pH-Sensitive O6-Benzylguanosine Polymer Modified Magnetic Nanoparticles for Treatment of Glioblastomas.
pH-Sensitive O6-Benzylguanosine Polymer Modified Magnetic Nanoparticles for Treatment of Glioblastomas.
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DOI：
10.1021/acs.bioconjchem.6b00545
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发表时间：
2017-01-18
影响因子：
4.7
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Stephen ZR;Gebhart RN;Jeon M;Blair AA;Ellenbogen RG;Silber JR;Zhang M
纳米颗粒介导的化疗药物递送已经证明了通过增加血清半衰期和提供组织特异性和受控药物释放以改善疏水性化疗药物的生物分布来改善抗癌功效的潜力。然而，次优的药物负载，特别是对于固体核纳米颗粒（NP），仍然是限制其临床应用的挑战。在这项研究中，我们制定了一个NP包被的pH值敏感的聚合物的O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）抑制剂类似物，二醛修饰的O 6-苄基鸟苷（DABGS），以实现高载药量和聚乙二醇（PEG），以改善水溶性，同时保持NP的稳定性。基础纳米载体由涂覆有酰肼官能化PEG（IOPH）的氧化铁核心（9 nm）组成。DABGS和PEG-二酰肼聚合在氧化铁纳米颗粒表面（IOPH-pBGS）通过酸不稳定的腙键，利用快速，冻融催化方法。通过FTIR证实DABGS聚合并通过UV-Vis光谱定量。IOPH-pBGS表现出33.4 ± 5.1重量%的优异载药量，同时保持小尺寸（36.5 ± 1.8 nm）。在生物学相关pH下监测药物释放，并证明pH依赖性释放，在pH 5.5（细胞内条件）下释放最大，在生理pH（7.4）下释放最小。IOPH-pBGS在体外显著抑制了MGMT的活性并增强了替莫唑胺（TMZ）的毒性，证明了其作为胶质母细胞瘤（GBM）新治疗选择的潜力。将MGMT抑制剂、二醛修饰的O 6-苄基鸟苷和聚乙二醇的pH敏感性交替共聚物聚合在氧化铁纳米颗粒的表面上，以实现高载药量并改善疏水性化疗剂的水溶性。高度稳定的纳米颗粒缀合物以pH依赖性方式释放MGMT抑制剂，抑制MGMT活性并增强替莫唑胺毒性。
Nanoparticle-mediated delivery of chemotherapeutics has demonstrated potential in improving anti-cancer efficacy by increasing serum half-life and providing tissue specificity and controlled drug release to improve biodistribution of hydrophobic chemotherapeutics. However, sub-optimal drug loading, particularly for solid core nanoparticles (NPs), remains a challenge that limits their clinical application. In this study we formulated a NP coated with a pH-sensitive polymer of O6-methylguanine-DNA methyltransferase (MGMT) inhibitor analog, dialdehyde modified O6-benzylguanosine (DABGS) to achieve high drug loading and with polyethylene glycol (PEG) to ameliorate water solubility while maintaining NP stability. The base nanovector consists of an iron oxide core (9 nm) coated with hydrazide functionalized PEG (IOPH). DABGS and PEG-dihydrazide were polymerized on the iron oxide nanoparticle surface (IOPH-pBGS) through acid-labile hydrazone bonds utilizing a rapid, freeze-thaw catalysis approach. DABGS polymerization was confirmed by FTIR and quantitated by UV-Vis spectroscopy. IOPH-pBGS demonstrated excellent drug loading of 33.4 ± 5.1% by weight while maintaining small size (36.5 ± 1.8 nm). Drug release was monitored at biologically relevant pHs and demonstrated pH dependent release with maximum release at pH 5.5 (intracellular conditions), and minimal release at physiological pH (7.4). IOPH-pBGS significantly suppressed activity of MGMT and potentiated temozolomide (TMZ) toxicity in vitro, demonstrating the potential as a new treatment option for glioblastomas (GBMs). A pH-sensitive alternating copolymer of MGMT inhibitor, dialdehyde modified O6-benzylguanosine, and polyethylene glycol was polymerized on the surface of iron oxide nanoparticles to achieve high drug loading and improve water solubility of the hydrophobic chemotherapeutic. The highly stable nanoparticle conjugate released MGMT inhibitor in a pH-dependent manner suppressing MGMT activity and potentiated temozolomide toxicity.
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影响因子：
8
作者：
Oh N;Park JH
通讯作者：
Park JH
DOI：
10.2217/17435889.3.5.703
发表时间：
2008-10
期刊：
Nanomedicine (London, England)
影响因子：
--
作者：
Longmire M;Choyke PL;Kobayashi H
通讯作者：
Kobayashi H
影响因子：
13.3
作者：
Faure, Anne-Charlotte;Dufort, Sandrine;Tillement, Olivier
通讯作者：
Tillement, Olivier
影响因子：
15
作者：
Kool ET;Park DH;Crisalli P
通讯作者：
Crisalli P
影响因子：
13.3
作者：
Fang, Chen;Bhattarai, Narayan;Sun, Conroy;Zhang, Miqin
通讯作者：
Zhang, Miqin