The complex role of multivalency in nanoparticles targeting the transferrin receptor for cancer therapies.
The complex role of multivalency in nanoparticles targeting the transferrin receptor for cancer therapies.
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DOI：
10.1021/ja1043177
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发表时间：
2010-08-18
影响因子：
15
通讯作者：
DeSimone, Joseph M.
中科院分区：
文献类型：
--
作者：
Wang, Jin;Tian, Shaomin;Petros, Robby A.;Napier, Mary E.;DeSimone, Joseph M.
转铁蛋白受体（TfR, CD71）因其在许多恶性组织中过表达而成为治疗靶点。在这项研究中，PRINT®纳米颗粒与TfR配体结合，用于靶向药物递送。圆柱形聚（乙二醇）基PRINT纳米颗粒（直径[d] = 200 nm，高度[h] = 200 nm）标记转铁蛋白受体抗体（NP-OKT9）或人转铁蛋白（NP-hTf），与阴性对照（IgG1对OKT9或牛转铁蛋白（bTf）对hTf）相比，所有被测试的人肿瘤细胞系都显示出高度特异性的tfr介导的摄取。靶向效率与颗粒浓度、配体密度、给药时间和细胞表面受体表达水平有关。有趣的是，NP-OKT9或NP-hTf对所有实体瘤细胞系几乎没有细胞毒性，但对拉莫斯b细胞淋巴瘤有很大毒性，而游离OKT9或hTf没有毒性。颗粒表面的TfR配体密度与细胞活力和颗粒摄取有很强的相关性。NP-OKT9和NP-hTf被内化到酸性细胞内区室中，但不局限于富含EEA1的早期内体或溶酶体中。caspase 3/7活性升高表明颗粒处理激活了凋亡途径。补充铁可抑制NP-OKT9的毒性，而不抑制NP-hTf的毒性，提示NP-hTf和NP-OKT9对拉莫斯细胞施加细胞毒性的机制不同。基于这样的观察，讨论了多价态在纳米颗粒中的复杂作用。此外，我们的数据清楚地表明，当靶向分子用于纳米颗粒时，人们必须谨慎地宣称“没有毒性”，并且在设计靶向化疗纳米递送剂时，也要注意意想不到的脱靶效应。
Transferrin receptor (TfR, CD71) has long been therapeutic target due to its over-expression on many malignant tissues. In this study, PRINT® nanoparticles were conjugated with TfR ligands for targeted drug delivery. Cylindrical poly(ethylene glycol)-based PRINT nanoparticles (diameter [d] = 200 nm, height [h] = 200 nm) labeled with transferrin receptor antibody (NP-OKT9) or human transferrin (NP-hTf), showed highly specific TfR-mediated uptake by all human tumor cell lines tested, relative to negative controls (IgG1 for OKT9 or bovine transferrin (bTf) for hTf). The targeting efficiency was dependent on particle concentration, ligand density, dosing time and cell surface receptor expression level. Interestingly, NP-OKT9 or NP-hTf showed little cytotoxicity on all solid tumor cell lines tested but were very toxic to Ramos B-cell lymphoma, whereas free OKT9 or hTf was not toxic. There was a strong correlation between TfR ligand density on particle surface and cell viability and particle uptake. NP-OKT9 and NP-hTf were internalized into acidic intracellular compartments but were not localized in EEA1 enriched early endosomes or lysosomes. Elevated caspase 3/7 activity indicates activation of apoptosis pathways upon particle treatment. Supplementation of iron suppressed the toxicity of NP-OKT9 but not NP-hTf, suggesting different mechanisms by which NP-hTf and NP-OKT9 exerts cytotoxicity on Ramos cells. Based on such an observation, the complex role of multivalency in nanoparticles is discussed. In addition, our data clearly reveal that one must be careful in making claims of “lack of toxicity” when a targeting molecule is used on nanoparticles and also raise concerns for unanticipated off-target effects when one is designing targeted chemotherapy nano-delivery agents.
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影响因子：
15
作者：
Huang, Yu-Fen;Liu, Haipeng;Xiong, Xiangling;Chen, Yan;Tan, Weihong
通讯作者：
Tan, Weihong
影响因子：
38.3
作者：
Jiang, Wen;Kim, Betty Y. S.;Chan, Warren C. W.
通讯作者：
Chan, Warren C. W.
将EGF和转铁蛋白分选在质膜上，并通过货物特异性信号传导向EEA1富集的内体。
影响因子：
4
作者：
Leonard D;Hayakawa A;Lawe D;Lambright D;Bellve KD;Standley C;Lifshitz LM;Fogarty KE;Corvera S
通讯作者：
Corvera S
DOI：
10.1083/jcb.129.6.1509
发表时间：
1995-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Marsh EW;Leopold PL;Jones NL;Maxfield FR
通讯作者：
Maxfield FR
影响因子：
15
作者：
Kang, Bin;Mackey, Megan A.;El-Sayed, Mostafa A.
通讯作者：
El-Sayed, Mostafa A.