Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of CD44-positive and drug-resistant tumors.
Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of CD44-positive and drug-resistant tumors.
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DOI：
10.1021/bc300632w
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发表时间：
2013-04-17
影响因子：
4.7
通讯作者：
Vinogradov, Serguei V.
中科院分区：
文献类型：
--
作者：
Wei, Xin;Senanayake, Thulani H.;Warren, Galya;Vinogradov, Serguei V.
许多耐药肿瘤和癌症干细胞（CSC）表达升高水平的CD 44受体，一种结合透明质酸（HA）的细胞糖蛋白。在这里，我们报告了基于膜亲性胆固醇-HA（CHA）的纳米凝胶-药物缀合物的合成，用于有效靶向和抑制耐药肿瘤。这些缀合物显著增加了先前报道的具有抗CSC活性的难溶性药物的生物利用度，如依托泊苷、盐霉素和姜黄素。小的纳米凝胶颗粒（直径）20-40 nm），具有疏水核和高载药量（高达20%），并在生物可降解酯键水解后显示出持续的药物释放。重要的是，与游离药物和未修饰的HA-药物缀合物相比，CHA-药物纳米凝胶在表达CD 44的耐药性人乳腺癌和胰腺癌细胞中表现出2-7倍的细胞毒性。这些纳米凝胶通过CD 44受体介导的内吞作用和与癌细胞膜的同时相互作用而有效地内化。与未修饰的HA-药物缀合物相比，纳米凝胶展开后细胞膜中胆固醇部分的包裹明显引起癌细胞中更有效的药物积累。CHA-药物纳米凝胶能够穿透多细胞癌球体，并且在系统建模肿瘤环境中显示出比游离药物和HA-药物缀合物更高的细胞毒性作用。总之，所提出的纳米凝胶-药物缀合物的设计使我们能够显着提高药物生物利用度，癌细胞靶向，以及对耐药癌细胞和多细胞球体的治疗效果。
Many drug-resistant tumors and cancer stem cells (CSC) express elevated levels of CD44 receptor, a cellular glycoprotein binding hyaluronic acid (HA). Here, we report the synthesis of nanogel-drug conjugates based on membranotropic cholesteryl-HA (CHA) for efficient targeting and suppression of drug-resistant tumors. These conjugates significantly increased the bioavailability of poorly soluble drugs with previously reported activity against CSC, such as etoposide, salinomycin, and curcumin. The small nanogel particles (diam. 20–40 nm) with a hydrophobic core and high drug loads (up to 20%) formed after ultrasonication and demonstrated a sustained drug release following the hydrolysis of biodegradable ester linkage. Importantly, CHA-drug nanogels demonstrated 2–7 times higher cytotoxicity in CD44-expressing drug-resistant human breast and pancreatic adenocarcinoma cells compared to free drugs and non-modified HA-drug conjugates. These nanogels were efficiently internalized via CD44 receptor-mediated endocytosis and simultaneous interaction with the cancer cell membrane. Anchoring by cholesterol moieties in the cellular membrane after nanogel unfolding evidently caused more efficient drug accumulation in cancer cells compared to non-modified HA-drug conjugates. CHA-drug nanogels were able to penetrate multicellular cancer spheroids and displayed higher cytotoxic effect in the system modeling tumor environment than both free drugs and HA-drug conjugates. In conclusion, the proposed design of nanogel-drug conjugates allowed us to significantly enhance drug bioavailability, cancer cell targeting, and the treatment efficacy against drug-resistant cancer cells and multicellular spheroids.
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影响因子：
4.7
作者：
Senanayake, Thulani H.;Warren, Galya;Vinogradov, Serguei V.
通讯作者：
Vinogradov, Serguei V.
影响因子：
17.1
作者：
Huang K;Ma H;Liu J;Huo S;Kumar A;Wei T;Zhang X;Jin S;Gan Y;Wang PC;He S;Zhang X;Liang XJ
通讯作者：
Liang XJ
影响因子：
10.8
作者：
Cho, Hyun-Jong;Yoon, Hong Yeol;Kim, Dae-Duk
通讯作者：
Kim, Dae-Duk
影响因子：
3.6
作者：
KECK, GE;BODEN, EP;WILEY, MR
通讯作者：
WILEY, MR
影响因子：
6.2
作者：
Luo, Y;Ziebell, MR;Prestwich, GD
通讯作者：
Prestwich, GD