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  目前，通過化學療法治療癌癥患者是臨床研究熱點之一，但是由于抗癌藥物的副作用和多次藥物后的免疫力現象導致化學療法在臨床醫學上受到極大限制。由于腫瘤細胞擴散較快，單純的基因治療難以達到長期抑制的作用。因此聯合基因和藥物控釋治療方法，抑制腫瘤細胞并避免多次服用藥物引起的藥物免疫性，目前已成為新的研究方向。這種方法對載體材料提出了較高要求，需要同時負載抗癌藥物和目標基因并且互不干擾，有效地將藥物和基因輸送到靶細胞并進行釋放和表達。

  這項工作通過點擊化學反應和酰胺化反應，合成以殼聚糖 (Cs) 為主鏈、聚酰胺-胺樹枝狀分子 (polyamidoamine, PAMAM) 基元和脫氧膽酸 (DCA) 為側鏈的兩親性梳形聚合物 (PAMAM-Cs-DCA) (Scheme 1)。¹H NMR和FTIR表征確定了產物的結構 (Figure 1)。

Scheme 1. (A) Schematic representation of co-delivering hydrophobic drug and pDNA by PAMAM-Cs-DCA. Synthesis routes of (B) 6-N₃-Cs and (C) PAMAM-Cs-DCA.

Figure 1. (a) FT-IR spectra of propargyl focal point PAMAM dendron (G=3), 6-N₃-Cs-DCA and PAMAM-Cs-DCA. (b) ¹H NMR spectra of PAMAM dendron (G=3), 6-N₃-Cs-DCA₇, and PAMAM₁₄-Cs-DCA₇ in DMSO-d₆.

  PAMAM-Cs-DCA在水中自組裝形成以PAMAM和Cs為親水外殼、DCA為疏水內核的納米膠束，通過熒光光譜、動態光散射(DLS)和TEM測試，研究了PAMAM-Cs-DCA的膠束化行為 (Figure 2)。

Figure 2. Intensity ratios (I₁/I₃) from pyrene emission spectra in PBS buffer (pH 7.4) against the logarithm of concentration of (a) PAMAM₁₂-Cs-DCA₁₁ NPs or (b) PAMAM₁₄-Cs-DCA₇. TEM images and size distributions obtained from DLS of the NPs from (c) ) PAMAM₁₂-Cs-DCA₁₁ and (d) PAMAM₁₂-Cs-DCA₁₁-DOX.

  以阿霉素為模型藥物，考察了PAMAM-Cs-DCA納米膠束的藥物負載能力和藥物釋放行為，藥物負載率隨著DCA取代度的增加而增加，在整個藥物釋放過程中載藥膠束PAMAM-Cs-DCA-DOX的藥物釋放速率都保持緩慢而穩定，并隨著pH值的降低而變快 (Figure 3)。

Figure 3. In vitro release profiles of entrapped DOX from PAMAM₁₂-Cs-DCA₁₁ NPs and PAMAM₁₄-Cs-DCA₇ NPs in phosphate buffer (pH 7.4 or 5.2) at 37 ℃. The inset is an enlarged image for showing the initial release. (n=3, mean ± standard deviation)

  凝膠電泳實驗表明當N/P值大于等于1:1時，PAMAM-Cs-DCA和負載藥物的PAMAM-Cs-DCA-DOX都能通過親水殼PAMAM基元包裹pDNA，并完全阻滯pDNA在凝膠電泳中的遷移。DLS和Zeta電位測試表明，PAMAM-Cs-DCA和PAMAM-Cs-DCA-DOX能和pDNA形成粒徑為200-300 nm的球形復合物，表面電荷為正值。MTT測試表明PAMAM-Cs-DCA和PAMAM-Cs-DCA-DOX在293T細胞中具有較低的細胞毒性，遠低于PEI(25 KDa)的細胞毒性；負載藥物的PAMAM-Cs-DCA-DOX的細胞毒性稍大于PAMAM-Cs-DCA。PAMAM-Cs-DCA / pDNA復合物和PAMAM-Cs-DCA-DOX / pDNA復合物都能有效地將pDNA轉進293T細胞中，轉染效率隨N/P值的增加而增加；并且負載阿霉素后，復合物的轉染效率稍微降低 (Figure 4和Figure 5)。

Figure 4. Transfection efficiency of PAMAM₁₂-Cs-DCA₁₁ NPs/pDNA, PAMAM₁₄-Cs-DCA₇ NPs/pDNA, PAMAM₁₂-Cs-DCA₁₁-DOX NPs/pDNA and PAMAM₁₄-Cs-DCA₇ -DOX NPs/pDNA complexes in 293T cells at various N/P ratios using PEI/DNA complexes as the control. (*p<0.05, n=3, mean ± standard deviation)

Figure 5. Representative fluorescence images of 293T cells transfected by PAMAM₁₂-Cs-DCA₁₁NPs/pDNA complex (a: N/P 5:1; b: N/P 10:1; c: N/P 20:1), PAMAM₁₂-Cs-DCA₁₁-DOX NPs/pDNA complex (d: N/P 5:1; e: N/P 10:1; f: N/P 20:1), PEI/pDNA complex (g: N/P 10) and native pDNA (h) (AI and BI: fluorescence field images; AII and BII: bright field images).

  以上相關成果以“Cationic nanoparticles self-assembled from amphiphilic chitosan derivatives containing poly(amidoamine) dendrons and deoxycholic acid as a vector for co-delivery of doxorubicin and gene”為題在 Carbohydrate Polymers (2021，Article 117706) [SCI impact factor: 7.182] 上發表。論文的共同第一作者為陳珊珊博士生和鄧俊杰博士，通訊作者為中山大學材料科學與工程學院張黎明教授。該研究得到國家自然科學基金、廣東省自然科學基金和聚合物復合材料及功能材料教育部重點實驗室的資助與支持。

  論文鏈接: https://www.sciencedirect.com/science/article/abs/pii/S014486172100093X