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  開發(fā)滿足不同特定需求的功能材料在生物醫(yī)學中應用具有重大的挑戰(zhàn)性。樹枝狀聚合物，憑借其精確的結構和多價協(xié)同性，是定制精密功能材料典范。近日，法國國家科學研究中心-馬賽跨學科納米研究中心與中國藥科大學合作并成功開發(fā)了一種基于bola型兩親性樹形分子（bola-amphiphilic dendrimers）的精確載體平臺, 可選擇性遞送不同類型核酸藥物（siRNA和DNA）(Figure 1)，用于腫瘤治療。結果發(fā)表在綜合性期刊Proceedings of the National Academy of Sciences of the U. S. A.(DOI: 10.1073/pnas.2220787120)

  合作團隊設計和開發(fā)了不同代數(shù)的bola型兩親性樹形分子并對其遞送不同核酸分子的能力進行了研究。結果表明，bola樹形分子的代數(shù)、核酸分子的大小以及bola樹形分子與核酸分子之間多價協(xié)同作用在很大程度上影響其選擇性遞送核酸分子的能力。例如，更高代數(shù)的bola8A能更有效地將大尺寸質(zhì)粒DNA 壓縮成小的納米復合物，顯著提高了DNA在靶細胞的攝取，展現(xiàn)出更為優(yōu)異的DNA轉(zhuǎn)染活性；較低代數(shù)的bola4A則在有效保護短鏈siRNA分子的同時，能更高效地促進siRNA 的胞內(nèi)釋放，進而發(fā)揮強有力的基因沉默效果 (Figure 2)。此外, 該類bola兩親性樹形分子所構建的核酸藥物遞送系統(tǒng)能選擇性富集在腫瘤組織，并在腫瘤細胞內(nèi)ROS刺激下特異性地釋放核酸，實現(xiàn)核酸藥物在腫瘤細胞的靶向遞送。更令人欣喜的是，上述遞送體系在宮頸癌和卵巢癌異種移植小鼠腫瘤模型、以及高侵襲性的黑色素瘤和三陰性乳腺癌轉(zhuǎn)移模型中，均表現(xiàn)出可媲美商業(yè)化載體的核酸遞送效率，能夠精準調(diào)控致病基因的表達，發(fā)揮高效的抗腫瘤活性和抗腫瘤轉(zhuǎn)移效果 (Figure 3)。本研究成果彰顯了bola型兩親性樹形分子作為按需定制核酸藥物遞送載體的巨大潛力。

Fig. 3. Effective inhibition of tumor metastasis using DNA and siRNA therapeutics delivered by bola8A and bola4A respectively in lung metastatic cancer model. (A-E) 4T1-luc metastatic tumor-bearing mice received intravenous injections of PBS buffer (control), p53 alone, p53/bola8A complex, p53/Lipo complex (2.0 mg/kg DNA, 1.5 mg/kg bola8A, N/P ratio of 1.0), siAKT2 alone, siAKT2/bola4A complex, or siAKT2/MC3 complex (1.0 mg/kg siRNA, 3.9 mg/kg bola4A, N/P ratio of 5.0) (n=5): (A) In vivo bioluminescence imaging of 4T1-luc tumor metastases in the mice. (B) Ex vivo bioluminescence imaging of 4T1-luc tumor metastases in the lung at the experimental end point post treatment. (C) Histological analysis of lung tissues from 4T1-luc metastatic tumor-bearing mice at the experimental end point post treatment. The metastatic lesions (red solid outlines) were identified as cell clusters with darkly stained nuclei. Scale bars, 1 mm. (D) p53 and (E) AKT2 protein expression revealed by immunohistochemistry staining after treatments. Scale bar, 200 μm. (F-J) B16-F10-luc metastatic tumor-bearing mice received intravenous injections of PBS buffer (control), p53 alone, p53/bola8A complex, p53/JetPEI complex (2.0 mg/kg DNA, 1.5 mg/kg bola8A, N/P ratio of 1.0), siAKT2 alone, siAKT2/bola4A complex, or siAKT2/MC3 complex (1.0 mg/kg siRNA, 3.9 mg/kg bola4A, N/P ratio of 5.0) (n=5): (F) in vivo bioluminescence imaging of B16-F10-luc tumor metastases in the mice. (G) Ex vivo bioluminescence imaging of B16-F10-luc tumor metastases in the lung tissue or images of excised lung tissues at the experimental end point post treatment. (H) Histological analysis of lung tissues from B16-F10-luc metastatic tumor-bearing mice at the experimental end point post treatment. The metastatic lesions (red solid outline) were identified as cell clusters with darkly stained nuclei. Scale bars, 1.0 mm. (I) p53 and (J) AKT2 protein expression revealed by immunohistochemistry staining after treatments. Scale bar, 200 μm. p53: plasmid DNA expressing tumor suppressor protein p53, siAKT2: siRNA targeting AKT2.

  原文鏈接：https://www.pnas.org/doi/10.1073/pnas.2220787120