Dual-Drug Conjugated Glyco-Nanoassemblies for Tumor-Triggered Targeting and Synergistic Cancer Therapy,ACS Applied Bio Materials

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Dual-Drug Conjugated Glyco-Nanoassemblies for Tumor-Triggered Targeting and Synergistic Cancer Therapy
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2022-11-08 , DOI: 10.1021/acsabm.2c00749
Tugba Gencoglu Katmerlikaya ₁ , Aydan Dag _{2,

3} , Pınar Sinem Omurtag Ozgen _{4,

5} , Busra Cetin Ersen ₆

Affiliation

Drug-conjugated nanoassemblies potentiate the efficiency of anticancer drugs through the advantages of high drug-loading capacity and passive/active targeting ability in cancer therapy. This study describes the synthesis of gemcitabine (Gem) and cisplatin (cisPt) dual-drug-functionalized glyco-nanoassemblies (GNs) for anticancer drug delivery systems. It also investigates the pH-triggered drug delivery of the conventional anticancer drug cisPt. A Gem-functionalized well-defined glycoblock copolymer backbone (P(iprFruMA-b-MAc)-Gem), which consists of fructose and methacrylic acid segments, was synthesized via a reversible addition–fragmentation chain transfer (RAFT) polymerization method. Following the hydrolysis of the protecting groups on the backbone copolymer, cisPt functionalization of P(FruMA-b-MAc)-Gem in aqueous media was carried out during the transformation of glycoblock polymers into self-assembled spherical glyco-nanoassemblies (GN3). Monodrug-functionalized glyco-nanoassemblies were also prepared either with Gem (GN1) or cisPt (GN2) to compare the synergetic effect of dual-drug conjugated glyco-nanoassemblies (GN3). The sizes of glyco-nanoassemblies GN1, GN2, and GN3 were found as 5.76 ± 0.64, 59.80 ± 0.13, and 53.80 ± 3.90 nm and dispersity (Đ) values as 0.476, 0.292, and 0.311 by dynamic light scattering (DLS) measurement, respectively. The in vitro studies revealed that the drug-free glyco-nanoassemblies are biocompatible at concentrations higher than 296 μg/mL. The drug-conjugated glyco-nanoassemblies (GN1 and GN2) exhibited in vitro cytotoxicity against human breast cancer cell lines of MDA-MB-231 comparable to free Gem and cisPt, illustrating an efficient drug release into the tumor environment. Additionally, GNs exhibited higher selectivity and preferential cellular internalization in MDA-MB-231 when compared to healthy cell lines of CCD-1079Sk. These dual-drug conjugated GNs can effectively enhance the killing of cancer cells and increase synergistic chemotherapy.

中文翻译：

用于肿瘤触发靶向和协同癌症治疗的双药共轭糖纳米组件

药物偶联纳米组件通过在癌症治疗中具有高载药量和被动/主动靶向能力的优势，提高了抗癌药物的效率。本研究描述了用于抗癌药物递送系统的吉西他滨 (Gem) 和顺铂 (cisPt) 双药物功能化糖纳米组件 (GNs) 的合成。它还研究了传统抗癌药物 cisPt 的 pH 触发药物递送。通过以下方法合成了由果糖和甲基丙烯酸片段组成的Gem 功能化明确的糖嵌段共聚物主链 (P( ipr FruMA- b -MAc)-Gem)一种可逆加成-断裂链转移 (RAFT) 聚合方法。在主链共聚物上的保护基水解后，在将糖嵌段聚合物转化为自组装球形糖纳米组件 (GN3) 的过程中，在水性介质中对 P(FruMA- b -MAc)-Gem 进行顺铂功能化。还用 Gem (GN1) 或 cisPt (GN2) 制备了单药功能化的糖纳米组装体，以比较双药共轭糖纳米组装体 (GN3) 的协同作用。通过动态光散射 (DLS) 测量，糖纳米组装体 GN1、GN2 和 GN3 的大小分别为 5.76 ± 0.64、59.80 ± 0.13 和 53.80 ± 3.90 nm，分散度 ( Đ ) 值为 0.476、0.292 和 0.311，分别。体外_研究表明，无药物糖纳米组件在浓度高于 296 μg/mL 时具有生物相容性。药物偶联的糖纳米组装体（GN1 和 GN2）对人乳腺癌细胞系 MDA-MB-231 表现出与游离 Gem 和 cisPt 相当的体外细胞毒性，说明药物可以有效释放到肿瘤环境中。此外，与 CCD-1079Sk 的健康细胞系相比，GNs 在 MDA-MB-231 中表现出更高的选择性和优先细胞内化。这些双药共轭GNs可以有效增强对癌细胞的杀伤力，增加化疗的协同作用。

更新日期：2022-11-08

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