Functional cRGD-Conjugated Polymer Prodrug for Targeted Drug Delivery to Liver Cancer Cells.
Functional cRGD-Conjugated Polymer Prodrug for Targeted Drug Delivery to Liver Cancer Cells.
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DOI：
10.1021/acsomega.2c02683
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发表时间：
2022-06-21
期刊：
影响因子：
4.1
通讯作者：
Ni, Peihong
中科院分区：
文献类型：
--
作者：
Zhou, Ru;Zhang, Mingzu;He, Jinlin;Liu, Jian;Sun, Xingwei;Ni, Peihong
为了克服传统纳米药物在肿瘤靶向效率方面的局限性，将靶向配体偶联到聚合物纳米颗粒上可以增强纳米药物与肿瘤的特异性结合。Cyclo（Arg-Gly-Asp-d-Phe-Lys）（简称c（RGDfK））肽由于其与肿瘤标志物αvβ3整合素受体的高亲和力而被广泛采用。在这项研究中，我们开发了一种cRGD肽缀合的喜树碱（CPT）前药，它能够自组装纳米颗粒，用于精确靶向和富集肿瘤组织。我们首先合成了具有还原敏感键的喜树碱衍生物（CPT-ss-N3），同时修饰PEG以获得cRGD-PEG-N3。2-（丁-3-炔-1-氧基）-2-氧代-1，3，2-二氧磷杂环戊烷（BYP）经开环聚合后，通过铜催化的叠氮-炔环加成（CuAAC）反应得到两亲性聚合物前药cRGD-PEG-g-（PBYP-ss-CPT）。通过DLS和TEM研究了cRGD功能前药在缓冲溶液中的自组装。考察了cRGD-PEG-g-（PBYP-ss-CPT）纳米粒的体外释药行为。结果表明，纳米粒子具有还原响应性，结合的CPT可以被释放。内吞作用和MTT测定表明，cRGD缀合的前药对肿瘤细胞具有更好的亲和力，在细胞内积累更多，因此更有效。体内药物代谢研究表明，纳米粒大大延长了药物在循环中的滞留时间。通过监测药物在肿瘤和各种组织中的分布，我们发现游离CPT可以快速代谢，导致所有组织中的低蓄积。然而，cRGD-PEG-g-（PBYP-ss-CPT）纳米颗粒在肿瘤组织中的累积量高于PEG-g-（PBYP-ss-CPT）纳米颗粒，除了不可避免地被肝脏捕获。这表明含有cRGD的纳米药物具有一定的靶向性，可以提高药物的释放效率。
To overcome the limitation of conventional nanodrugs in tumor targeting efficiency, coupling targeting ligands to polymeric nanoparticles can enhance the specific binding of nanodrugs to tumors. Cyclo(Arg-Gly-Asp-d-Phe-Lys) (abbreviated as c(RGDfK)) peptide has been widely adopted due to its high affinity to the tumor marker αvβ3 integrin receptor. In this study, we develop a cRGD peptide-conjugated camptothecin (CPT) prodrug, which enables self-assembly of nanoparticles for precise targeting and enrichment in tumor tissue. We first synthesized a camptothecin derivative (CPT-ss-N3) with a reduction-sensitive bond and simultaneously modified PEG to obtain cRGD-PEG-N3. After ring-opening polymerization of the 2-(but-3-yn-1-yolxy)-2-oxo-1,3,2-dioxaphospholane (BYP), an amphiphilic polymeric prodrug, referred to as cRGD-PEG-g-(PBYP-ss-CPT), was obtained via copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. The self-assembly in buffer solution of the cRGD-functional prodrug was studied through DLS and TEM. The in vitro drug release behavior of cRGD-PEG-g-(PBYP-ss-CPT) nanoparticles was investigated. The results show that the nanoparticles are reduction-responsive and the bonded CPT can be released. Endocytosis and MTT assays demonstrate that the cRGD-conjugated prodrug has better affinity for tumor cells, accumulates more intracellularly, and is therefore, more effective. The in vivo drug metabolism studies show that nanoparticles greatly prolong the retention time in circulation. By monitoring drug distribution in tumor and in various tissues, we find that free CPT can be rapidly metabolized, resulting in low accumulation in all tissues. However, cRGD-PEG-g-(PBYP-ss-CPT) nanoparticles accumulate in tumor tissues in higher amounts than PEG-g-(PBYP-ss-CPT) nanoparticles, except for the inevitable capture by the liver. This indicates that the nanomedicine with cRGD has a certain targeting property, which can improve drug delivery efficiency.
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DOI：
10.3390/molecules26185567
发表时间：
2021-09-13
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Li W;Li M;Qi J
通讯作者：
Qi J
影响因子：
62.1
作者：
Kamaly N;Yameen B;Wu J;Farokhzad OC
通讯作者：
Farokhzad OC
影响因子：
11.7
作者：
Kemp JA;Kwon YJ
通讯作者：
Kwon YJ
影响因子：
6
作者：
Bauer, Kristin N.;Liu, Lei;Wurm, Frederik R.
通讯作者：
Wurm, Frederik R.
用多肽-地塞米松缀合物中和促肿瘤炎症，用于微环境调节和结直肠癌治疗
影响因子：
14
作者：
Ma, Sheng;Song, Wantong;Chen, Xuesi
通讯作者：
Chen, Xuesi