom uas muaj cov khoom sib xyaw no. Yog li ntawd, FDA qhia tias txhua yam khoom muaj mPEG yuav dhau los ntawm ib tus neeg kuaj xyuas kom paub meej tias nws qhov profile ruaj ntseg. Qhov no yog vim qhov xav tau ntau yam hauv daim thiab nthuav dav ntawm mPEG cov khoom.
Tsis tas li ntawd, kev tiv thaiv yuav yog qhov tseem ceeb rau cov neeg muaj mob raum, vim lawv yuav tsis tuaj yeem tso tawm mPEG los ntawm lawv lub cev kom tsim nyog. Kev soj ntsuam kaw thiab kev hloov pauv hauv kev ntsuas yuav xav tau nyob rau hauv cov xwm txheej zoo li no txhawm rau txo qis kev phom sij.
Uas tau hais tias, mPEGs feem ntau tau qhia txog keeb kwm ntawm kev ruaj ntseg hauv cov ntawv thov sib txawv. Thaum siv kom tsim nyog thiab nyob rau hauv cov cai tau hais tseg, mPEG tuaj yeem pom tias muaj kev nyab xeeb rau kev siv. Ib yam li nrog txhua qhov sib xyaw, nws yog ib qho tseem ceeb kom ua raws li cov cai tswj hwm thiab tham nrog cov kws kho mob rau cov lus ntuas thiab cov lus qhia.
Cov ntaub ntawv:
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Fishburn, CS, 2013. Tus kws tshuaj ntawm PEGylation: Ntsuas PD nrog PK los tsim cov kev kho tshiab. Phau ntawv Journal of pharmaceutical sciences, 102(10), pp. 3413-3425.
Harris, JM, Chess, RB, 2003. Cov nyhuv ntawm pegylation ntawm kws tshuaj. Nat. Rev. Drug Discov. 2, 214–221 : kuv.
Jevševar, S., Kunstelj, M., Porekar, VG, 2010. PEGylation of therapeutic proteins. Biotechnol. J. 5, 113–128.
Turecek, PL, Bossard, MJ, Schoetens, F., Ivens, IA, 2016. PEGylation ntawm biopharmaceuticals: kev tshuaj xyuas ntawm chemistry thiab nonclinical kev nyab xeeb cov ntaub ntawv ntawm cov tshuaj pom zoo. J. Pharm. Sci. 105, 460–475 : kuv.
Van Brunt, J., 2001. Qee lub sij hawm kev hloov pauv hloov cov khoom sib txuas rau qhov zoo dua-PEGylation hloov pauv kev faib tawm, muaj zog, thiab kev tiv thaiv kab mob. Signals Mag.