Al-Thani Hissa F, Shurbaji Samar, Zakaria Zain Zaki, Hasan Maram H, Goracinova Katerina, Korashy Hesham M, Yalcin Huseyin C
Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar.
Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar.
Materials (Basel). 2022 Jun 2;15(11):3960. doi: 10.3390/ma15113960.
Tyrosine kinase inhibitors (TKIs) are the new generation of anti-cancer drugs with high potential against cancer cells' proliferation and growth. However, TKIs are associated with severe cardiotoxicity, limiting their clinical value. One TKI that has been developed recently but not explored much is Ponatinib. The use of nanoparticles (NPs) as a better therapeutic agent to deliver anti-cancer drugs and reduce their cardiotoxicity has been recently considered. In this study, with the aim to reduce Ponatinib cardiotoxicity, Poly(D,L-lactide-co-glycolide)-b-poly(ethyleneoxide)-b-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymer was used to synthesize Ponatinib in loaded PLGA-PEG-PLGA NPs for chronic myeloid leukemia (CML) treatment. In addition to physicochemical NPs characterization (NPs shape, size, size distribution, surface charge, dissolution rate, drug content, and efficacy of encapsulation) the efficacy and safety of these drug-delivery systems were assessed in vivo using zebrafish. Zebrafish are a powerful animal model for investigating the cardiotoxicity associated with anti-cancer drugs such as TKIs, to determine the optimum concentration of smart NPs with the least side effects, and to generate a xenograft model of several cancer types. Therefore, the cardiotoxicity of unloaded and drug-loaded PLGA-PEG-PLGA NPs was studied using the zebrafish model by measuring the survival rate and cardiac function parameters, and therapeutic concentration for in vivo efficacy studies was optimized in an in vivo setting. Further, the efficacy of drug-loaded PLGA-PEG-PLGA NPs was tested on the zebrafish cancer xenograft model, in which human myelogenous leukemia cell line K562 was transplanted into zebrafish embryos. Our results demonstrated that the Ponatinib-loaded PLGA-PEG-PLGA NPs at a concentration of 0.001 mg/mL are non-toxic/non-cardio-toxic in the studied zebrafish xenograft model.
酪氨酸激酶抑制剂（TKIs）是新一代具有强大潜力抑制癌细胞增殖和生长的抗癌药物。然而，TKIs与严重的心脏毒性相关，限制了它们的临床价值。波纳替尼是最近开发但尚未深入研究的一种TKI。最近人们考虑使用纳米颗粒（NPs）作为更好的治疗剂来递送抗癌药物并降低其心脏毒性。在本研究中，为了降低波纳替尼的心脏毒性，使用聚（D，L-丙交酯-共-乙交酯）-b-聚（环氧乙烷）-b-聚（D，L-丙交酯-共-乙交酯）（PLGA-PEG-PLGA）三嵌段共聚物合成了负载波纳替尼的PLGA-PEG-PLGA NPs，用于慢性髓性白血病（CML）的治疗。除了对NPs进行物理化学表征（NPs形状、大小、大小分布、表面电荷、溶解速率、药物含量和包封效率）外，还使用斑马鱼在体内评估了这些药物递送系统的疗效和安全性。斑马鱼是一种强大的动物模型，可用于研究与TKIs等抗癌药物相关的心脏毒性，确定副作用最小的智能NPs的最佳浓度，并建立多种癌症类型的异种移植模型。因此，通过测量存活率和心脏功能参数，使用斑马鱼模型研究了未负载和负载药物的PLGA-PEG-PLGA NPs的心脏毒性，并在体内环境中优化了用于体内疗效研究的治疗浓度。此外，在斑马鱼癌症异种移植模型上测试了负载药物的PLGA-PEG-PLGA NPs的疗效，该模型将人髓性白血病细胞系K562移植到斑马鱼胚胎中。我们的结果表明，在所研究的斑马鱼异种移植模型中，浓度为0.001 mg/mL的负载波纳替尼的PLGA-PEG-PLGA NPs无毒/无心脏毒性。
