Reduced Cardiotoxicity of Ponatinib-Loaded PLGA-PEG-PLGA Nanoparticles in Zebrafish Xenograft Model

Abstract

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.

Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity

“…Ponatinib is among the most cardiotoxic TKIs that have been approved by the Federal Drug Administration (FDA). 11 Although recent efforts have been made in engineering new ponatinib analogs that retain antitumor efficacy with a reduced cardiotoxic profile, [80][81][82] these studies remain experimental, highlighting an unmet gap in better understanding the mechanisms underlying ponatinibinduced cardiotoxicity. Using human iPSC-CMs as a platform to study ponatinib-induced cardiotoxicity, we show that ponatinib-induced cardiac injury is associated with activation of the ISR.…”

Toxicological Aspects and Bioanalysis of Nanoparticles: Zebrafish Model

“…In a study, in which an inulin-based fructan obtained from chicory plant extract was structured and characterized with selenium nanoparticles (CIP-SeNPs) to improve antitumor effects, CIP-SeNPs were found to significantly suppress the proliferation and spread of tumors as well as angiogenesis in transgenic zebrafish in the concentration range of 1-4 μg/mL [57]. It was shown that PLGA-PEG-PLGA nanoparticles loaded with ponatinib at a concentration of 001 mg/ml were not cardiotoxic in the conventional zebrafish xenograft model [64]. It was also revealed that many nanoparticle therapies used in the diagnosis and treatment of various types of cancer could be usefully utilized as an initial step (Figure 7).…”

Special Issue: “Functionalized Nanomaterials and Structures for Biomedical Applications”

“…Furthermore, the MTT assay against the normal fibroblast L929 cell line demonstrated low cytotoxicity compared with the free drug, suggesting that the pH-responsive composite nanoemulsion would significantly reduce the serious side effects of cytostatic therapy. To mitigate the severe cardiotoxicity of tyrosinase inhibitors (TKIs), a new generation of potent antiproliferative and anti-growth agents, Al-Thani et al [9] loaded the smart triblock copolymer PLGA-PEG-PLGA, in which the middle hydrophilic homopolymer segment is flanked by two hydrophobic polymer segments, with the TKI Ponatinib. They transplanted the human myelogenous leukemia cell line K562 into zebra fish embryos and used this xenograft as a suited in vivo animal model to assess the toxicity of both genuine and Ponatinib-loaded polymeric nanoparticles at various concentrations in terms of survival rate and an analysis of their cardiovascular structure and function.…”