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  癌癥由于其固有的異質(zhì)性和動(dòng)態(tài)演變，仍然是一種難以治療的疾病。其治療迫切需要能夠克服腫瘤異質(zhì)性和動(dòng)態(tài)演變的藥物輸送系統(tǒng)，以實(shí)現(xiàn)藥物在腫瘤組織進(jìn)行動(dòng)態(tài)深層遠(yuǎn)端遞送。

  近日，來(lái)自法國(guó)國(guó)家科研中心馬賽納米科學(xué)跨學(xué)科中心（CINaM，CNRS）的彭玲博士團(tuán)隊(duì)在PNAS發(fā)表題為Dendrimer nanosystems for adaptive tumor-assisted drug delivery via extracellular vesicle hijacking (PNAS,  2023,  Vol. 120, No. 7, e2215308120)的論文，報(bào)告了一種基于自組裝樹(shù)形分子納米載藥膠束(ADNMs)通過(guò)現(xiàn)場(chǎng)劫持內(nèi)源性細(xì)胞外囊泡(EVs)的方式,克服腫瘤內(nèi)微環(huán)境其異質(zhì)性和動(dòng)態(tài)演變, 深層遞送抗癌藥物 （圖1）, 表現(xiàn)出出色的抗癌活性。

  細(xì)胞外囊泡是一種內(nèi)源性的運(yùn)輸系統(tǒng)，是細(xì)胞間進(jìn)行物質(zhì)與信號(hào)交流的重要工具。幾乎所有的細(xì)胞類(lèi)型都分泌細(xì)胞外囊泡。細(xì)胞外囊泡具有納米和微米尺寸，可以裝載各種內(nèi)源性的蛋白質(zhì)和核酸，以及外源性材料。重要的是，細(xì)胞外囊泡在進(jìn)化上是保守的，而在腫瘤中是過(guò)度產(chǎn)生的。在腫瘤內(nèi)原位產(chǎn)生的細(xì)胞外囊泡不僅可以實(shí)現(xiàn)靶向運(yùn)輸，還能夠隨著腫瘤微環(huán)境中的母體細(xì)胞一同進(jìn)化, 是一個(gè)理想的藥物輸送系統(tǒng),能夠適應(yīng)異質(zhì)性和進(jìn)化的腫瘤微環(huán)境，同時(shí)深入腫瘤進(jìn)行有效的深層遠(yuǎn)端遞送。

  文中報(bào)道，自組裝樹(shù)形分子納米膠束在到達(dá)腫瘤后,誘導(dǎo)腫瘤分泌的細(xì)胞外囊泡,并將所攜帶的藥物重新包裝進(jìn)入細(xì)胞外囊泡。這些原位生成的細(xì)胞外囊泡被其他細(xì)胞進(jìn)一步攝取和運(yùn)輸（圖2），將藥物送入腫瘤組織深處，提高了藥物輸送效率和癌細(xì)胞殺傷力（圖3）。在胰腺癌和結(jié)直腸癌的二維、三維和異種移植小鼠模型中, 表現(xiàn)了出色的抗癌效力，同時(shí)消除了藥物的不良影響 （圖3）。

  該研究成果凸顯了自組裝樹(shù)形分子納米系統(tǒng)作為藥物遞送載體的巨大潛力，為癌癥藥物的適應(yīng)性遞送提供了新的思路，即利用腫瘤的固有特征與自組裝樹(shù)形分子超分子化學(xué)一起開(kāi)發(fā)智能、高效的藥物輸送系統(tǒng)，以克服腫瘤內(nèi)微環(huán)境其異質(zhì)性和動(dòng)態(tài)演變，從而改善癌癥治療，最終提高癌癥治療的效果。

Figure 1: Amphiphilic dendrimer nanomicelles (ADNMs) encapsulate the anticancer drug and induce tumor-assisted drug delivery via extracellular vesicle (EV)-mediated intercellular transport. The amphiphilic dendrimer (AD) encapsulates the anticancer drug and forms nanomicelles (ADNMs) which reach the tumor lesion via the enhanced permeability and retention (EPR) effect. There they induce in situ tumor-assisted drug delivery for deep tumor penetration via EV-mediated intercellular transport. This EV-mediated delivery process involves: (1) internalization of ADNMs inside cells within the tumor tissue; (2) repackaging of ADNM payload into EVs; (3) intercellular transport of the generated EVs; (4) internalization of the generated EVs by the recipient cell.

Figure 2. ADNM induced EV payload-packaging and cellular uptake. EVs, generated by cells upon treatment with ADNMs (R/AD, Cy3/R/AD and Dil/R/AD), were characterized using TEM (a), cryogenic electron microscopy (Cryo-EM) (b), fluorescent microscopy (c) and EV using western blotting (d). e, Confocal images of cryo-sectioned tumor tissues from HCT-8GFP xenograft mice treated with ADNM (DiI/R/AD) show the process of EV-mediated delivery in the tumor. The DiI fluorescence appeared in EVs derived from HCT-8GFP tumor (arrows). The hollow-donut shape of red DiI signal with green GFP filling highlights the HCT-8GFP-derived EVs with the DiI-labelled phospholipid bilayer and the HCT-8GFP-derived contents inside. Box 1, a DiI-loaded EV (arrow) located within the intercellular space; Box 2–4, the DiI-loaded EVs mediated intercellular transport within the tumor. Box 2, DiI-loaded EVs adhered onto the cell surface; Box 3, a DiI-loaded EV entering into a cell; Box 4, a DiI-loaded EV inside a cell. The tumor tissues were collected 24 hours after intravenous injection of DiI/R/AD in HCT-8GFP xenografts. AD: amphiphilic dendrimer; C: Cy3; Dil: fluorescent dye; R: rapamycin.

Figure 3. ADNMs were effective for inhibiting tumor growth, reducing drug toxicity and preventing tumor metastasis via specific accumulation and deep penetration through EVs in tumor. a, Tumor growth curves of the patient-derived pancreatic cancer xenografts PDAC087T and PDAC074T, and the colorectal cancer HCT-8 xenografts in mice upon treatment with ADNM carrying either doxorubicin (DOX) or rapamycin R, respectively. Mice treated with PBS buffer, drug alone or dendrimer alone were used as the controls. Data are presented as the mean?±?s.e.m. The statistical significance was calculated by two-way ANOVA with a Tukey''s multiple comparisons test. n?=?6 mice for all groups. *P?<?0.05, **P?<?0.01, ***P?<?0.001, ****P?<?0.0001. b, Accumulation of R/AD in tumors in the PDAC074T and HCT-8 xenograft mice was analyzed using fluorescent imaging with ADNM carrying both rapamycin and the near-infrared fluorescent dye DiR (DiR/R/AD). The in vivo fluorescence images were acquired 48 hours after intravenous administration of DiR/R/AD in PDAC074T (upper panel) and HCT-8 (lower panel) xenografts. Mice treated with PBS, free DiR, and a simple mixture of DiR, rapamycin and AD (DiR+R+AD), were used as controls. Arrows point to the tumor locations. c, Confocal images of tumor tissues show a deep intratumoral penetration of R/AD, using ADNM loaded with both rapamycin and the fluorescent dye DiI (DiI/R/AD). Mice treated with PBS, DiI alone, or a simple mixture of DiI, rapamycin and AD (DiI+R+AD), were used as controls. Tumors were harvested from PDAC074T (left) and HCT-8 (right) xenografts 24 hours post-intravenous administration, then cryosectioned and imaged by tracing DiI fluorescence (red). Blood vessels were labelled with DyLight488-labelled Lycopersicon esculentum lectin (green), and nuclei with DAPI (blue). d, HE stain of heart tissue issued from PDAC087T xenografts treated with PBS, AD, DOX and DOX/AD (n = 6). Treatment with DOX/AD prevented DOX-induced hyperemia and myocardial fiber breakage (arrows) in heart. e, HPS stain of lung tissues issued from HCT-8 xenografts treated with PBS, AD, R and R/AD (n = 6). Treatment with R/AD prevented the rapamycin-induced lung metastasis (T represents the tumor). Lung metastases were observed in mice treated with R, but not in those treated with PBS, dendrimer alone (AD) or the R/AD. Lung tissue was collected from mice at the end of treatment.

  這項(xiàng)研究由法國(guó)馬賽納米科學(xué)跨學(xué)科中心（CINaM）彭玲博士主導(dǎo)，合作者包括馬賽癌癥研究中心（CRCM）Juan Iovanna博士和中國(guó)國(guó)家納米科學(xué)與技術(shù)中心（NCNST）梁興杰教授團(tuán)隊(duì)，本項(xiàng)工作得到了法國(guó)國(guó)家抗癌聯(lián)盟, 中法科技合作蔡元培項(xiàng)目和歐盟納米科技項(xiàng)目的支持。

  本文的第一作者是姜一帆博士，主要致力于藥物的靶向輸送并開(kāi)發(fā)藥物傳遞的新途徑，用以生物影像和藥物遞送等方面的應(yīng)用。

  彭玲博士是自組裝超分子樹(shù)形分子化學(xué)的先驅(qū)，開(kāi)創(chuàng)了自組裝樹(shù)形分子在藥物遞送和生物醫(yī)學(xué)方面的研究，并成功開(kāi)發(fā)了一系列自組裝樹(shù)形分子超分子納米體系用于遞送抗癌藥物 (PNAS 2023, 120, e2215308120; Chem. Commun. 2018, 54, 5956-5959; PNAS 2015, 112, 2978–2983), 核酸藥物 (PNAS 2023, 120, e2220787120 ; Nat. Protoc. 2021, 16, 327–351; Nano Research, 2021, 14, 2247–2254) 和顯像劑 (PNAS 2018, 115, 11454-11459; Chem. Commun. 2020, 56, 301-304 ; Small 2020, 16, 2003290)，為生物醫(yī)用材料領(lǐng)域的發(fā)展開(kāi)辟了新方向 (Acc. Chem. Res. 2020, 53, 2936-2946; Acc. Mater. Res. 2022, 3, 484-497).

  原文鏈接:https://doi.org/10.1073/pnas.2215308120