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Acid-responsive nanoparticles as a novel oxidative stress-inducing anticancer therapeutic agent for colon cancer.

ABSTRACT: Objective:Nanoparticles can efficiently carry and deliver anticancer agents to tumor sites. Mounting evidence indicates that many types of cancer cells, including colon cancer, have a weakly acidic microenvironment and increased levels of reactive oxygen species. The construction of nano drug delivery vehicles "activatable" in response to the tumor microenvironment is a new antitumor therapeutic strategy. Methods:Cinnamaldehyde (CA) was designed to link directly with dextran to form a polymer through an acid cleavable acetal bond. Herein, a novel pH-sensitive drug delivery system was constructed with co-encapsulated 10-hydroxy camptothecin (HCPT). Dynamic light scattering (DLS) analysis, transmission electron microscopy (TEM) analysis, and release kinetics analysis of HCPT-CA-loaded nanoparticles (PCH) were conducted to investigate the physical and chemical properties. The cellular uptake signatures of the nanoparticles were observed by confocal microscopy and flow cytometry. Cell viability, cell scratch assay, apoptosis assay, and colony formation assay were performed to examine the potent antiproliferative and apoptotic effects of the PCH. The antitumor mechanism of the treatment with PCH was evaluated by Western blotting, flow cytometry, and TEM analysis. The pharmacokinetics of PCH were examined in healthy Sprague Dawley rats within 6 hours after sublingual vein injection. We lastly examined the biodistribution and the in vivo anticancer activity of PCH using the xenograft mouse models of HCT116 cells. Results:Both HCPT and CA were quickly released by PCH in an acidic microenvironment. PCH not only induced cancer cell death through the generation of intracellular reactive oxygen species in vitro but also facilitated the drug uptake, effectively prolonged drug circulation, and increased accumulation of drug in tumor sites. More attractively, PCH exhibited excellent therapeutic performance and better in vivo systemic safety. Conclusion:Overall, PCH not only utilized the tumor microenvironment to control drug release, improve drug pharmacokinetics, and passively target the drug to the tumor tissue, but also exerted a synergistic anticancer effect. The acid-responsive PCH has enormous potential as a novel anticancer therapeutic strategy.

SUBMITTER: Zhao C

PROVIDER: S-EPMC6400122 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Acid-responsive nanoparticles as a novel oxidative stress-inducing anticancer therapeutic agent for colon cancer.

Zhao Chengwei C Cao Weilan W Zheng Hailun H Xiao Zhongxiang Z Hu Jie J Yang Lehe L Chen Min M Liang Guang G Zheng Suqing S Zhao Chengguang C

International journal of nanomedicine 20190228

<h4>Objective</h4>Nanoparticles can efficiently carry and deliver anticancer agents to tumor sites. Mounting evidence indicates that many types of cancer cells, including colon cancer, have a weakly acidic microenvironment and increased levels of reactive oxygen species. The construction of nano drug delivery vehicles "activatable" in response to the tumor microenvironment is a new antitumor therapeutic strategy.<h4>Methods</h4>Cinnamaldehyde (CA) was designed to link directly with dextran to fo ...[more]

PMID: 30880968

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Project description:BackgroundIron oxide nanoparticles have been approved by food and drug administration for clinical application as magnetic resonance imaging (MRI) and are considered to be a biocompatible material. Large iron oxide nanoparticles are usually used as transversal (T2) contrast agents to exhibit dark contrast in MRI. In contrast, ultrasmall iron oxide nanoparticles (USPIONs) (several nanometers) showed remarkable advantage in longitudinal (T1)-weighted MRI due to the brighten effect. The study of the toxicity mainly focuses on particles with size of tens to hundreds of nanometers, while little is known about the toxicity of USPIONs.ResultsWe fabricated Fe3O4 nanoparticles with diameters of 2.3, 4.2, and 9.3 nm and evaluated their toxicity in mice by intravenous injection. The results indicate that ultrasmall iron oxide nanoparticles with small size (2.3 and 4.2 nm) were highly toxic and were lethal at a dosage of 100 mg/kg. In contrast, no obvious toxicity was observed for iron oxide nanoparticles with size of 9.3 nm. The toxicity of small nanoparticles (2.3 and 4.2 nm) could be reduced when the total dose was split into 4 doses with each interval for 5 min. To study the toxicology, we synthesized different-sized SiO2 and gold nanoparticles. No significant toxicity was observed for ultrasmall SiO2 and gold nanoparticles in the mice. Hence, the toxicity of the ultrasmall Fe3O4 nanoparticles should be attributed to both the iron element and size. In the in vitro experiments, all the ultrasmall nanoparticles (< 5 nm) of Fe3O4, SiO2, and gold induced the generation of the reactive oxygen species (ROS) efficiently, while no obvious ROS was observed in larger nanoparticles groups. However, the ·OH was only detected in Fe3O4 group instead of SiO2 and gold groups. After intravenous injection, significantly elevated ·OH level was observed in heart, serum, and multiple organs. Among these organs, heart showed highest ·OH level due to the high distribution of ultrasmall Fe3O4 nanoparticles, leading to the acute cardiac failure and death.ConclusionUltrasmall Fe3O4 nanoparticles (2.3 and 4.2 nm) showed high toxicity in vivo due to the distinctive capability in inducing the generation of ·OH in multiple organs, especially in heart. The toxicity was related to both the iron element and size. These findings provide novel insight into the toxicology of ultrasmall Fe3O4 nanoparticles, and also highlight the need of comprehensive evaluation for their clinic application.

Dataset Information

Acid-responsive nanoparticles as a novel oxidative stress-inducing anticancer therapeutic agent for colon cancer.

Publications

Acid-responsive nanoparticles as a novel oxidative stress-inducing anticancer therapeutic agent for colon cancer.

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