Dataset Information

Improved Efficacy and Reduced Toxicity Using a Custom-Designed Irinotecan-Delivering Silicasome for Orthotopic Colon Cancer.

ABSTRACT: Irinotecan is a key chemotherapeutic agent for the treatment of colorectal (CRC) and pancreatic (PDAC) cancer. Because of a high incidence of bone marrow and gastrointestinal (GI) toxicity, Onivyde (a liposome) was introduced to provide encapsulated irinotecan (Ir) delivery in PDAC patients. While there is an ongoing clinical trial (NCT02551991) to investigate the use of Onivyde as a first-line option to replace irinotecan in FOLFIRINOX, the liposomal formulation is currently prescribed as a second-line treatment option (in combination with 5-fluorouracil and leucovorin) for patients with metastatic PDAC who failed gemcitabine therapy. However, the toxicity of Onivyde remains a concern that needs to be addressed for use in CRC as well. Our goal was to custom design a mesoporous silica nanoparticle (MSNP) carrier for encapsulated irinotecan delivery in a robust CRC model. This was achieved by developing an orthotopic tumor chunk model in immunocompetent mice. With a view to increase the production volume and to expand the disease applications, the carrier design was improved by using an ethanol exchange method for coating of a supported lipid bilayer (LB) that entraps a protonating agent. The encapsulated protonating agent was subsequently used for remote loading of irinotecan. The excellent irinotecan loading capacity and stability of the LB-coated MSNP carrier, also known as a "silicasome", previously showed improved efficacy and reduced toxicity when compared to an in-house liposomal carrier in a PDAC model. Intravenous injection of the silicasomes in a well-developed orthotopic colon cancer model in mice demonstrated improved pharmacokinetics and tumor drug content over free drug and Onivyde. Moreover, improved drug delivery was accompanied by substantially improved efficacy, increased survival, and reduced bone marrow and GI toxicity compared to the free drug and Onivyde. We also confirmed that the custom-designed irinotecan silicasomes outperform Onivyde in an orthotopic PDAC model. In summary, the Ir-silicasome appears to be promising as a treatment option for CRC in humans based on improved efficacy and the carrier's favorable safety profile.

SUBMITTER: Liu X

PROVIDER: S-EPMC6554030 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Improved Efficacy and Reduced Toxicity Using a Custom-Designed Irinotecan-Delivering Silicasome for Orthotopic Colon Cancer.

Liu Xiangsheng X Jiang Jinhong J Chan Ryan R Ji Ying Y Lu Jianqin J Liao Yu-Pei YP Okene Michael M Lin Joshua J Lin Paulina P Chang Chong Hyun CH Wang Xiang X Tang Ivanna I Zheng Emily E Qiu Waveley W Wainberg Zev A ZA Nel Andre E AE Meng Huan H

ACS nano 20181211 1

Irinotecan is a key chemotherapeutic agent for the treatment of colorectal (CRC) and pancreatic (PDAC) cancer. Because of a high incidence of bone marrow and gastrointestinal (GI) toxicity, Onivyde (a liposome) was introduced to provide encapsulated irinotecan (Ir) delivery in PDAC patients. While there is an ongoing clinical trial (NCT02551991) to investigate the use of Onivyde as a first-line option to replace irinotecan in FOLFIRINOX, the liposomal formulation is currently prescribed as a sec ...[more]

PMID: 30525443

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Project description:Advances in aerosol technology over the past 10 years have enabled the generation and design of ultrafine nanoscale materials for many applications. A key new method is flame spray pyrolysis (FSP), which produces particles by pyrolyzing a precursor solution in the gas phase. FSP is a highly versatile technique for fast, single-step, scalable synthesis of nanoscale materials. New innovations in particle synthesis using FSP technology, including variations in precursor chemistry, have enabled flexible, dry synthesis of loosely agglomerated, highly crystalline ultrafine powders (porosity ≥ 90%) of binary, ternary, and mixed-binary-and-ternary oxides. FSP can fulfill much of the increasing demand, especially in biological applications, for particles with specific material composition, high purity, and high crystallinity. In this Account, we describe a strategy for creating nanoparticle libraries (pure or Fedoped ZnO or TiO₂) utilizing FSP and using these libraries to test hypotheses related to the particles' toxicity. Our innovation lies in the overall integration of the knowledge we have developed in the last 5 years in (1) synthesizing nanomaterials to address specific hypotheses, (2) demonstrating the electronic properties that cause the material toxicity, (3) understanding the reaction mechanisms causing the toxicity, and (4) extracting from in vitro testing and in vivo testing in terrestrial and marine organisms the essential properties of safe nanomaterials. On the basis of this acquired knowledge, we further describe how the dissolved metal ion from these materials (Zn²⁺ in this Account) can effectively bind with different cell constituents, causing toxicity. We use Fe-S protein clusters as an example of the complex chemical reactions taking place after free metal ions migrate into the cells. As a second example, TiO₂ is an active material in the UV range that exhibits photocatalytic behavior. The induction of electron-hole (e⁻/h⁺) pairs followed by free radical production is a key mechanism for biological injury. We show that decreasing the bandgap energy increases the phototoxicity in the presence of near-visible light. We present in detail the mechanism of electron transfer in biotic and abiotic systems during light exposure. Through this example we show that FSP is a versatile technique for efficiently designing a homologous library, meaning a library based on a parent oxide doped with different amounts of dopant, and investigating the properties of the resulting compounds. Finally, we describe the future outlook and state-of-the-art of an innovative two-flame system. A double-flame reactor enables independent control over each flame, the nozzle distances and the flame angles for efficient mixing of the particle streams. In addition, it allows for different flame compositions, flame sizes, and multicomponent mixing (a grain-grain heterojunction) during the reaction process.

Project description:BackgroundIrinotecan is a chemotherapeutic agent used to treat a variety of tumors, including colorectal cancer (CRC). In the intestine, it is transformed into SN-38 by gut microbial enzymes, which is responsible for its toxicity during excretion.ObjectiveOur study highlights the impact of Irinotecan on gut microbiota composition and the role of probiotics in limiting Irinotecan-associated diarrhea and suppressing gut bacterial β-glucuronidase enzymes.Material and methodsTo investigate the effect of Irinotecan on the gut microbiota composition, we applied 16S rRNA gene sequencing in three groups of stool samples from healthy individuals, colon cancer, and Irinotecan treated patients (n = 5/group). Furthermore, three Lactobacillus spp.; Lactiplantibacillus plantarum (L. plantarum), Lactobacillus acidophilus (L. acidophilus), Lacticaseibacillus rhamnosus (L. rhamnosus) were used in a single and mixed form to in-vitro explore the effect of probiotics on the expression of β-glucuronidase gene from E. coli. Also, probiotics were introduced in single and mixed forms in groups of mice before the administration of Irinotecan, and their protective effects were explored by assessing the level of reactive oxidative species (ROS) as well as studying the concomitant intestinal inflammation and apoptosis.ResultsThe gut microbiota was disturbed in individuals with colon cancer and after Irinotecan treatment. In the healthy group, Firmicutes were more abundant than Bacteriodetes, which was the opposite in the case of colon-cancer or Irinotecan treated groups. Actinobacteria and Verrucomicrobia were markedly present within the healthy group, while Cyanobacteria were noted in colon-cancer and the Irinotecan-treated groups. Enterobacteriaceae and genus Dialister were more abundant in the colon-cancer group than in other groups. The abundance of Veillonella, Clostridium, Butryicicoccus, and Prevotella were increased in Irinotecan-treated groups compared to other groups. Using Lactobacillus spp. mixture in mice models significantly relieved Irinotecan-induced diarrhea through the reduction of both β-glucuronidase expression and ROS, in addition to guarding gut epithelium against microbial dysbiosis and proliferative crypt injury.ConclusionsIrinotecan-based chemotherapy altered intestinal microbiota. The gut microbiota participates greatly in determining both the efficacy and toxicity of chemotherapies, of which the toxicity of Irinotecan is caused by the bacterial ß-glucuronidase enzymes. The gut microbiota can now be aimed and modulated to promote efficacy and decrease the toxicity of chemotherapeutics. The used probiotic regimen in this study lowered mucositis, oxidative stress, cellular inflammation, and apoptotic cascade induction of Irinotecan.

Dataset Information

Improved Efficacy and Reduced Toxicity Using a Custom-Designed Irinotecan-Delivering Silicasome for Orthotopic Colon Cancer.

Publications

Improved Efficacy and Reduced Toxicity Using a Custom-Designed Irinotecan-Delivering Silicasome for Orthotopic Colon Cancer.

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