Nano-Drug Design Raws li Lub Cev Muaj Zog Ntawm Glutathione

Abstract:Glutathione (GSH) koom nrog thiab tswj cov haujlwm tseem ceeb ntawm lub cev ntawm lub cev ua ib qho tseem ceeb antioxidant. GSH plays lub luag haujlwm tseem ceeb hauvtiv thaiv oxidation, detoxification, anti-aging, txhim khu kev tiv thaiv, thiabtiv thaiv qog nqaij hlav. Ntawm no, raws li lub cev muaj zog ntawm GSH hauv cov kab mob sib txawv, feem ntau suav nrogmuaj zog reducibility ntawm GSH, GSH cov ntsiab lus siab hauv cov qog hlwb, thiab covNADPH depletion thaum GSSH raug txo rau GSH, peb nthuav qhia cov qauv tsim, cov nyhuv, thiab cov teeb meem muaj peev xwm ntawm ntau yamnano-tshuaj hauv ntshav qab zib, mob qog noj ntshav, cov kab mob hauv paj hlwb, fluorescent probes, duab, thiab zaub mov. Cov kev tshawb fawb no ua rau siv tag nrho cov txiaj ntsig ntawm lub cev thiab cov kab mob pathological ntawm GSH thiab tsim cov qauv tsim zoo heev ntawmnano tshuajntsig txog GSH, uas qhia txog qhov tseem ceeb ntawm kev tshawb fawb thiab cov ntawv thov tseem ceeb rau kev tshawb fawb txog kab mob uas GSH koom nrog lossis teb rau.

Ntsiab lus:glutathione; physiological khoom; nano-tshuaj; tshuaj xyuas

Nyem qhov no Kom Tau Txais Cistanche Rau Anti-aging

1. Glutathione Structure

Glutathione (GSH) tau tshawb pom los ntawm Hopkins hauv xyoo 1921 [1], thiab yog ib qho tripeptide compound tsim los ntawm glutamic acid, cysteine, thiab glycine los ntawm peptide bond condensation. Nws lub npe tshuaj yog -L-glutamyl-L-cysteyl-glycine, thiab cov mis mos molecular yog C10H17O6SN3 [2]. Muaj ob hom glutathione, uas yog txo glutathione (GSH) thiab oxidized glutathione (GSSG). Cov qauv ntawm GSH muaj cov pab pawg txo qis, sulfhydryl (-SH), uas yooj yim oxidized thiab dehydrogenated. Glutathione peroxidase (GSH-Px) tuaj yeem ua rau GSH rau GSSG, thaum glutathione reductase (GSH-R) tuaj yeem siv nicotinamide adenine dinucleotide phosphate (NADPH) los catalyze GSSG rau GSH. Cov pab pawg tseem ceeb ntawm GSSG yog disulfide daim ntawv cog lus (-SS-). GSH biosynthesis yog tswj ncaj qha los ntawm lub synthase system, es tsis zoo li cov protein synthesis ntawm ribosome [3-5]. Cov qauv tshwj xeeb thiab cov txheej txheem synthesis yog qhia hauv daim duab 1.

2. Lub cev muaj nuj nqi ntawm GSH

GSH muaj nyob rau hauv yuav luag txhua lub cell ntawm lub cev [6], thiab dav nthuav dav nyob rau hauv ntau yam tseem ceeb hauv nruab nrog cev thiab cov ntaub so ntswg, xws li ntshav, siab, thiab raum, uas lub siab thiab lub raum yog lub ntsiab hluavtaws, metabolic, thiab excretory. lub cev ntawm GSH [7]. Feem ntau, GSH ua lub luag haujlwm tseem ceeb hauv lub cev hauv lub cev, thaum GSSG yuav tsum tau txo qis rau GSH kom ua tiav lub cev muaj zog. GSH tswj lub cev ua haujlwm ntawm lub cev tsis muaj zog thiab muaj cov teebmeem antioxidant thiab detoxification. Ntxiv mus, tus qauv tshwj xeeb ntawm GSH ua rau nws yog ib qho tseem ceeb dawb-radical scavenger hauv lub cev [8-10]. Yog li, GSH muaj qhov zoo ntawm lub luag haujlwm zoo hauv kev tiv thaiv kev laus, txhim kho kev tiv thaiv kab mob, thiab tiv thaiv qog nqaij hlav [11–13]. Thaum ib qho me me ntawm H2O2 tsim nyob rau hauv lub cell, GSH txo H2O2 rau H2O nrog GSH-Px, thaum raug oxidized rau GSSG. GSSG lees txais H ntxiv thiab txo rau GSH nrog GSH-R, kom cov tshuaj tiv thaiv ntawm cov dawb radicals hauv lub cev tuaj yeem txuas ntxiv, uas tiv thaiv cov qauv thiab kev ua haujlwm ntawm cov cell membrane los ntawm kev cuam tshuam thiab kev puas tsuaj ntawm oxides [14]. Tsis tas li ntawd, GSH kuj tseem muaj cov kev ua kom txo qis ntawm neuronal excitatory intoxication [15], uas tuaj yeem siv los txo cov tshuaj lom thiab sab nraud tshwm sim los ntawm kev siv tshuaj khomob rau cov neeg mob qog nqaij hlav malignant [16].

Txawm hais tias GSH ua lub luag haujlwm tseem ceeb hauv kev ua haujlwm ntawm lub cev, cov kev txwv tseem ceeb tseem nyob, suav nrog nws qhov tsis muaj peev xwm nkag mus rau cov cell membranes, oxidation yooj yim, tsis muaj kev ruaj ntseg, thiab tsis muaj bioavailability, uas cuam tshuam qhov kev kho mob ntawm cov kab mob. Nanotechnology yog ib lub tshuab xa tshuaj tshiab uas ua rau cov tshuaj lom neeg lom zem kos lossis hloov kho ntawm nanomaterials feem ntau los ntawm lub cev, tshuaj, thiab lwm yam kev sib txuas. Nanoparticles tsim los ntawm encapsulation lossis self-assembly tuaj yeem tsis tsuas yog tiv thaiv kev ua haujlwm lom neeg ntawm GSH tab sis kuj txhim kho nws txoj kev ruaj ntseg thiab bioavailability. Tsis tas li ntawd, qhov muaj zog txo tus yam ntxwv ntawm GSH hauv microenvironment tuaj yeem siv los txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau ua tiav cov teebmeem ntawm kev tswj-tso tawm thiab lub hom phiaj ntawm cov tshuaj. Yog li ntawd, nyob rau hauv qhov kev tshuaj xyuas no, peb tsom cais ntawm cov qauv tsim, cov teebmeem, thiab cov teeb meem muaj peev xwm ntawm ntau yam tshuaj nano-raws li cov cuab yeej physiological ntawm GSH hauv cov kab mob sib txawv. Tsis tas li ntawd, cov kev cov nyom tam sim no thiab cov tswv yim yav tom ntej rau kev tsim cov tshuaj nano kuj tau tham los ntawm kev siv tswv yim pom.

3. Nano-Drug Delivery Systems

Nrog rau kev nqis peev siab thiab kev loj hlob sai hauv xyoo tas los no, nanotechnology tau siv rau hauv txhua qhov chaw ntawm biomedical science thiab technology [17]. Ib yam li ntawd, nanotechnology muab txoj hauv kev tshiab rau kev xa tshuaj, tshwj xeeb tshaj yog tsom rau kev xa tshuaj. Lub hom phiaj siv tshuaj xa mus xa cov tshuaj xav tau mus rau qhov chaw muaj kab mob thiab txo qis kev faib mus rau cov ntaub so ntswg lossis cov hlwb [18]. Qhov zoo ntawm nanoparticles raws li kev xa cov tshuaj tau piav qhia raws li hauv qab no: (1) Dissolve insoluble tshuaj thiab tiv thaiv cov tshuaj degradation ntawm lub cev; (2) ncua lub sij hawm ncig ntawm cov tshuaj; (3) pom zoo biocompatibility thiab biodegradability; (4) muaj peev xwm thauj khoom siab thiab tsis muaj tshuaj lom; (4) xaiv xa cov tshuaj mus rau cov hom phiaj kho mob, xws li cov qog nqaij hlav, cov qog hlwb, cov qog nqaij hlav stromal, thiab cov kab mob hauv nruab nrog cev [19]. Txog tam sim no, ntau cov ntaub ntawv xws li polymers, lipids, thiab inorganic cov ntaub ntawv tau tsim thiab siv los ua cov neeg nqa tshuaj los tswj tus cwj pwm tso tawm ntawm cov tshuaj [20,21]. Tsis tas li ntawd, REDOX cov lus teb stimulation tau txais txiaj ntsig zoo hauv kev kho mob thiab tau siv dav hauv kev xa tshuaj nanomedical [22,23]. REDOX muaj peev xwm hauv microenvironments muaj ntau yam sib txawv hauv cov ntaub so ntswg sib txawv thiab tuaj yeem siv los tsim REDOX-sensitive xa cov tshuab. Yog li ntawd, kev tsim thiab tsim khoom ntawm glutathione-responsive nanoparticles tej zaum yuav yog ib qho kev cog lus rau kev xa tshuaj rau lub hom phiaj [24].

4. Nano-Drug Design rau ntshav qab zib raws li lub cev muaj zog ntawm GSH

4.1. Nano-Drug Design Raws li lub luag haujlwm ntawm GSH hauv Oxidative Stress

Oxidative stress tau raug lees paub tias yog qhov tseem ceeb tshaj plaws rau kev mob ntshav qab zib mellitus, thiab hyperglycemia yog qhov tseem ceeb tshaj plaws rau kev txhawb nqa kev tsim cov pa oxygen reactive (ROS). Muaj ntau hom ROS, xws li superoxide anion (O2−), hydrogen peroxide (H2O2), hydroxyl radical (OH−), nitrogen dioxide (NO2) thiab nitric oxide (NO) dawb radicals, thiab lwm yam [25]. Cov tshuaj antioxidants hauv lub cev ib txwm muaj xws li vitamin A, vitamin C, vitamin E, GSH, superoxide dismutase (SOD), GSH-Px, thiab GSH-R, thiab lwm yam, [26]. Ntawm lawv, GSH yog ib qho tseem ceeb ntawm lub cev endogenous antioxidant. Nws muaj qhov zoo ntawm kev tshem tawm cov dawb radicals, alleviating puas thiab tswj redox equilibrium hauv hlwb [27]. Thaum lub cev raug tawm tsam los ntawm cov dawb radicals, GSH tuaj yeem siv los ua qhov ncaj qha scavenger ntawm cov dawb radicals, co-substrate ntawm GSH-Px, cofactor ntawm cov tshuaj tiv thaiv enzymatic, thiab ib qho kev sib txuas ntawm ntau cov tshuaj endogenous los txhim kho oxidative kev nyuaj siab thiab ncua sij hawm. Kev kho mob ntshav qab zib mellitus [28]

Qhov tseem ceeb, ntau tus kws tshawb fawb tau tsim cov tshuaj nano rau kev kho mob ntshav qab zib thiab teeb meem raws li lub luag haujlwm ntawm lub cev ntawm GSH hauv oxidative stress. Wei Wang et al. [29] tsim ib qho tshiab antioxidant glutathione liposome (GSH-LIP) los siv rau hauv kev kho mob ntshav qab zib nephropathy. GSH-LIP tuaj yeem tsis tsuas yog txhim kho bioavailability ntawm GSH, tab sis kuj tshem tawm cov ROS ntau dhau los ntawm oxidative kev nyuaj siab thiab txhim kho lub peev xwm antioxidant. Xiao et al. [30] tsim ib qho kev xa tawm uas muaj xws li enteric Eudragit L100- cysteine ​​/ txo glutathione nanoparticles (Eul-cys / GSH NPs) rau qhov ncauj xa ntawm insulin. Lawv pom tias Eul-cys / GSH NPs tuaj yeem txhawb txoj hnyuv nqus ntawm insulin, thiab ncua sij hawm txo cov ntshav qab zib, uas tau qhia tias Eul-cys / GSH NPs yuav yog ib qho kev cog lus rau kev kho mob ntshav qab zib. Cov tshuaj nano-tshuaj tsim saum toj no ntawm GSH yog cov tshuaj tau ntim hauv phospholipids lossis amphiphilic cov ntaub ntawv, xws li liposomes, thiab micelles, raws li qhia hauv daim duab 2A. Kuan et al. [31] tsim cov GSH-bound magnetic nanoparticles uas tau npaj los ntawm covalent daim ntawv cog lus ntawm GSH thiab nanoparticles. Nws tau qhia tias qhov GSH-bound sib nqus nanoparticle tuaj yeem khaws kwv yees li 87 feem pua ​​​​ntawm cov enzyme kev ua haujlwm thiab tau txais glucagon-zoo li peptide -1, peptide hormone rau kev kho mob ntshav qab zib hom 2. Qhov tsim ntawm nano-tshuaj no tau sib txuas SH hauv GSH nrog silla-NH2 los ntawm covalent daim ntawv cog lus, raws li qhia hauv daim duab 2B. Mottaghipisheh et al. [32] pom tias S. marianum, B. vulgaris, thiab D. sophia extracts combining CuO nanoparticles pom muaj qee yam cuam tshuam rau cov nas mob ntshav qab zib, thiab lawv tuaj yeem txo cov ntsiab lus ntawm GSH-Px los tiv thaiv GSH oxidation. Pab pawg tshawb fawb Gurunathan [33] ua haujlwm Au nanoparticles (AuNPs) los kho cov ntshav qab zib thiab them nyiaj rau lub qhov khoob hauv lub cev tiv thaiv kab mob antioxidant. Cov txiaj ntsig kev sim qhia tau hais tias qib ntawm GSH, superoxide dismutase (SOD), catalase thiab GSH-Px tau nce ntxiv hauv cov kab mob ntshav qab zib tau kho nrog AuNPs, los ntawm inhibition ntawm lipid peroxidation thiab ROS tiam thaum hyperglycemia. Feem ntau ntawm cov tshuaj nano yog cov active nano enzymes uas ncaj qha ua rau GSH los yog GSH-Px los tswj GSH synthesis, raws li qhia nyob rau hauv daim duab 2C.

Daim duab 2. Cov tshuaj Nano rau ntshav qab zib yog tsim los ntawm GSH. (A) GSH tau encapsulated rau hauv Enteric eudragit L100-cysteine ​​los npaj txo glutathione nanoparticles (Eul-cys/GSH NPs) [30]; (B) GSH-bound magnetic nanoparticles (SPION@silica-NH2 ). GSH tau reacted nrog maleic anhydride los ua SPION@silica-GSH nanoparticles [31]; (C) kis tau tus mob electron microscope duab ntawm CuO nanoparticles thiab Au nanoparticles enzyme [32,33]

4.2. Nano-Drug Design Raws li Lub Luag Haujlwm ntawm GSH hauv Polyol Pathway

Thaum cov ntshav qabzib concentration hauv cov ntshav qab zib nce ntxiv thiab ntau dua li cov peev txheej metabolic, ntau cov piam thaj tau metabolized los ntawm txoj kev polyol. Aldose reductase (AR) nyob rau hauv txoj kev polyol txo cov piam thaj ntau dhau rau sorbitol los ntawm NADPH ua cov cofactor. Ib tug loj npaum li cas ntawm sorbitol tsub zuj zuj ua rau ntau tshaj sorbitol nyob rau hauv lub cell thiab puas lub cell permeability vim lawv cov lipophilicity tsawg. Tom qab ntawd, sorbitol tsis nkag mus rau hauv lub cell membrane, thiab ua rau cov cell o thiab rupture, inducing ib tug series ntawm cov ntshav qab zib thiab mob ntev kev loj hlob [34-37]. GSSH tuaj yeem deplete NADPH thiab raug txo rau GSH los ntawm GSH-R. Yog tias qhov sib xyaw ua ke ntawm GSH yog qhov qub, lossis qhov kev poob qis hauv GSH tshwm sim, NADPH noj tau raug khi kom nce [21]. Li no, txoj hauv kev polyol tau thim rov qab los txwv kev tsim cov sorbitol, uas muab lub hom phiaj tshiab rau kev tiv thaiv thiab txo qis ntshav qab zib (Daim duab 3A).

Los ntawm kev sib tw rau NADPH nrog GSH-R thiab yog li ua rau txo qis ntawm GSH, txoj hauv kev polyol ua rau muaj kev cuam tshuam rau intracellular oxidative kev nyuaj siab. Wang et al. [29] npaj tshiab antioxidant GSH liposomes (GSH-LIP) uas tau siv rau hauv kev kho mob ntshav qab zib nephropathy. Nws tau qhia tias GSH-LIP tau ua haujlwm zoo rau NADPH los thaiv txoj hauv kev polyol, thiab txo qis ntshav qab zib nephropathy, uas muab lub hauv paus tshiab rau kev tshawb fawb nano-tshuaj hauv kev kho mob ntshav qab zib nephropathy.

5. Nano-Drug Design rau qog raws li Physiological Properties ntawm GSH

5.1. Nanoparticles Siv cov qog Targeting Delivery Mechanisms

5.1.1. Passive Targeting

Passive targeting tsuas yog nyob ntawm nws qhov loj nanometer thiab cov qauv microvascular ntawm qhov chaw qog. Piv nrog rau cov ntaub so ntswg ib txwm, feem ntau cov qog nqaij hlav tsis ua tiav vascular remodeling vim muaj zog loj hlob thiab cov metabolism, nrog qhov sib txawv ntawm 10-1000 nm ntawm vascular endothelium. Yog li ntawd, nanoparticles ntawm qhov loj me tuaj yeem ncav cuag cov qog nqaij hlav los ntawm cov ntshav ncig thiab ua kom cov nqaij mos los ntawm kev txhim kho permeability thiab tuav (EPR) nyhuv [38]. Nws yog feem ntau ntseeg tias 10-100 nm nanoparticles muaj qhov zoo EPR nyhuv [39]. Ntawm qhov tod tes, txoj kev loj hlob ntawm lub xeev thiab qhov ceev ntawm vascular endothelial hauv cov qog nqaij hlav tuaj yeem cuam tshuam rau EPR cov nyhuv [40].

5.1.2. Active Targeting

Txhawm rau ntxiv dag zog rau kev txhawb nqa ntawm nano-tshuaj xa khoom los ntawm cov qog hlwb, qhov chaw ntawm nanoparticles tuaj yeem hloov kho nrog cov hom phiaj ligands, kom lawv tuaj yeem nkag mus rau cov hlwb los ntawm receptor-ligand-mediated endocytosis los ntawm kev paub txog cov receptors tshwj xeeb ntawm lub cev. nto ntawm cov qog cell [41] Piv nrog rau lub hom phiaj passive, active targeting nanoparticles muaj zog tshwj xeeb thiab muaj peev xwm ua rau kom cov tshuaj intracellular concentration nyob rau hauv cov qog hlwb [42].

5.1.3. Tumor Microenvironment Responsive Nano-Drug Delivery System

Piv nrog rau cov ntaub so ntswg ib txwm, qog nqaij hlav, thiab cov hlwb muaj cov yam ntxwv tshwj xeeb ntawm microenvironment, feem ntau cuam tshuam txog cov hauv qab no [43]: (1) pH tus nqi: cov qog ib puag ncig tsis muaj zog acidic, pH 6.5-7.0. Cov qog cell suav nrog lossis lysosomes muaj pH qis dua ntawm 4.0–6.0 [44]; (2) cov qog hlwb nthuav tawm qhov chaw txo qis uas glutathione concentration tuaj yeem ncav cuag 1-10 mM, uas yog 100-1000 npaug tshaj li cov ntshav ib puag ncig [45]; (3) mitochondria ntawm cov qog hlwb nthuav tawm ib puag ncig oxidative, nyob rau hauv uas cov concentration ntawm reactive oxygen hom (ROS) tuaj yeem ncav cuag mM qib [46]. pH-responsive nano-drug delivery system: kev hloov pauv ntawm lub cev lub zog nyob rau hauv pH stimulation ua rau cov nanoparticles depolymerize kom ua tiav lub hom phiaj ntawm kev xa tshuaj hauv cov qog hlwb [47]. Reductive nano-drug delivery system: Raws li qhov sib txawv ntawm qhov sib txawv ntawm GSH hauv cov qog hlwb thiab cov ntaub so ntswg, txo cov khoom siv nanocarrier yog tsim. Disulfide lossis dis-selenium daim ntawv cog lus muaj nyob rau hauv cov khoom thauj tuaj yeem raug txo los ntawm intracellular GSH thiab tawg, yog li ua rau muaj kev hloov pauv loj ntawm cov khoom thauj thiab tso tawm cov tshuaj encapsulated [48].

5.2. Nano-Drug Design Raws li NADPH Depletion thaum GSSG Txo hauv Ferroptosis

Ferroptosis yog ib qho programmed cell tuag txoj hauv kev uas muaj kev hloov pauv hlau thiab redox homeostasis. Qhov tshwj xeeb ntawm ferroptosis feem ntau ntseeg tau tias yog qhov tsub zuj zuj ntawm ROS cia siab rau cov hlau, uas ua rau muaj qhov tshwm sim ntawm lipid peroxidation thiab cell tuag [49]. Tsis tas li ntawd, ferroptosis kuj qhia tau hais tias qhov kev poob qis ntawm kev tswj hwm ntawm cov tub ntxhais enzyme GPX4 hauv cov kab mob oxidative (glutathione system). Cov lipid peroxides yuav raug tshem tawm los ntawm GPX4. Yog tias qhov kev ua ntawm GPX4 yog inhibited, ntau lipid peroxides yuav raug tsim ua rau oxidative imbalance thiab ferroptosis tshwm sim [50]. Yog li ntawd, GPX4 inhibition lossis modulation ntawm GSH biosynthesis kom txo GPX4 kev ua haujlwm yog ob txoj hauv kev rau ferroptosis induction. GSSG raug txo rau GSH nrog GSH-R thiab noj NADPH. NADPH yog ib qho tseem ceeb hauv kev txo tus neeg sawv cev rau kev tshem tawm lipid hydroperoxides, thiab thaum cov txheej txheem no tsis zoo, ferroptosis tau tshwm sim [51]. Tsis tas li ntawd, lwm lub tswv yim ntawm ferroptosis yog arachidonic acid / adrenic acid (AA / AdA), nyob rau hauv uas cov PE-AA-OOH yog lwm qhov pom tseeb ntawm ferroptosis. Nws yog ib qho tsim nyog sau cia tias qhov sib xyaw ntawm PE-AA-OOH hauv hlwb nyob ntawm kev ua haujlwm ntawm GPX4, thiab PE-AA-OOH tuaj yeem oxidized rau PE-AA-OH nyob rau hauv lub xub ntiag ntawm GPX4 [52-54]. Yog li ntawd, NADPH depletion, ntau dhau PE-AA-OOH, thiab GPX4 tsis muaj peev xwm feem ntau tau hais tias yog cov yam ntxwv tseem ceeb ntawm induced ferroptosis [55–57], raws li qhia hauv daim duab 3B.

Daim duab 3. Pathogenesis ntawm GSH koom nrog: (A) cov txheej txheem ntawm txoj kev polyol [21]; (B) lub mechanism ntawm ferroptosis [58].

Wang et al. [58] tsim cov azobenzene txuas nrog nitroimidazole-conjugated polypeptide (DHM@RSL3), uas cleaved nyob rau hauv ib puag ncig anaerobic. DHM@RSL3 nano-micelles nkag mus rau hauv lub hlwb thiab cleaved tso RSL3, ib yam ntawm GPX4 inhibitor. Lub caij no, azobenzene depletes NADPH, ib qho tseem ceeb coenzyme nyob rau hauv kev sib txuas ntawm GSH thiab Trx (SH) 2, ua rau txo cov ntsiab lus ntawm GSH thiab Trx (SH) 2, thiab dual inducing ferroptosis los txhawb qog cell apoptosis. Zhao et al. [59] npaj ib lub RSL3 hlau FL fluorescence inducer, uas tau encapsulated hauv micelles rau phiaj GPX4. Lawv pom tias hauv cov tshuaj tiv thaiv tib neeg ntawm zes qe menyuam adenocarcinoma cell qauv, RSL3 micelles tau pom tias muaj 30 npaug ntawm cov tshuaj lom ntau dua li cov micelles tswj tau. Qhov no feem ntau yog vim qhov poob qis hauv GSH, uas txhim kho lub peev xwm ntawm RSL3 los ua rau ferroptosis.

5.3. Nano-Drug Design Raws li GSH Reductive Ability hauv Tumor Microenvironment

5.3.1. Txoj kev xav ntawm Redox-Sensitive hauv Nano-Drug Delivery System

GSH raug suav hais tias yog thawj mercaptan-disulfide redox tsis ua tus neeg sawv cev hauv cov hlwb [60,61]. Qhov siab ntawm GSH hauv cov ntshav tsuas yog 0.1 feem pua ​​​​rau 1 feem pua ​​​​ntawm cov hlwb [62], yog li cov ntshav feem ntau yog ib puag ncig uas GSH tsis tshua muaj kev cuam tshuam redox. Txawm li cas los xij, cov qog nqaij hlav qog nqaij hlav yog qhov txawv txav ntawm cov qog nqaij hlav metabolism thiab nce qib GSH thaum oxidative kev nyuaj siab raug tsim, thiab cytosolic GSH concentration hauv cov qog hlwb (2-20 mmol·L −1) yog 1000 npaug ntau dua li hauv cov hlwb li qub, ua rau nthuav qhia muaj zog txo ib puag ncig [63,64]. Qhov sib txawv ntawm qhov sib txawv no ua rau GSH los ua tus redox trigger hauv kev xa tshuaj. Yog li ntawd, lub redox-rhiab heev lub hom phiaj nano-drug xa system tau tshwm sim, uas nws lub ntsiab tsim feature yog kev qhia txog cov tshuaj tiv thaiv kab mob nyob rau hauv cov cab kuj, sab saw los yog crosslinking tus neeg saib xyuas. Ntxiv mus, cov tshuaj tiv thaiv kab mob no kuj ruaj khov nyob rau hauv ib puag ncig ntawm tib neeg lub cev nrog rau cov ntshav thiab cov ntaub so ntswg, tab sis lawv yog ib qho yooj yim rau undergo redox cov tshuaj tiv thaiv nrog siab concentrations GSH, ua rau lub cleavage ntawm tshuaj bonds tso tshuaj, thiab ua kom tiav kev xa khoom. ntawm cov tshuaj hauv cov qog hlwb [65,66].

5.3.2. Chemical Bonds React nrog GSH

Lub redox-rhiab tshuaj lom neeg daim ntawv cog lus ua lub luag haujlwm tseem ceeb hauv redox-sensitive targeted nano-drug system, uas yog sib npaug rau kev hloov ntawm kev xa khoom thiab cuam tshuam ncaj qha rau cov tshuaj tso tawm. Muaj qee qhov kev sib koom ua ke ntawm cov tshuaj tiv thaiv kab mob, xws li daim ntawv cog lus disulfide (-SS-), mono thioether daim ntawv cog lus (-S-), daim ntawv cog lus ntawm -Pt-O-, diselenide-conjugated daim ntawv cog lus (-Se-Se-) , daim ntawv cog lus ntawm -Se-N-, mono selenium daim ntawv cog lus (-Se-). Ntawm lawv, daim ntawv cog lus disulfide tau siv dav los tsim kho cov tshuaj txo qis rau kev kho mob qog noj ntshav. Cov hom thiab cov yam ntxwv ntawm cov tshuaj redox-sensitive chemical bonds muaj nyob rau hauv Table 1.

5.3.3. Nano-Drug Design Raws li cov tshuaj sib txawv ntawm Nano-Drug nrog SS

Disulfide daim ntawv cog lus (SS) yog ib qho ntawm feem ntau GSH txo rhiab heev daim ntawv cog lus, thiab cov txheej txheem tseem ceeb ntawm kev qhia -SS- yog tsim cov tshuaj nrog redox-sensitive bonds. Shao et al. [67] ntse ua ke camptothecin thiab chlorambucil los ntawm disulfide bonds los tsim ib tug tshiab tshuaj-conjugated prodrug. Raws li qhov siab ntawm GSH nyob rau hauv cov qog hlwb, cov disulfide bonds raug rhuav tshem thiab tso tawm ob cov tshuaj tiv thaiv kab mob. Piv nrog rau ib qho tshuaj tiv thaiv kab mob, ob cov tshuaj tiv thaiv kab mob tuaj yeem tsis tsuas yog tua cov qog hlwb, tab sis kuj tseem ceeb txo cov kev mob tshwm sim ntawm cov hlwb ib txwm muaj (Daim duab 4A). Khosand et al. [68] tsim cov thiol-responsive degradable micelles uas muaj cov pendant disulfide-labeled methacrylate polymer block (PHMssEt) thiab hydrophilic poly (ethylene oxide) (PEO) block. Lub disulfide daim ntawv cog lus nyob rau hauv PEO-b-PHMssEt yog cleaved nyob rau hauv qhov kev txiav txim ntawm GSH, ua rau lub instability ntawm tus kheej-tsim micelles. Qhov GSH-triggered micelle instability hloov pauv lawv qhov loj me thiab tsim cov aggregates loj, yog li txhim kho kev tso tawm cov tshuaj tiv thaiv kab mob encapsulated thiab muab cov ntawv thov siv tshuaj ntau yam (Daim duab 4B). Sun et al. [69] npaj PTX-SS CIT nanoparticles nrog siab dual dual redox rhiab heev, sai qog cov tshuaj tshwj xeeb tso tawm, thiab muaj zog tiv thaiv qog ua haujlwm (Daim duab 4C). Luo et al. [70] tsim cov tshiab redox-responsive conjugates los ntawm bridging PTX thiab OA nrog ib tug disulfide daim ntawv cog lus (PTX-SS-OA). PTX SS-OA nanoparticles tau nthuav tawm qhov zoo tshaj plaws ntawm ob qho tib si taxol thiab PTX-OA, thiab cov qog yuav luag ploj tag nrho hauv cov nas tom qab kev kho mob los ntawm nanoparticles (Daim duab 4D). Tsis tas li ntawd, muaj ntau ntau cov tshuaj nano-tshuaj rau kev kho mob qog noj ntshav raws li disulfide daim ntawv cog lus [71,72], uas muab kev pom zoo rau kev tsim qauv ntawm nano-drug xa system.

Daim duab 4. Schematic tsim ntawm txawv GSH teb tshuaj anticancer nrog disulfide daim ntawv cog lus. (A) Camptothecin thiab chlorambucil conjugated nrog disulfide bond (SS) supramolecular anticancer tshuaj. Nanoparticles cleavage rau CPT nrog GSH [67]; (B) GSH-responsive degradable PEO-b PHMssEt micelles. PEO-b-PHMssEt cleavage to PEO-b-PHMSH with GSH [68]; (C) cov disulfide daim ntawv cog lus-bridged prodrugs PTX-SS-CIT cleavage rau sib txawv tebchaw nrog GSH [60]; (D) redox responsive conjugates los ntawm bridging PTX thiab OA nrog disulfide daim ntawv cog lus (PTX-SS-OA). PTX-SS-OA cleavage rau PTX nrog GSH [70].

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