ISSN 1000-3304CN 11-1857/O6

聚谷氨酸接枝聚乙二醇抗肿瘤药物靶向输送系统

汤朝晖 陈学思

引用本文: 汤朝晖, 陈学思. 聚谷氨酸接枝聚乙二醇抗肿瘤药物靶向输送系统[J]. 高分子学报, 2019, 50(6): 543-552. doi: 10.11777/j.issn1000-3304.2019.19036 shu
Citation:  Zhao-hui Tang and Xue-si Chen. Tumor-targeting Drug Delivery Systems Based on Poly(L-glutamic acid)-g-Poly(ethylene glycol)[J]. Acta Polymerica Sinica, 2019, 50(6): 543-552. doi: 10.11777/j.issn1000-3304.2019.19036 shu

聚谷氨酸接枝聚乙二醇抗肿瘤药物靶向输送系统

    作者简介: 陈学思,男,1959年生. 1982年毕业于吉林大学化学系高分子专业,获得学士学位. 1985 ~ 1992年在中国科学院长春应用化学研究所任实习员、助理研究员. 1988年获得中国科学院长春应用化学研究所功能高分子实验室高分子化学专业硕士学位,1997年获得日本早稻田大学应用化学科高分子科学专业博士学位. 1997 ~ 1999年在美国宾夕法尼亚大学医学院从事博士后研究,1999年回到中国科学院长春应用化研究所,任研究员/课题组长,2005年获得国家杰出青年科学基金资助. 主要从事生物可降解高分子的合成及其相关生物医用应用的研究;
    通讯作者: 陈学思, E-mail: xschen@ciac.ac.cn
摘要: 基于聚乙二醇-聚氨基酸载体材料的肿瘤靶向药物输送系统在降低药物毒副作用,在提高治疗指数,增加候选药物成药性方面具有巨大潜力. 本文围绕以聚谷氨酸接枝聚乙二醇为载体的肿瘤靶向药物输送系统,对近年来课题组肿瘤治疗相关基础研究领域的一些进展进行了总结,梳理了高分子载体结构对纳米药物体内行为的影响规律,提出了“边缘与中心”协同治疗和“凝血靶向”的概念,发现了纳米药物的瘤内低渗透性可显著提高血管阻断剂的肿瘤血管靶向性和抑瘤能力,创建了联合使用血管阻断剂纳米药物与乏氧激活前药的高效实体肿瘤治疗新策略.

English

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  • Figure 1.  (a) Preparation of CDDP-NPs; (b) Time profiles of platinum concentration in the plasma after i.v. administration of free CDDP and CDDP-NPs. Drugs were administered to healthy rats at a dose of 5 mg·kg–1 based on CDDP. Each group is expressed as mean ± STD (n = 3); (c) Time profiles for platinum concentrations in the tumor after a single i.v. injection of CDDP (5 mg·kg–1) and CDDP-NPs (5 mg·kg–1 on the basis of CDDP) in LLC bearing mice (male), values are expressed as the mean ± STD (n = 4). (Reprinted with permission from Ref.[23]; Copyright (2015) Elsevier B.V.)

    Figure 2.  (a) Schematic representation of the mechanism of coadministration of CDDP-NPs plus CA4P. CDDP-NPs mainly act on the tumor periphery, while leaving the central regions unaffected. CA4P eradicates tumor cells in the central regions of a solid tumor. In contrast, the coadministration of CDDP-NPs plus CA4P results in the eradication of the entire tumor; (b) Orthogonal views of MSOT images of MDA-MB-435 tumor bearing mice at 4 h after injection of IR830-labeled CDDP-NPs without (left) or with (right) CA4P (100 mg/kg). The 3D coordinate system defines the orientations and positions of the orthogonal views. The regions circled with dashed yellow and white lines are bladder and tumor regions, respectively; (c, d) Tumor therapy effect of saline, CDDP (4 mg/kg), CDDP-NPs (4 mg CDDP equivalent/kg), CA4P (100 mg/kg) and CDDP-NPs (4 mg CDDP equivelent/kg) + CA4P (100 mg/kg) on MDA-MB-435 tumors-bearing Balb/C nude mice. Injections were carried out on day 1, 3, 8, 10, 15, and 17 except CDDP. Because of severe systemic toxicity, CDDP was only administered on day 1, 3, and 17 (n = 6, *p < 0.05, **p < 0.01, ***p < 0.001). (Reprinted with permission from Ref.[32]; Copyright (2015) Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)

    Figure 3.  (a) Illustration of a cooperative tumor-targeted drug delivery platform. DMXAA selectively disrupts the tumor vasculature and creates a unique artificial coagulation environment in a tumor. A15-PGA-CisPt are selectively recruited to the tumor by binding to fibrin clots via transglutamination; (b) Preparation of coagulation-targeted poly(L-glutamic acid)-cisplatin conjugates (A15-PGA-CisPt); (c) Mechanism of DMXAA-induced coagulation cascade in tumors; (d) Mechanism of A15-PGA-CisPt participation in fibrin cross-linking reaction; (e) Pt accumulation in C26 tumors at 24 h following administration of free cisplatin (4.0 mg/kg), A15-PGA-CisPt (4.0 mg cisplatin equivalent/kg), or DMXAA (15.0 mg/kg) + A15-PGA-CisPt (4.0 mg cisplatin equivalent/kg) (n = 4, **p < 0.01, ***p < 0.001); (f) Therapeutic efficacy of the cooperative drug delivery platform on C26 tumor-bearing Balb/C mice. 1: saline; 2: cisplatin, 4.0 mg/kg; 3: A15-PGA-CisPt (4.0 mg cisplatin equivalent/kg); 4: DMXAA (15.0 mg/kg); 5: DMXAA (15.0 mg/kg) + A15-PGA-CisPt (4.0 mg cisplatin equivalent/kg). Drugs were administered on the 1st, 3rd and 8th day (n = 6, ***p < 0.001). (Reprinted with permission from Ref.[40]; Copyright (2016) The Royal Society of Chemistry)

    Figure 4.  (a) Preparation of PLG-CA4; (b) Intra-tumor distribution of PLG-CA4. Immunofluorescence analysis of the C26 tumor at 24 h following injection with RhoB-labeled PLG-CA4. RhoB-labeled PLG-CA4 (red) are primarily located around the tumor blood vascular regions (green), which suggests that PLG-CA4 directs the conjugates to the vasculature within tumors; (c) In vivo tumor therapy results, (Left) C26 tumor volumes after injection with saline, PLG-CA4 and CA4P on days 1, 5 and 9, (Right) Body weight changes, (n = 6, ***p < 0.001); (d) Summarized percentage of necrotic areas across time determined by hematoxylin and eosin analysis of tumor tissues after treatment with CA4P or PLG-CA4 at a CA4 dose of 50.0 mg/kg (n = 4, ***p < 0.001); (e) Mechanism of PLG-CA4 and CA4P for solid tumor treatment. After tail vein injection, PLG-CA4 nanomedicine arrive and arrest around tumor vessels because of low tissue penetration, CA4 is gradually released and acts constantly on endothelial cells of tumor vessel, resulting in endothelial cells deformation, diminished blood flow, oxygen and nutrient deprivation and widespread tumor cell necrosis. CA4P arrives and arrests around tumor vessels for a short period of time resulting in tumor cells that are alive and less necrotic than when treated with PLG-CA4. (Reprinted with permission from Ref.[41]; Copyright (2017) Elsevier B.V.)

    Figure 5.  (a) Schematic illustration of the hypoxia-inducing nanoparticles combined with hypoxia-activated treatment strategy; (b) Confocal laser scanning microscopy imaging of hypoxia immunofluorescence staining after intravenous injection of CA4-NPs at 4 h and 24 h; (c) In vivo antitumor efficacies on BALB/c mice bearing 4T1 tumors with moderate sizes (~ 180 mm3). (Left) Tumor volume changes of mice during the treatment. (Right) The representative tumor at the end of the treatment. Group 1: PBS; Group 2: TPZ (40 mg/kg,); Group 3: CA4-NPs (24 mg/kg on CA4 basis); Group 4: CA4-NPs (36 mg/kg on CA4 basis); Group 5: CA4-NPs (48 mg/kg on CA4 basis); Group 6: TPZ + CA4-NPs (40 mg/kg + 24 mg/kg on CA4 basis); Group 7: TPZ + CA4-NPs (40 mg/kg + 36 mg/kg on CA4 basis); Group 8: TPZ + CA4-NPs (40 mg/kg + 48 mg/kg on CA4 basis). (Reprinted with permission from Ref.[45]; Copyright (2019) Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)

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  • 通讯作者:  陈学思, xschen@ciac.ac.cn
  • 收稿日期:  2019-02-21
  • 修稿日期:  2019-04-09
  • 网络出版日期:  2019-05-09
  • 刊出日期:  2019-06-01
通讯作者: 陈斌, bchen63@163.com
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    沈阳化工大学材料科学与工程学院 沈阳 110142

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