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  癌癥由于其固有的異質性和動態演變，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性和動態演變的藥物輸送系統，以實現藥物在腫瘤組織進行動態深層遠端遞送。

  近日，來自法國國家科研中心馬賽納米科學跨學科中心（CINaM，CNRS）的彭玲博士團隊在PNAS發表題為Dendrimer nanosystems for adaptive tumor-assisted drug delivery via extracellular vesicle hijacking (PNAS,  2023,  Vol. 120, No. 7, e2215308120)的論文，報告了一種基于自組裝樹形分子納米載藥膠束(ADNMs)通過現場劫持內源性細胞外囊泡(EVs)的方式,克服腫瘤內微環境其異質性和動態演變, 深層遞送抗癌藥物 （圖1）, 表現出出色的抗癌活性。

  細胞外囊泡是一種內源性的運輸系統，是細胞間進行物質與信號交流的重要工具。幾乎所有的細胞類型都分泌細胞外囊泡。細胞外囊泡具有納米和微米尺寸，可以裝載各種內源性的蛋白質和核酸，以及外源性材料。重要的是，細胞外囊泡在進化上是保守的，而在腫瘤中是過度產生的。在腫瘤內原位產生的細胞外囊泡不僅可以實現靶向運輸，還能夠隨著腫瘤微環境中的母體細胞一同進化, 是一個理想的藥物輸送系統,能夠適應異質性和進化的腫瘤微環境，同時深入腫瘤進行有效的深層遠端遞送。

  文中報道，自組裝樹形分子納米膠束在到達腫瘤后,誘導腫瘤分泌的細胞外囊泡,并將所攜帶的藥物重新包裝進入細胞外囊泡。這些原位生成的細胞外囊泡被其他細胞進一步攝取和運輸（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胞殺傷力（圖3）。在胰腺癌和結直腸癌的二維、三維和異種移植小鼠模型中, 表現了出色的抗癌效力，同時消除了藥物的不良影響 （圖3）。

  該研究成果凸顯了自組裝樹形分子納米系統作為藥物遞送載體的巨大潛力，為癌癥藥物的適應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形分子超分子化學一起開發智能、高效的藥物輸送系統，以克服腫瘤內微環境其異質性和動態演變，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.

  這項研究由法國馬賽納米科學跨學科中心（CINaM）彭玲博士主導，合作者包括馬賽癌癥研究中心（CRCM）Juan Iovanna博士和中國國家納米科學與技術中心（NCNST）梁興杰教授團隊，本項工作得到了法國國家抗癌聯盟, 中法科技合作蔡元培項目和歐盟納米科技項目的支持。

  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發藥物傳遞的新途徑，用以生物影像和藥物遞送等方面的應用。

  彭玲博士是自組裝超分子樹形分子化學的先驅，開創了自組裝樹形分子在藥物遞送和生物醫學方面的研究，并成功開發了一系列自組裝樹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)，為生物醫用材料領域的發展開辟了新方向 (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