Synthesis of a polyethylene glycol modified indocyanine small molecule and evaluation of its anti-renal cancer cell activity

Zifei WU; Shenglin LUO; Xie HUANG; Zaizhi DU; Shaolong YUAN; Jing LIU; Weidong WANG

doi:10.16016/j.2097-0927.202112145

您当前的位置：

首页 >

文章列表页 >

Synthesis of a polyethylene glycol modified indocyanine small molecule and evaluation of its anti-renal cancer cell activity

Biomedical Engineering | 更新时间：2026-01-09

- Synthesis of a polyethylene glycol modified indocyanine small molecule and evaluation of its anti-renal cancer cell activity
- Journal of Army Medical University Vol. 44, Issue 7, Pages: 656-664(2022)
- 作者机构：
  
  1.611731 成都，电子科技大学医学院附属肿瘤医院放疗中心
  2.400038 重庆，陆军军医大学(第三军医大学)军事预防医学系复合伤研究所，创伤、烧伤与复合伤国家重点实验室
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(82173457);the Project for Technology Innovation and Development of Science and Technology Bureau of Chengdu(2021-YF05-01659-SN)
- DOI：10.16016/j.2097-0927.202112145
  CLC： R914.2;R965;R979.1
- Received：17 December 2021，
  
  Revised：2022-01-26，
  
  Published：15 April 2022
- 稿件说明：
移动端阅览
Zifei WU, Shenglin LUO, Xie HUANG, et al. Synthesis of a polyethylene glycol modified indocyanine small molecule and evaluation of its anti-renal cancer cell activity[J]. Journal of Army Medical University, 2022, 44(7): 656-664.
DOI：

Zifei WU, Shenglin LUO, Xie HUANG, et al. Synthesis of a polyethylene glycol modified indocyanine small molecule and evaluation of its anti-renal cancer cell activity[J]. Journal of Army Medical University, 2022, 44(7): 656-664. DOI： 10.16016/j.2097-0927.202112145.

摘要

目的

在前期发现具有肿瘤靶向性的吲哚花菁小分子的结构基础上，对其进行聚乙二醇(polyethylene glycol

PEG)水溶性修饰，并评价其理化性质和肿瘤靶向光动力治疗作用。

方法

分别以2

3-三甲基吲哚、聚乙二醇单甲醚为原料，设计并化学合成PEG修饰吲哚花菁小分子，采用核磁氢谱、质谱等检测、表征其化学结构；通过水溶性比较、光学性质表征、肾脏正常细胞HK-2与肿瘤细胞RENCA摄入比较、细胞活力测试、单线态氧以及细胞活性氧测定等，评价其理化性质与肿瘤靶向光动力作用。

结果

通过汇聚合成策略，经过6步化学反应，成功合成PEG修饰的吲哚花菁小分子PEG-808-NM2，其结构经核磁氢谱、质谱等确证。与808-NM2相比，PEG-808-NM2水溶性显著增加，在甲醇和PBS中均表现出优异的近红外荧光特性。PEG-808-NM2优先被肾癌细胞RENCA摄取，并在808 nm激光照射下，诱导产生大量的单线态氧和细胞内活性氧自由基。

结论

合成的PEG-808-NM2在保留吲哚花菁小分子原有的肿瘤靶向、近红外成像作用基础上显著改善其理化及光敏特性，对肾癌细胞具有显著的光动力治疗作用。

Abstract

Objective

Based on previous studies on a class of tumor-targeted indocyanine small molecules

we aimed to synthesize a new analog modified with water-soluble polyethylene glycol (PEG) and then investigated its physicochemical properties and role in tumor targeting photodynamic therapy.

Methods

PEG-modified indocyanine small molecules were designed and synthesized by using 2

3-trimethylindole and polyethylene glycol monomethyl ether as raw materials. Its chemical structure was characterized by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS); its physicochemical properties and cancer targeting photodynamic effect were investigated by determining its water solubility

optical spectra

cell uptake

cell viability

singlet oxygen

and reactive oxygen production.

Results

Based on a converging strategy of synthesis and through 6 steps of chemical reactions

a PEG-modified indocyanine small molecule (PEG-808-NM2) was successfully produced. Its structure was confirmed by NMR spectroscopy and MS. Compared to 808-NM2

PEG-808-NM2 significantly increased water solubility and exhibited excellent near-infrared fluorescence property in both methanol and water solution. PEG-808-NM2 preferentially accumulated in RENCA cells (a mouse renal adenocarcinoma cell line) rather than HK-2 cells (a tubular cell line from normal human kidneys). Under 808 nm-laser irradiation

PEG-808-NM2 induced a great amount of singlet oxygen and intracellular reactive oxygen species.

Conclusion

Our synthesized PEG-modified indocyanine small molecules not only keep the cancer preferential accumulation and the role in near-infrared imaging as original indocyanine

but also obtain significantly improved physicochemical properties and photosensitizing effect. They exert significant photodynamic therapeutic effect on renal cell carcinoma cells.

关键词

Keywords

references

PARK E J, CHOI J, LEE K C, et al . Emerging PEGylated non-biologic drugs[J ] . Expert Opin Emerg Drugs, 2019, 24(2): 107-119. DOI: 10.1080/14728214.2019.1604684.

LI N, LU X Y, FANG M, et al . PEGylated triacontanol substantially enhanced the pharmacokinetics of triacontanol in rats[J ] . J Agric Food Chem, 2018, 66(33): 8722-8728. DOI: 10.1021/acs.jafc.8b02684.

YANG X, DING Y P, JI T J, et al . Improvement of the in vitro safety profile and cytoprotective efficacy of amifostine against chemotherapy by PEGylation strategy[J ] . Biochem Pharmacol, 2016, 108: 11-21. DOI: 10.1016/j.bcp.2016.02.014..

ZHAI B T, WU Q B, WANG W G, et al . Preparation, characterization, pharmacokinetics and anticancer effects of PEGylated β-elemene liposomes[J ] . Cancer Biol Med, 2020, 17(1): 60-75. DOI: 10.20892/j.issn.2095-3941.2019.0156.

HUANG Y Q, YUAN J D, DING H F, et al . Design, synthesis and antitumor activity of a novel PEG-A6-conjugated irinotecan derivative[J ] . Bioorg Med Chem Lett, 2020, 30(2): 126847. DOI: 10.1016/j.bmcl.2019.126847.

YAN J Y, SONG B, HU W N, et al . Antitumor effect of GO-PEG-DOX complex on EMT-6 mouse breast cancer cells[J ] . Cancer Biother Radiopharm, 2018, 33(4): 125-130. DOI: 10.1089/cbr.2017.2348.

AL-AMILI M, JIN Z, WANG Z M, et al . Self-assembled micelles of amphiphilic PEGylated drugs for cancer treatment[J ] . Curr Drug Targets, 2021, 22(8): 870-881. DOI: 10.2174/1389450122666201231130702.

CHEN S, YU S T, DU Z Z, et al . Synthesis of mitochondria-anchored nitroimidazoles with a versatile NIR fluorophore for hypoxic tumor-targeting imaging and chemoradiotherapy[J ] . J Med Chem, 2021, 64(6): 3381-3391. DOI: 10.1021/acs.jmedchem.0c02250.

TAN X, LUO S L, WANG D C, et al . A NIR heptamethine dye with intrinsic cancer targeting, imaging and photosensitizing properties[J ] . Biomaterials, 2012, 33(7): 2230-2239. DOI: 10.1016/j.biomaterials.2011.11.081.

PACHARRA S, MCMAHON S, DUFFY P, et al . Cytocompatibility evaluation of a novel series of PEG-functionalized lactide-caprolactone copolymer biomaterials for cardiovascular applications[J ] . Front Bioeng Biotechnol, 2020, 8: 991. DOI: 10.3389/fbioe.2020.00991.

CHEN H, FAN Y J, YU X, et al . Light-gated nano-porous capsules from stereoisomer-directed self-assemblies[J ] . ACS Nano, 2021, 15(1): 884-893. DOI: 10.1021/acsnano.0c07400.

NGUYEN K, KHACHEMOUNE A. An update on topical photodynamic therapy for clinical dermatologists[J]. J Dermatolog Treat, 2019, 30(8): 732-744. DOI: 10.1080/09546634.2019.1569752.

MOY L S, FROST D, MOY S. Photodynamic therapy for photodamage, actinic keratosis, and acne in the cosmetic practice[J]. Facial Plast Surg Clin North Am, 2020, 28(1): 135-148. DOI: 10.1016/j.fsc.2019.09.012.

宋慈珍, 宋弋洋. 光动力疗法联合手术治疗皮肤基底细胞癌的临床疗效[J]. 浙江创伤外科, 2021, 26(6): 1066-1067.

SONG C Z, SONG Y Y. The clinical effect of photodynamic therapy combined with surgery in the treatment of skin basal cell carcinoma[J]. Zhejiang J Trauma Surg, 2021, 26(6): 1066-1067.

熊超亮, 吴裕文, 钟谷平, 等. 光动力疗法治疗晚期消化道肿瘤的临床研究[J]. 中国医学创新, 2019, 16(33): 1-5.

XIONG C L, WU Y W, ZHONG G P, et al . Clinical study on photodynamic therapy in the treatment of advanced gastrointestinal cancer[J ] . Med Innov China, 2019, 16(33): 1-5.

OSUCHOWSKI M, BARTUSIK-AEBISHER D, OSUCHOWSKI F, et al . Photodynamic therapy for prostate cancer: a narrative review[J ] . Photodiagnosis Photodyn Ther, 2021, 33: 102158. DOI: 10.1016/j.pdpdt.2020.102158.

来嘉伟, 周建成, 尹健, 等. BT-ESD联合光动力治疗高危膀胱癌1例[J]. 现代肿瘤医学, 2021, 29(23): 4218-4220.

LAI J W, ZHOU J C, YIN J, et al . The combination of BT-ESD and photodynamic therapy treat s high-risk bladder cancer: a case[J ] . J Mod Oncol, 2021, 29(23): 4218-4220.

DONOHOE C, SENGE M O, ARNAUT L G, et al . Cell death in photodynamic therapy: from oxidative stress to anti-tumor immunity[J ] . Biochim Biophys Acta Rev Cancer, 2019, 1872(2): 188308. DOI: 10.1016/j.bbcan.2019.07.003.

HAMBLIN M R, ABRAHAMSE H. Factors affecting photodynamic therapy and anti-tumor immune response[J]. Anticancer Agents Med Chem, 2021, 21(2): 123-136. DOI: 10.2174/1871520620666200318101037.

TSUJIMOTO A, UEHARA H, YOSHIDA H, et al . Different hydration states and passive tumor targeting ability of polyethylene glycol-modified dendrimers with high and low PEG density[J ] . Mater Sci Eng C Mater Biol Appl, 2021, 126: 112159. DOI: 10.1016/j.msec.2021.112159.

ELSEWEDY H S, DHUBIAB B, MAHDY M A, et al . Development, optimization, and evaluation of PEGylated brucine-loaded PLGA nanoparticles[J ] . Drug Deliv, 2020, 27(1): 1134-1146. DOI: 10.1080/10717544.2020.1797237.

VASAN K, WERNER M, CHANDEL N S. Mitochondrial metabolism as a target for cancer therapy[J]. Cell Metab, 2020, 32(3): 341-352. DOI: 10.1016/j.cmet.2020.06.019.

KALYANARAMAN B, CHENG G, HARDY M, et al . A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: therapeutic targeting of tumor mitochondria with lipophilic cationic compounds[J ] . Redox Biol, 2018, 14: 316-327. DOI: 10.1016/j.redox.2017.09.020.

WANG R, LI X S, YOON J. Organelle-targeted photosensitizers for precision photodynamic therapy[J]. ACS Appl Mater Interfaces, 2021, 13(17): 19543-19571. DOI: 10.1021/acsami.1c02019.

WU C H, WANG L H, TIAN Y, et al . "Triple-punch" anticancer strategy mediated by near-infrared photosensitizer/CpG oligonucleotides dual-dressed and mitochondria-targeted nanographene[J ] . ACS Appl Mater Interfaces, 2018, 10(8): 6942-6955. DOI: 10.1021/acsami.7b18896.

ZHENG Z, ZHANG T F, LIU H X, et al . Bright near-infrared aggregation-induced emission luminogens with strong two-photon absorption, excellent organelle specificity, and efficient photodynamic therapy potential[J ] . ACS Nano, 2018, 12(8): 8145-8159. DOI: 10.1021/acsnano.8b03138.

PUCELIK B, SU ŁEK A, BARZOWSKA A, et al . Recent advances in strategies for overcoming hypoxia in photodynamic therapy of cancer[J ] . Cancer Lett, 2020, 492: 116-135. DOI: 10.1016/j.canlet.2020.07.007.

TAKAHASHI J, MISAWA M, IWAHASHI H. Transcriptome analysis of porphyrin-accumulated and X-ray-irradiated cell cultures under limited proliferation and non-lethal conditions[J]. Microarrays(Basel), 2015, 4(1): 25-40. DOI: 10.3390/microarrays4010025.

GHOODARZI R, CHANGIZI V, MONTAZERABADI A R, et al . Assessing of integration of ionizing radiation with Radachlorin-PDT on MCF-7 breast cancer cell treatment[J ] . Lasers Med Sci, 2016, 31(2): 213-219. DOI: 10.1007/s10103-015-1844-0.

QIAN C G, YU J C, CHEN Y L, et al . Light-activated hypoxia-responsive nanocarriers for enhanced anticancer therapy[J ] . Adv Mater, 2016, 28(17): 3313-3320. DOI: 10.1002/adma.201505869.

WANG W L, LIN L, MA X J, et al . Light-induced hypoxia-triggered living nanocarriers for synergistic cancer therapy[J ] . ACS Appl Mater Interfaces, 2018, 10(23): 19398-19407. DOI: 10.1021/acsami.8b03506.

BONNET M, HON G C R, WONG W W, et al . Next-generation hypoxic cell radiosensitizers: nitroimidazole alkylsulfonamides[J ] . J Med Chem, 2018, 61(3): 1241-1254. DOI: 10.1021/acs.jmedchem.7b01678.

LU J, ZHANG C, YANG X, et al . Synthesis and preliminary evaluation of a novel 18 F-labeled 2-nitroimidazole derivative for hypoxia imaging[J ] . Front Oncol, 2021, 10: 572097. DOI: 10.3389/fonc.2020.572097..

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Anti-tumor effect of mitochondrial targeted small molecule IR-780 on cisplatin-resistant bladder cancer cells

In vitro imaging of targeting fluorescent IR780 nanoparticles and their mediated photodynamics in rat choroidal endothelial cells

Preparation and performance of PEGylated chitosan nanoparticles for ocular drug delivery by eye drops

Preparation of sinoporphyrin sodium and IR780-based composite nanoparticles and its anti-tumor efficacy in sonodynamic therapy

Role of photodynamic therapy in prevention of arteriovenous fistula restenosis in rabbits

Related Author

Yi ZHI

Qiang FANG

Jinjin LI

Chongxing SHEN

Yuandi HUANG

Menglei WANG

Yijun RAN

Meng LI

Related Institution

Department of Urology, the Third Affiliated Hospital of Chongqing Medical University

Department of Ophthalmology, the Second Affiliated Hospital of Chongqing Medical University

Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging, Chongqing Medical University

Department of Ultrasonography, the Second Affiliated Hospital of Chongqing Medical University

Department of Ophthalmology, Yongchuan Hospital of Chongqing Medical University

⁰