Folate-PEG Conjugates of a Far-Red Light-Activatable Paclitaxel Prodrug to Improve Selectivity toward Folate Receptor-Positive Cancer Cells.
Folate-PEG Conjugates of a Far-Red Light-Activatable Paclitaxel Prodrug to Improve Selectivity toward Folate Receptor-Positive Cancer Cells.
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DOI：
10.1021/acsomega.7b01105
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发表时间：
2017-10-31
期刊：
影响因子：
4.1
通讯作者：
You Y
中科院分区：
文献类型：
--
作者：
Thapa P;Li M;Karki R;Bio M;Rajaputra P;Nkepang G;Woo S;You Y
我们最近展示了紫杉醇 (PTX) 的远红光激活前药 Pc-(L-PTX)2。在 690 nm 激光照射下，Pc-(L-PTX)2 显示出单线态氧的快速光动力疗法损伤导致的组合细胞杀伤，随后局部释放的 PTX 产生持续的化疗效果。然而，其高亲脂性（log D7.4 > 3.1）会导致在水溶液中聚集，并且对癌细胞具有非选择性。为了解决这些重要问题，我们制备了具有不同链长的聚乙二醇（PEG）间隔基的叶酸（FA）缀合和光活化的PTX前药：FA-PEGn-Pc-L-PTX [n = 0 (0k, 5), ∼23 (1k, 7a), ∼45 (2k, 7b), ∼80 (3.5k, 7c), 或〜114（5k，7d）]。与非聚乙二醇化前药 Pc-(L-PTX)2 相比，聚乙二醇化前药 7a-d 的亲水性大大提高。随着 PEG 长度的增加，前药的亲水性增加（1k、2k、3.5k 和 5k PEG 前药的 log D7.4 值分别为 1.28、0.09、-0.24 和 -0.59）。荧光光谱数据表明，聚乙二醇化前药在较低浓度（<1-2 μM）下在培养基中具有良好的溶解度，但由于在较高浓度（>2 μM）下溶解度有限而显示出荧光猝灭。动态光散射表明，所有前药在磷酸盐缓冲盐水和浓度为 5 μM 的培养基中均形成纳米尺寸颗粒。 PEG 长度影响非特异性和叶酸受体 (FR) 介导的前药摄取。在 FR 阳性 SKOV-3 细胞中，观察到具有中等大小 PEG（1k、2k 或 3.5k）的前药的细胞摄取增强，但没有 PEG 或具有最长 PEG（5k）的前药则没有，这表明 PEG 长度的最佳范围约为 1k–3.5k，以有效摄取我们的前药系统。与细胞摄取模式一致，中等大小的聚乙二醇化前药显示出比不含 PEG 或最长 PEG 的前药（IC50，〜400 nM）更有效的光毒性活性（IC50，〜130 nM）。总之，我们开发了远红光可激活的前药，与非靶向前药相比，它们具有改善的水溶性和 FR 靶向特性。
We recently demonstrated the far-red light-activatable prodrug of paclitaxel (PTX), Pc-(L-PTX)2. Upon illumination with a 690 nm laser, Pc-(L-PTX)2 showed combinational cell killing from rapid photodynamic therapy damage by singlet oxygen, followed by sustained chemotherapy effects from locally released PTX. However, its high lipophilicity (log D7.4 > 3.1) caused aggregation in aqueous solutions and has nonselectivity toward cancer cells. To solve these important problems, we prepared folic acid (FA)-conjugated and photoactivatable prodrugs of PTX with a polyethylene glycol (PEG) spacer of various chain lengths: FA-PEGn-Pc-L-PTX [n = 0 (0k, 5), ∼23 (1k, 7a), ∼45 (2k, 7b), ∼80 (3.5k, 7c), or ∼114 (5k, 7d)]. The PEGylated prodrugs 7a–d had a much improved hydrophilicity compared with the non-PEGylated prodrug, Pc-(L-PTX)2. As the PEG length increased, the hydrophilicity of the prodrug increased (log D7.4 values: 1.28, 0.09, −0.24, and −0.59 for 1k, 2k, 3.5k, and 5k PEG prodrugs, respectively). Fluorescence spectral data suggested that the PEGylated prodrugs had good solubility in the culture medium at lower concentrations (<1–2 μM), but showed fluorescence quenching due to limited solubility at higher concentrations (>2 μM). Dynamic light scattering indicated that all of the prodrugs formed nanosized particles in both phosphate-buffered saline and culture medium at a concentration of 5 μM. The PEG length affected both nonspecific and folate receptor (FR)-mediated uptake of the prodrugs. The enhanced cellular uptake was observed for the prodrugs with medium-sized PEGs (1k, 2k, or 3.5k) in FR-positive SKOV-3 cells, but not for the prodrugs with no PEG or with the longest PEG (5k), which suggests the optimal range of PEG length around 1k–3.5k for effective uptake of our prodrug system. Consistent with the cellular uptake pattern, medium-sized PEGylated prodrugs showed more potent phototoxic activity (IC50s, ∼130 nM) than prodrugs with no PEG or the longest PEG (IC50, ∼400 nM). In conclusion, we have developed far-red light-activatable prodrugs with improved water solubility and FR-targeting properties compared with the nontargeted prodrug.
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DOI：
10.3322/caac.20114
发表时间：
2011-07
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Agostinis P;Berg K;Cengel KA;Foster TH;Girotti AW;Gollnick SO;Hahn SM;Hamblin MR;Juzeniene A;Kessel D;Korbelik M;Moan J;Mroz P;Nowis D;Piette J;Wilson BC;Golab J
通讯作者：
Golab J
影响因子：
4.7
作者：
Danial, Maarten;van Dulmen, Tim H. H.;Klok, Harm-Anton
通讯作者：
Klok, Harm-Anton
影响因子：
2.7
作者：
Henne, Walter A.;Doorneweerd, Derek D.;Low, Philip S.
通讯作者：
Low, Philip S.
通过原药的双重活化实现抗癌药物的可见光控制释放
影响因子：
4.2
作者：
Hossion, Abugafar M. L.;Bio, Moses;You, Youngjae
通讯作者：
You, Youngjae
影响因子：
4.7
作者：
Lee, Hyukjin;Lee, Kyuri;Park, Tae Gwan
通讯作者：
Park, Tae Gwan