Aptamer-Based Strategies To Boost Immunotherapy in TNBC Part 2
May 23, 2023
Tsis tas li ntawd, aptamers zam ntau yam kev hloov kho tshuaj uas txhim kho lub hom phiaj kev ua tau zoo, cov tshuaj pharmacokinetic profile, thiab kev ruaj ntseg hauv ib puag ncig lom neeg, uas yuav tsum muaj rau lawv cov ntawv thov vivo [47]. Raws li kev tshuaj xyuas ntau nyob rau lwm qhov [27,48], qhov kev hloov kho siv feem ntau siv rau aptamers, xws li thaum lub sij hawm SELEX los yog post-SELEX, kom lawv tiv thaiv nucleases suav nrog (Daim duab 3): qhov hloov ntawm 2 0 -OH pawg ntawm ribose nrog fluoro, methoxy, thiol lossis amino pawg; lub capping los yog cyclization ntawm oligonucleotides 'kawg; hloov cov pob txha phosphodiester nrog phosphorothioate qaum; thiab kev taw qhia ntawm xauv nucleic acids. Ntxiv mus, L-aptamers, hu ua spiegelmers, tuaj yeem tsim tawm uas tsis lees paub los ntawm nucleases vim tias lawv yog enantiomers ntawm ntuj nucleic acids. Kev hloov kho tshuaj kuj tseem siv los kov yeej lub raum pom sai ntawm cov me me aptamers los ntawm conjugating lawv cov khoom loj heev, xws li polyethylene glycol (PEG) lossis cov roj cholesterol, yog li ua rau lawv lub sijhawm ncig tsis cuam tshuam rau kev nkag mus rau lub hom phiaj. Cov txheej txheem sophisticated kuj tau tsim los rau chemically conjugate aptamers nrog cov kev kho mob theem nrab hauv kev kho mob sib xyaw ua ke, thiab nthuav dav, cov tswv yim tshiab tau tshawb nrhiav los qhia txog cov tshuaj lom neeg hauv cov aptamer molecule kom ncua lawv txoj haujlwm thiab kov yeej qhov tsis muaj tshuaj lom neeg sib txawv hauv nucleic acids [49 ].
Nucleases hais txog cov enzymes uas tuaj yeem ua kom cov tshuaj tiv thaiv hydrolysis ntawm RNA lossis DNA thiab muaj ntau yam kev ua haujlwm lom neeg. Hauv lub cev tiv thaiv kab mob, nucleases yog cov cuab yeej tseem ceeb rau kev paub thiab tshem tawm cov kab mob. Tom qab tus kab mob kis mus rau ib lub cell, nws yuav tso RNA los yog DNA mus rau hauv lub cell. Cov nucleic acid molecules no yuav raug lees paub thiab hydrolyzed los ntawm nuclease ntawm cov kab mob ntawm tes, yog li tiv thaiv tus kab mob replication thiab kis tau tus kab mob.
Tsis tas li ntawd, nucleases kuj tau koom nrog hauv kev tswj hwm ntawm lub cev thiab hloov lub cev tiv thaiv kab mob. Nucleases tuaj yeem tswj hwm qib kev qhia cov noob los ntawm kev tswj cov degradation thiab ruaj khov ntawm RNA lossis DNA. Hauv lub cev tiv thaiv kab mob, nucleases tswj cov kab mob tiv thaiv kab mob xws li apoptosis, kev nthuav qhia antigen, thiab T-cell sib txawv.
Zuag qhia tag nrho, nucleases ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob, paub txog kev kis tus kab mob, hloov cov noob qhia, thiab hloov kho lub cev tiv thaiv kab mob. Yog li ntawd, muaj ntau yam mechanisms rau kev tiv thaiv kab mob. Los ntawm qhov kev pom no, nws yog ib qho tsim nyog yuav tsum tau them sai sai rau kev txhim kho kev tiv thaiv. Cistanche txhim khu kev tiv thaiv. Cistanche yog nplua nuj nyob rau hauv ntau yam antioxidants, xws li vitamin C, vitamin C, carotenoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem tshem tawm cov dawb radicals, txo oxidative kev nyuaj siab, thiab txhim kho kev tiv thaiv. tiv thaiv kab mob.
Nyem cistanche tubulosa cov txiaj ntsig
Lwm lub tswv yim los txhim kho kev sib raug zoo ntawm kev sib raug zoo, lub hom phiaj xaiv, thiab hauv vivo bioavailability ntawm aptamers yog sawv cev los ntawm cov tiam ntawm qeeb-tawm-txoj kev hloov kho aptamers (SOMAmers). Cov no yog DNA aptamers uas dais tshuaj hloov kho nucleotides functionalized ntawm 5- txoj hauj lwm ntawm uridine nrog moieties uas tsis tau tsuas yog koom nyob rau hauv kev sib cuam tshuam nrog lub hom phiaj protein tab sis kuj tsim tshiab theem nrab thiab tertiary structural motifs uas zoo heev ua rau lub repertoire ntawm lub hom phiaj siv tau. rau cov me nyuam [50]
Txog rau tam sim no, ib qho tshuaj hloov kho ntau yam aptamer (lub npe hu ua Macugen), lub hom phiaj ntawm isoform 165 ntawm vascular endothelial txoj kev loj hlob, tau pom zoo rau kev kho mob ntawm cov hnub nyoog ntsig txog macular degeneration, thiab kaum ib aptamers nyob rau hauv kev sim tshuaj rau kev kho mob ntawm tib neeg cov kab mob sib txawv. [51,52]. Ntawm lawv, anti-nucleolin AS1411 aptamer thiab anti-stromal cell-derived factor 1 NOX-A12 aptamer tau ua tiav theem II kev sim tshuaj rau kev kho mob qog noj ntshav. Ntxiv mus, anti-protein tyrosine kinase-7 Sgc8 DNA aptamer, sau nrog 68 Ga, yog nyob rau theem pib kuv rau kev ntsuas nws tus nqi kuaj mob hauv cov neeg mob plab (ClinicalTrials.gov Identifier: NCT03385148).
3. Aptamer-based Immune Strategies rau Kev Kho Mob TNBC
Genetic thiab epigenetic mutations nyob rau hauv cov qog nqaij hlav qog nqaij hlav ua rau muaj ntau cov qog-sociated antigens uas IS lees paub tias tsis yog tus kheej thiab, yog li ntawd, rhuav tshem cov hlwb. Txawm li cas los xij, nws paub zoo tias cov qog nqaij hlav qog nqaij hlav hloov ntau lub tswv yim kom khiav tawm ntawm lub cev tiv thaiv kab mob thiab hloov cov microenvironment nyob ib puag ncig lawv qhov kev nyiam ua rau cov qog loj hlob, cuam tshuam, thiab metastasis (53 55].
Lub hom phiaj ntawm kev tiv thaiv kab mob qog noj ntshav yog txhawm rau txhim kho lossis rov kho IS lub peev xwm los kuaj xyuas thiab rhuav tshem cov qog nqaij hlav cancer los ntawm kev kov yeej cov txheej txheem uas cov qog evade thiab suppress lub cev tiv thaiv kab mob. Striking aptamer-raws li cov tswv yim tau tsim nyob rau hauv ob peb xyoos dhau los los kho qhov yog mus rau ib qho kev tiv thaiv kab mob hauv TNBC. Raws li tau tham hauv qab no nce cov pov thawj qhia tau hais tias aptamer lub peev xwm los ua kom muaj zog cytotoxic kev ua haujlwm ntawm lub cev tiv thaiv kab mob, thaiv cov tshuaj tiv thaiv kab mob, lossis nrhiav cov tshuaj tiv thaiv kab mob rau cov qog nqaij hlav (Daim duab 4).
3.1. Tumor-Infiltrating Lymphocytes
Cov hom loj ntawm lub cev tiv thaiv kab mob hauv TNBC microenvironment yog TILs, thiab lawv qhov muaj feem cuam tshuam nrog cov txiaj ntsig zoo ntawm kev ciaj sia nyob hauv cov neeg mob uas muaj cov qog nqaij hlav ntxov ntxov [56]. TILs suav nrog tag nrho CD3 ntxiv rau T hlwb, uas tuaj yeem txhawb nqa qog nqaij hlav (CD8 ntxiv rau cytotoxic T hlwb) thiab cov tshuaj tiv thaiv kab mob (CD4 ntxiv rau T-helper 1) lossis txwv cov tshuaj tiv thaiv kab mob tiv thaiv kab mob (CD4 ntxiv rau T-helper 2, suav nrog Forkhead box P3 ( FOXP3), CD4 ntxiv rau kev tswj T hlwb).
Tsis ntev los no, Zhao et al. tau npaj ib lub tswv yim qub uas siv lub hom phiaj lub peev xwm ntawm aptamers los tsim lub "super-cytotoxic T lymphocyte" rau kev txhim kho cov tshuaj tiv thaiv kab mob hauv kev kho mob qog noj ntshav [59]. Lawv tsim cov kua qaub-degradable hlau-organic-raws li thiab lysosome-targeting nanoparticles uas tau ntim nrog perforin thiab granzyme B, ob qho tshuaj tiv thaiv kab mob muaj nyob hauv lysosomes ntawm CD8 ntxiv rau T hlwb, thiab ua haujlwm nrog ib qho aptamer tsom rau CD63 receptor ntawm lysosome. Ca2 ntxiv tau tso rau ntawm nano platform los txhim kho nws cov biocompatibility thiab stability thiab potentiate toxin kev ua. Cov kws sau ntawv tau ua tiav los ntawm kev siv lub aptamer-guided platform (lub npe LYS-NPs) rau kev txhawb nqa lysosomes cov ntsiab lus cytotoxic ntawm CD8 ntxiv rau T hlwb.
Thaum kuaj hauv TNBC 4T1 nas qauv, T hlwb preactivated nrog cov txheej txheem 4T1- tshwj xeeb antigens thiab recombined los ntawm LYS-NPs thiab tso tawm cov ntsiab lus lysosomal rau hauv immunological synapses, ua rau muaj zog antitumor cov tshuaj tiv thaiv (Daim duab 4). Lub tswv yim aptamer-based immunotherapy muaj peev xwm kov yeej cov teeb meem tseem ceeb hauv T cell immunotherapy rau cov qog nqaij hlav uas feem ntau sawv cev los ntawm cov cim muaj zog tiv thaiv kab mob, uas ua rau txo qis T cell activation thiab txo qis synthesis thiab tso tawm ntawm cytotoxic proteins [60].
3.2. Immune Checkpoint-Expressing Cells
Alatrash pawg tau tshaj tawm tias qhov kev qhia ntawm PD-L1 gene hauv cov neeg mob TNBC yog qhov siab dua li cov uas tsis yog TNBC (19]. PD-L1, yog ib qho ntawm cov qog loj ntawm cov qog nqaij hlav hauv lub cev tiv thaiv kab mob, tau qhia ntau yam ntawm lub cev tiv thaiv kab mob. , xws li macrophages, ib co activated T hlwb, B hlwb, thiab nyob rau hauv ntau cov qog nqaij hlav, nrog rau BC hlwb. dendritic cells, thiab monocytes [61]. Kev khi ntawm PD-L1 thiab PD-1 ua rau inhibition ntawm CD8 ntxiv rau TILs, hloov lawv mus rau hauv daim ntawv tsis txaus ntseeg thiab, yog li ntawd, kev tiv thaiv kab mob qog noj ntshav.
Ntxiv mus, PD-1/PD-L1 axis modulates nyob rau hauv cov qog hlwb ntau yam proliferative thiab ciaj sia taus signaling txoj kev xws li PI3K/AKT, MAPK, thiab JAK/STAT [62], thiab, tseem ceeb heev, nyob rau hauv TNBC, qhov ua kom ntawm no axis txhawb kev hloov pauv ntawm epithelial-mesenchymal (EMT), ib qho phenotype txuam nrog cov qog nqaij hlav loj heev thiab metastatic [63].
Kev sib txawv ntawm aptamer-raws li txoj hauv kev hauv TNBC tam sim no tab tom tshawb nrhiav kom thim rov qab PD-1/PD-L1 teebmeem (Daim duab 5).
Daim duab 5. Schematic sawv cev ntawm aptamer-raws li tswv yim los thaiv PD-1/PD-L1 axis hauv TNBC. (a) TNBC aptamer-decorated nanoparticles loaded nrog anti-PD-L1 siRNA; (b) anti-CD44 thiab antiPD-L1 aptamer-decorated liposomes loaded nrog ob qho tib si doxorubicin thiab anti-IDO1 siRNA; (c) antiPD-L1 aptamer conjugated rau paclitaxel; (d) anti-EGFR aptamer covalently txuas rau anti-PD-L1 lossis anti-CTLA-4 mAbs (saib cov ntawv nyeem kom paub meej). Tsim nrog BioRender.com ( nkag mus rau 2 Lub Peb Hlis 2023).
Hauv cov ntsiab lus no, peb pab pawg tau tshawb xyuas, thawj zaug, kev sib xyaw ua ke ntawm cov tshuaj tiv thaiv PD-L1 mAb nrog cov tshuaj tiv thaiv platelet-derived kev loj hlob receptor (PDGFR) aptamer, hu ua Gint4.T, hauv TNBC [64]. Gint4.T yog ib qho nuclease-resistant 20 -fluoropyrimidines (20F-Py) RNA aptamer uas khi rau thiab inhibits PDGFR qhia nyob rau saum npoo ntawm tib neeg mob qog noj ntshav, suav nrog TNBC hlwb [65], thiab TNBC TME cov khoom, suav nrog mesenchymal qia hlwb [66], thiab T cells [64]. Interestingly, thaum txhaj tshuaj intravenously nyob rau hauv TNBC 4T1 syngeneic nas, lub aptamer muaj zog potentiates cov nyhuv ntawm antiPD-L1 mAbs nyob rau hauv inhibiting qog loj hlob thiab lub ntsws metastases tsim los ntawm kev ua ntawm ob lub qog hlwb thiab TME Cheebtsam [64].
Tsis tas li ntawd, kev sib xyaw ua ke ntawm PDGFR thiab PD-L1 ua rau cov FOXP3 ntxiv rau Treg hlwb thiab nce CD8 ntxiv rau T hlwb thiab granzyme B ntau dua li kev kho mob monotherapy. Cov txiaj ntsig no tau tsim lub hauv paus los tsim cov tshuaj tiv thaiv bispecific immunoconjugate uas muaj cov tshuaj tiv thaiv PD-L1 cov tshuaj tiv thaiv kab mob sib txuas nrog Gint4.T aptamer, yog li ua kom muaj txiaj ntsig zoo ntawm kev sib xyaw ua ke. Bispecific constructs tau los ntawm covalently txuas ib qho anti-epidermal loj hlob yam receptor (EGFR) 20F-Py RNA aptamer rau immunomodulators anti-PD-L1 (10_12) [67] los yog anti-CTLA-4 (ipilimumab) [68] mAbs tau tsim los ntawm Passariello li al. thiab ua pov thawj los tswj cov kev ua haujlwm lom neeg ntawm ob leeg niam txiv moieties, yog li ua kom muaj zog cytotoxic kev ua haujlwm tawm tsam BC hlwb.
Lwm lub tswv yim los tiv thaiv PD-L1 mAbs rau PD-L1 lub hom phiaj yog sawv cev los ntawm kev tawm tsam ntawm PD-L1 los ntawm gene silencing, uas muaj peev xwm kov yeej qee qhov kev cuam tshuam ntawm mAbs-raws li kev kho mob, xws li lawv lub sijhawm- thiab tus nqi. -siv ntau lawm, lub peev xwm rau immunogenicity, thiab tsis tshua muaj stability. Tsis tas li ntawd, lub tswv yim no tso cai rau kev thaiv ntawm lub luag haujlwm ntawm lub hauv paus pro-tumorigenic ntawm cytoplasmic PD-L1 [69] uas, hloov pauv, tsis tuaj yeem siv los ntawm cov tshuaj tiv thaiv. Qhov muaj peev xwm ntawm synthesizing mob cancer-cell-targeting aptamers nrog cov pab pawg ua haujlwm ntawm lawv qhov kawg, tso cai rau kev sib txuas rau nano vectors, yog ib qho kev tawm tsam kom xa, tshwj xeeb rau cov qog, me me-interfering RNA (siRNA) cargos, loaded nyob rau hauv nano vectors. , yog li kov yeej qhov tsis zoo ntawm siRNAs rau nucleases thiab lawv tsis muaj peev xwm nkag mus rau hauv cov phiaj hlwb. Tsis ntev los no, poly (lactic-co-glycolic)-block-PEG (PLGAb-PEG)-raws li nanoparticles tau ntim nrog anti-PD-L1 siRNA thiab dai kom zoo nkauj nrog 20F-Py RNA aptamer tuaj yeem khi thiab sab hauv tshwj xeeb rau hauv TNBC hlwb. [70,71].
Qhov tshwm sim aptamer-conjugated nano vectors, raws li 90 min incubation ntawm TNBC hlwb, zoo xa siRNA rau hauv lub hom phiaj hlwb, uas muaj peev xwm ua rau yuav luag tag nrho PD-L1 qhia [72]. Qhov tseem ceeb, aptamer-decorated nanocarriers muab qhov muaj peev xwm los txuas cov ligands sib txawv rau saum npoo ntawm NPs, yog li ua kom qhov tshwj xeeb ntawm cov hom phiaj, thiab txhawm rau txhawm rau hauv NPs ntau yam kev kho mob, yog li tso cai rau cov kev kho mob ua ke zoo. Piv txwv li, kev tswj hwm kev sib koom ua ke ntawm cisplatin [40] thiab siPD-L1 [72] los ntawm PLGA polymeric nanoparticles, uas peb nruab nrog TNBC aptamers, yuav tsis tsuas yog txhawb kev txo qis hauv cov tshuaj lom neeg, tab sis kuj tiv thaiv cov kev qhia tsis zoo ntawm cisplatin. Kev tswj hwm ntawm kev txhawb nqa ntawm PD-L1 ntxiv rau lub cev tiv thaiv kab mob TNBC hlwb [73].
Hauv qhov no, Kim et al. npaj ib lub tshuab ua haujlwm ntau yam uas muaj ob lub DNA aptamers sib txuas rau sab nraud ntawm liposomes thiab ob txoj kev kho mob sib txawv hauv nano vectors rau kev sib koom ua ke chemoimmunotherapy hauv TNBC [74]. Tshwj xeeb, lawv tau siv, rau TNBC hlwb lub hom phiaj, yav dhau los xaiv los tiv thaiv CD44 [75] thiab anti-PD-L1 [76] DNA aptamers, txhua thiol-hloov kho thiab covalently conjugated rau pawg txiv neej ntawm PEGylated-DSPE micelles los ntawm thiol-maleimide chemistry. Nanosized liposomes tau ntim nrog ob qho tib si doxorubicin thiab siRNA cuam tshuam nrog kev qhia ntawm IDO1, cov protein uas txhawb nqa kev tiv thaiv kab mob TME thiab tau tswj hwm los ntawm kev kho doxorubicin. Thaum txhaj tshuaj rau hauv TNBC 4T1 qog-xenograft nas, nano vectors tau txo qis cov qog loj hlob thiab inhibited metastasis tsim los ntawm synergistically combining cancer-cell-targeted immunogenic cell tuag induction thiab reversal ntawm immunosuppression [74].
Tsis ntev los no, sib txawv PD-L1 aptamers tau tsim thiab sim ua ib leeg antagonists, bispecific conjugates, thiab xa cov neeg ua haujlwm kho mob hauv lub ntsws, daim siab, thiab cov qog nqaij hlav hauv plab, uas, zoo ib yam li cov tshuaj tiv thaiv PD-L1, cuam tshuam nrog lub PD-1/PD-L1 axis los ntawm thaiv cov PD-L1 (Table 2). Ib qho aptamer, lub npe hu ua XQ-P3, tau tsim los ntawm kev xaiv zoo ntawm PD-L1 overexpressing MDA-MB-231 hlwb los ntawm kev siv PD-L1 knockout hlwb rau counterselection [77]. Txawm hais tias tseem tsis tau sim hauv vivo, nws zoo nkaus li muaj txiaj ntsig zoo hauv kev sib koom ua ke ntawm TNBC MDA-MB-231 hlwb thiab lub cev tiv thaiv kab mob Jurkat los ntawm kev thaiv kev cuam tshuam nrog PD-1 thiab rov ua haujlwm T cell. Tsis tas li ntawd, ib qho XP-Q3 aptamer-paclitaxel conjugate tau pom tias muaj kev tiv thaiv kev loj hlob hauv PD-L1 overexpressed TNBC hlwb [77].
3.3. Macrophages
Tumor-associated macrophages (TAMs) yog cov kab mob tiv thaiv kab mob ntau tshaj plaws hauv TME ntawm ntau hom qog noj ntshav thiab tuaj yeem ua los txhawb lossis txo cov tshuaj tiv thaiv kab mob tiv thaiv kab mob [86,87]. Tseeb, vim lawv cov qib siab ntawm plasticity, lawv hloov mus rau ob hom phenotypes nyob rau hauv cov lus teb rau ntau yam micro-environmental stimuli: classical activated, proinflammatory M1, thiab activated anti-inflammatory M2, uas tso saib ib tug sib txawv qhia profiles rau cell nto markers thiab. sib txawv cytokine thiab chemokine ntau lawm. M1 macrophages feem ntau siv cov tshuaj tiv thaiv kab mob, thaum M2 macrophages txhawb cov qog nqaij hlav. Hauv feem ntau cov qog nqaij hlav hnyav, suav nrog TNBC, TAMs zoo ib yam li M2-zoo li phenotype uas feem ntau suav nrog kev tsis ua haujlwm ntawm cov kev kho mob thiab kev tiv thaiv kab mob tiv thaiv kab mob. Vim li no, ob peb txoj hauv kev tiv thaiv kab mob tiv thaiv kab mob tshiab tau tsom mus rau lub hom phiaj thiab tshem tawm M2 macrophages lossis reprogram lawv mus rau qhov xav tau phenotype [88,89].
Txhawm rau xaiv cov aptamers tsom rau tib neeg M2-zoo li macrophages, thawj cell-SELEX txoj hauv kev tau siv rau tib neeg macrophages tau los ntawm monocytes ntawm ntau tus neeg pub dawb thiab polarized rau M2-zoo li phenotype [90]. Txawm hais tias qhov zoo tshaj plaws M2-targeting DNA aptamer los ntawm kev xaiv tsis muaj peev xwm cais cov hom phiaj ntawm cov hlwb los ntawm qhov tsis sib xws ntawm M0-zoo li thiab monocytes thiab tseem khi ntawm qis dua rau M1-zoo li macrophages, nws sai sai internalized rau hauv CD14 ntxiv rau monocytes, yog li tuav lub peev xwm rau monocyte-targeted tshuaj daim ntawv thov.
Lwm qhov kev tawm tsam ntawm aptamers rau kev kho mob qog noj ntshav muaj peev xwm muaj peev xwm M1 macrophage tshwj xeeb rau cov qog hlwb los ntawm kev tsim kho lawv nrog mob qog noj ntshav-tshuaj aptamers. Chimeric antigen receptor T (CAR-T) cell immunotherapy, uas infuses cov neeg mob nrog CAR-T hlwb, tau qhia tau zoo heev nyob rau hauv kev kho mob ntawm ib co leukemias thiab lymphomas tab sis tsuas yog me ntsis tshwm sim nyob rau hauv cov qog nqaij hlav vim qhov nyuaj ntawm nkag mus rau cov qog [91] . Vim tias muaj peev xwm ntawm macrophages nkag mus rau cov qog nqaij hlav, ntau txoj hauv kev tau tsis ntev los no tau hais tias cov noob caj noob ces ua kom lawv nthuav qhia chimeric CARs (CAR-M) rau kev tsom cov qog hlwb thiab pib lub hom phiaj antitumor teb [92]. Txhawm rau kov yeej qhov teeb meem loj cuam tshuam nrog kev kho mob CAR-M, xws li kev tsim tawm qis ntawm cov khoom siv hluav taws xob thiab cov teeb meem kev nyab xeeb, Qian li al. tau npaj ib txoj hauv kev tshiab CAR-M raws li kev siv aptamers [93].
Lub murine ruaj khov macrophage cell kab, RAW 264.7, yog thawj zaug incubated nrog azide-muaj metabolic glycoprotein labeling reagent thiab lipopolysaccharide los tsim cov suab thaj azido ntawm M1 cell nto. Tom qab ntawd, M1 hlwb tau sib txuas los ntawm kev nias chemistry cov tshuaj tiv thaiv rau ob qho tib si AS1411 aptamer, uas khi rau nucleolin qhia rau ntau lub qog nqaij hlav cancer, thiab PD-L1 aptamer, rau tib lub hom phiaj qog nqaij hlav thiab lub cev tiv thaiv kab mob. Qhov tseem ceeb, nyob rau hauv vivo, cov duab ntawm nas bearing 4T1 TNBC thiab intravenously txhaj nrog M1 hlwb, functionalized nrog fluorescent aptamers, pom ib tug ntau dua tsub zuj zuj nyob rau hauv cov qog piv nrog unmodified M1 hlwb. Tsis tas li ntawd, thaum kuaj rau kev ua haujlwm antitumor, dual-aptamer-engineered M1 ua rau muaj kev txo qis hauv cov qog loj hlob thiab metastasis tsim, uas tau nrog lub cev tiv thaiv kab mob TME reprogramming nrog nce T cell infiltration hauv qog thiab txhim kho T cell cytotoxicity.
Xwb, Chen et al. npaj polyvalent spherical aptamers (PSAs) raws li ib tug macrophage engineering tswv yim [94]. PSAs tau tsim los ntawm kev ua haujlwm ntawm kub nanoparticles nrog ob qho tib si thiol-hloov kho AS1411 aptamer thiab DNA txuas uas nqa, ntawm qhov chaw dawb, pab pawg ua haujlwm rau kev ua haujlwm nrog cov cim npe azide tsim ntawm M0 macrophages los ntawm cov lus hais saum toj no metabolic. labeling thiab biorthogonal nyem cov tshuaj tiv thaiv (Daim duab 6). Lub phenotypic transformation ntawm engineered non-polarized macrophages rau hauv M1 subtype yog qhib los ntawm X-rays nyob rau hauv vitro thiab paub tseeb tias nyob rau hauv nas bearing 4T1 qog xenografts, ua rau muaj zog qog-tshwj xeeb tua yam tsis muaj cov tsos mob ntawm cov kab mob toxicity.
3.4. Ntuj Killer Cells
NK hlwb yog cytotoxic lymphocytes nyob rau hauv lub hauv paus IS, muaj peev xwm tsim inflammatory cytokines thiab chemokines. Lawv raug hu ua "thawj kab ntawm kev tiv thaiv" vim hais tias, txawv ntawm T lymphocytes, lawv tsis qhia antigen tshwj xeeb T cell receptors tab sis ua tawm tsam cov hlwb uas tsis muaj kev xav ua ntej lossis kev nthuav dav clonal [95]. NK cell adoptive immunotherapy ua tsis tau tejyam rau kev kho mob ntawm cov qog nqaij hlav, ib nrab vim lub immunosuppressive TME thiab tsis muaj NK cell tshwj xeeb rau cov qog [96].
Yog li ntawd, ntawm txoj hauv kev los txhim kho NK cell anticancer therapeutic efficacy, ib qho kev siv zog zoo yog tsom mus rau kev qhia txog kev mob qog noj ntshav los ntawm kev qhia ntawm CARs lossis kev sib txuas ntawm cov qog nqaij hlav ligands [97]. Zu thiab cov npoj yaig tshawb nrhiav aptamers ua cov neeg ua haujlwm mob qog noj ntshav los ntawm kev sib txuas cov aptamer, muaj peev xwm paub txog CD30 receptor, ntawm cov qog ntshav qog ntshav mus rau saum npoo ntawm NK coj mus muag kab lossis NK hlwb tau los ntawm peb tus neeg noj qab haus huv [98]. Cov DNA-hom aptamer yav dhau los tau xaiv los ntawm tib pab pawg los ntawm hybrid SELEX mus kom ze, nyob rau hauv cov kauj ruam ntawm kev xaiv ntawm CD30 ntxiv rau cov qog ntshav qog ntshav tau ua raws li cov kauj ruam xaiv ntawm CD30 recombinant protein [99]. Lub aptamer tau hloov kho ntawm 30 xaus nrog lipophilic ob chav C18 hydrocarbon chains rau anchoring mus rau hauv daim nyias nyias ntawm NK hlwb, uas yog li qhia tshwj xeeb rau lymphoma hlwb kom tua lawv [98]. Tsis ntev los no, tib cov kws sau ntawv tau siv tib txoj hauv kev hauv TNBC los ntawm kev xa cov DNA aptamer muaj peev xwm los khi cov protein uas tseem tsis tau paub txog ntawm TNBC hlwb mus rau saum npoo ntawm NK hlwb. Aptamer-engineered NK cells inhibited ntsws metastasis los ntawm MDA-MB-231 cov hlwb tau txhaj rau hauv cov nas uas tsis muaj tshuaj lom rau cov nqaij ib txwm [100].
Txhawm rau txhim kho cov qog-qhov tshwj xeeb ntawm NK hlwb hauv cov qog nqaij hlav, ob lub aptamer-nruab NK hlwb tau tsim los ntawm kev siv ob qho tib si aptamer targeting hepatocellular carcinoma cells thiab AptPD-L1 aptamer [81]. Qhov tshwm sim engineered NK hlwb tau zoo dua li cov hlwb tsis sib txuas lossis sib txuas nrog tsuas yog ib qho ntawm ob lub aptamers hauv inhibiting kev loj hlob ntawm hepatocellular carcinoma hauv cov nas uas tau txais kev hloov pauv. Lwm qhov kev txwv rau kev ua haujlwm ntawm kev tiv thaiv kab mob nrog NK hlwb yog lawv cov infiltration tsis txaus hauv cov qog nqaij hlav. Ib zaug ntxiv, aptamers tau ua pov thawj tias yog cov cuab yeej zoo tshaj plaws los daws qhov teeb meem no. Hock pawg tau tsim ib qho kev sib txuas ntawm bispecific aptamer-raws li conjugate muaj peev xwm ntawm ib txhij khi rau c-Met, ib qho receptor zoo heev qhia ntawm ntau lub qog hlwb, thiab rau Fcg receptor III (CD16a), cov protein qhia ntawm NK hlwb [101]. Lub conjugate yog tsim los ntawm ob qho tshwj xeeb c-Met thiab CD16a DNA aptamers uas tau fused los ntawm cov sib txuas sib txawv, khaws cia ∼65 Å-zoo tagnrho nrug rau ib txhij khi rau ob receptors. Lub conjugate muaj peev xwm ua tau zoo ua raws li cov tshuaj tiv thaiv kab mob ntawm cov cellular cytotoxicity los ntawm kev nrhiav NK hlwb rau cov qog nqaij hlav cancer. Tom qab ntawd, tib CD16 aptamer tau fused rau PD-L1 DNA aptamer los tsim ib qho kev tsim muaj peev xwm los nrhiav ob leeg NK hlwb rau PD-L1 ntxiv rau cov qog hlwb thiab ua rau PD-1/PD-L1 immunosuppressive axis los ntawm reactivating TILs. tawm tsam qog nqaij hlav hauv cov nas uas muaj kabmob [82]. Txoj hauv kev no tau qhia tshwj xeeb rau cov qog nqaij hlav uas muaj qib siab ntawm PD-L1, xws li TNBC.
4. Cov lus xaus
Cov kev tshawb fawb tsis ntev los no tau tham txog ntawm no kom meej meej qhia tau hais tias muaj peev xwm loj ntawm oligonucleotide aptamers los ua kom peb cov IS tiv thaiv qog noj ntshav. Aptamers tuaj yeem siv los ua cov tshuaj tiv thaiv kab mob tib yam li mAbs tab sis pheej yig dua, tsim tau sai dua thiab muaj kev tsim tawm ntau dua, thiab tsawg dua immunogenic dua li cov tshuaj tiv thaiv. Txawm li cas los xij, nws yuav tsum tau lees paub tias qhov tuaj txog ntawm aptamers hauv tsev kho mob tau ua pov thawj qeeb dua li qhov xav tau; Qhov tseeb, txawm tias ntau tshaj 30 xyoo tau dhau los txij li thawj SELEX [25,26], tsuas yog peb aptamers tam sim no nyob rau hauv kev sim tshuaj rau kev kho mob qog noj ntshav [51].
Qhov kev poob qis no feem ntau yog vim qee qhov kev sib tw uas txwv cov kev ua tau zoo ntawm cov neeg mob, xws li lawv qhov kev ruaj ntseg tsis ruaj khov thiab ib nrab-lub neej, tshwj xeeb tshaj yog nyob rau hauv qhov nyuaj thiab tsis tu ncua hloov zuj zus microenvironment uas nyob ib puag ncig cov qog. Txawm li cas los xij, cov tswv yim xav tsis thoob uas tau tsim nyob rau hauv ob peb xyoos dhau los kom kov yeej cov teeb meem uas tau hais tseg saum toj no thiab qhov kev vam meej tsis ntev los no hauv aptamer nrhiav thiab kev hloov kho rau kev yoog rau txhua qhov kev xav tau ua rau nws tsim nyog los sib cav tias kev xyaum siv aptamers yuav sai sai no. yuav tsum paub txog cov qog nqaij hlav xws li TNBC, uas xav tau kev kho mob sai sai.
Tus sau kev koom tes:
Kev xav, LC; sau ntawv—kev npaj ua ntej, LC; sau — tshuaj xyuas thiab kho LA, Ad, RN, MF, SC, thiab LC Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Nyiaj txiag:
Qhov kev tshawb fawb no tau txais nyiaj los ntawm Fondazione AIRC per la Ricerca sul Cancro, IG 23052, rau LCLA tau txais kev txhawb nqa los ntawm AIRC kev sib raug zoo rau Ltalis.
Institutional Review Board Statement:
Tsis siv tau.
Cov ntaub ntawv muaj nyob:
Tsis siv tau.
Kev lees paub:
Peb ua tsaug rau A. Caliendo rau kev sib tham pom zoo.
Kev tsis sib haum xeeb ntawm kev txaus siab:
Cov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab.
Cov ntaub ntawv
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