Dataset Information

Function of Epirubicin-Conjugated Polymeric Micelles in Sonodynamic Therapy.

ABSTRACT: The combinatory use of high-intensity focused ultrasound (HIFU) and epirubicin (EPI)-conjugated polymeric micellar nanoparticles (NC-6300) is thought to be a less invasive and more efficient method of cancer therapy. To investigate the mechanism underlying the combination effect, we examined the effect of trigger-pulsed HIFU (TP-HIFU) and NC-6300 from the perspective of reactive oxygen species (ROS) generation, which is considered the primary function of sonodynamic therapy (SDT), and changes in drug characteristics. TP-HIFU is an effective sequence for generating hydroxyl radicals to kill cancer cells. EPI was susceptible to degradation by TP-HIFU through the production of hydroxyl radicals. In contrast, EPI degradation of NC-6300 was suppressed by the hydrophilic shell of the micelles. NC-6300 also exhibited a sonosensitizer function, which promoted the generation of superoxide anions by TP-HIFU irradiation. The amount of ROS produced by TP-HIFU reached a level that caused structural changes to the cellular membrane. In conclusion, drug-conjugated micellar nanoparticles are more desirable for SDT because of accelerated ROS production and drug protection from ROS. Furthermore, a combination of NC-6300 and TP-HIFU is useful for minimally invasive cancer therapy with cooperative effects of HIFU-derived features, antitumor activity of EPI, and increased ROS generation to cause damage to cancer cells.

SUBMITTER: Takemae K

PROVIDER: S-EPMC6536629 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Function of Epirubicin-Conjugated Polymeric Micelles in Sonodynamic Therapy.

Takemae Kazuhisa K Okamoto Jun J Horise Yuki Y Masamune Ken K Muragaki Yoshihiro Y

Frontiers in pharmacology 20190521

The combinatory use of high-intensity focused ultrasound (HIFU) and epirubicin (EPI)-conjugated polymeric micellar nanoparticles (NC-6300) is thought to be a less invasive and more efficient method of cancer therapy. To investigate the mechanism underlying the combination effect, we examined the effect of trigger-pulsed HIFU (TP-HIFU) and NC-6300 from the perspective of reactive oxygen species (ROS) generation, which is considered the primary function of sonodynamic therapy (SDT), and changes in ...[more]

PMID: 31164824

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Project description:UnlabelledImaging of apoptosis can allow noninvasive assessment of disease states and response to therapeutic intervention for a variety of diseases. The purpose of this study was to develop and evaluate a multimodal nanoplatform for the detection of apoptosis.MethodsTo modulate the pharmacokinetics of annexin A5, a 36-kDa protein that binds specifically with phosphatidylserine, annexin A5 was conjugated to polyethylene glycol-coated, core-cross-linked polymeric micelles (CCPMs) dually labeled with near-infrared fluorescence fluorophores and a radioisotope ((111)In). To evaluate the specificity of the binding of annexin A5-CCPM to apoptotic cells, both fluorescence microscopy and cell-binding studies were performed in vitro. Pharmacokinetics, biodistribution, dual nuclear and optical imaging, and immunohistochemical studies were performed in 2 xenografted tumor models to evaluate the potential applications of annexin A5-CCPM.ResultsIn cell-based studies, annexin A5-CCPM exhibited strongly specific binding to apoptotic tumor cells. This binding could be efficiently blocked by annexin A5. In mice, annexin A5-CCPM displayed a mean elimination half-life of 12.5 h. The mean initial concentration in blood was 22.4% of the injected dose/mL, and annexin A5-CCPM was mainly distributed in the central blood compartment. In mice bearing EL4 lymphoma treated with cyclophosphamide and etoposide and in mice bearing MDA-MB-468 breast tumors treated with poly(L-glutamic acid)-paclitaxel and cetuximab (IMC-C225) anti-epidermal growth factor receptor antibody, the tumor apoptosis was clearly visualized by both SPECT and fluorescence molecular tomography. In contrast, there was little accumulation of this nanoradiotracer in the tumors of untreated mice. The biodistribution data were consistent with the imaging data, with tumor-to-muscle and tumor-to-blood ratios of 38.8 and 4.1, respectively, in treated mice, and 14.8 and 2.2, respectively, in untreated mice bearing EL4 lymphoma. Moreover, further studies demonstrated that the conventional (99m)Tc-labeled hydrazinonicotinamide annexin A5 and the plain CCPM control exhibited significantly lower uptake in the tumors of the treated mice than annexin A5-CCPM. Immunohistochemistry staining study showed that radioactivity count correlated with fluorescence signal from the nanoparticles, and both signals colocalized with the region of tumor apoptosis.ConclusionAnnexin A5-CCPM allowed visualization of tumor apoptosis by both nuclear and optical techniques. The complementary information acquired with multiple imaging techniques should be advantageous in assessing and validating early response to therapy.

Dataset Information

Function of Epirubicin-Conjugated Polymeric Micelles in Sonodynamic Therapy.

Publications

Function of Epirubicin-Conjugated Polymeric Micelles in Sonodynamic Therapy.

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