Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed

Ando, Hidenori; Kobayashi, Sakiko; Lila, Amr S. Abu; Eldin, Noha Essam; Kato, Chiho; Shimizu, Taro; Ukawa, Masami; Kawazoe, Kazuyoshi; Ishida, Tatsuhiro

doi:10.1016/j.jconrel.2015.10.019

Cited by 33 publications

(15 citation statements)

References 32 publications

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“…to determine a potential synergistic effect (49)(50)(51)(52)(53)(54)(55). Liposomal PMTX formulations have been tested in an orthotopic mouse model (56). Due to the diversity of the assays, it is difficult to compare their predictability.…”

Section: Preclinical Modelsmentioning

confidence: 99%

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

2020

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Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options. Recently, clinical trials that used immunotherapy strategies have yielded promising results, but the benefits are restricted to a limited number of patients. To develop new therapeutic strategies and define predictors of treatment response to existing therapy, better knowledge of the cellular and molecular mechanisms of MM tumors and sound preclinical models are needed. This review aims to provide an overview of our present knowledge and issues on both subjects. MM shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations. MM is also a heterogeneous cancer. The recently described molecular classifications for MPM could better consider inter-tumor heterogeneity, while histo-molecular gradients are an interesting way to consider both intra-and inter-tumor heterogeneities. Classical preclinical models are based on use of MM cell lines in culture or implanted in rodents, i.e., xenografts in immunosuppressed mice or isografts in syngeneic rodents to assess the anti-tumor immune response. Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells. Multicellular tumor spheroids are an interesting in vitro model to reduce animal experimentation; they are more accessible than tumoroids. They could be relevant, especially if they are co-cultured with stromal and immune cells to partially reproduce the human microenvironment. Even if preclinical models have allowed for major advances, they show several limitations: (i) the anatomical and biological tumor microenvironments are incompletely reproduced; (ii) the intra-tumor heterogeneity and immunological contexts are not fully reconstructed; and (iii) the inter-tumor heterogeneity is insufficiently considered. Given that these limitations vary according to the models, preclinical models must be carefully selected depending on the objectives of the experiments. New approaches, such as organ-on-a-chip technologies or in silico biological systems, should be explored in MM research. More pertinent cell models, based on our knowledge on mesothelial carcinogenesis and considering MM heterogeneity, need to be developed. These endeavors are mandatory to implement efficient precision medicine for MM.

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Section: Preclinical Modelsmentioning

confidence: 99%

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

2020

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“…We demonstrated that the shRNA formulated in shRNA/liposome-complexes prevents shRNA degradation in pleural fluid, and the shRNA/liposome-complexes remain in the pleural cavity for an extended period of time following intrapleural injection [28]. A long retention would increase the opportunity for DNAs/liposome-complexes to interact with the targeted cells and transfect DNAs into the cells.…”

Section: Discussionmentioning

confidence: 95%

A Unique Gene-Silencing Approach, Using an Intelligent RNA Expression Device (iRed), Results in Minimal Immune Stimulation When Given by Local Intrapleural Injection in Malignant Pleural Mesothelioma

et al. 2020

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Background: We have recently introduced an intelligent RNA expression device (iRed), comprising the minimum essential components needed to transcribe short hairpin RNA (shRNA) in cells. Use of iRed efficiently produced shRNA molecules after transfection into cells and alleviated the innate immune stimulation following intravenous injection. Methods: To study the usefulness of iRed for local injection, the engineered iRed encoding luciferase shRNA (Luc iRed), complexed with cationic liposomes (Luc iRed/liposome-complexes), was intrapleurally injected into an orthotopic mesothelioma mouse model. Results: Luc iRed/liposome-complexes markedly suppressed the expression of a luciferase marker gene in pleurally disseminated mesothelioma cells. The suppressive efficiency was correlated with the expression level of shRNA within the mesothelioma cells. In addition, intrapleural injection of iRed/liposome-complexes did not induce IL-6 production in the pleural space and consequently in the blood compartment, although plasmid DNA (pDNA) or dsDNA (the natural construct for iRed) in the formulation did. Conclusion: Local delivery of iRed could augment the in vivo gene silencing effect without eliciting pronounced innate immune stimulation. Our results might hold promise for widespread utilization of iRed as an RNAi-based therapeutic for intracelial malignant cancers.

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“…Ando and colleagues investigated intrapleural delivery of two liposomal formulations of pemetrexed: cholesterolcontaining, and cholesterol-free liposomes, in an orthotopic mouse model of mesothelioma. 48 The authors found that only the cholesterol-free liposomes reduced tumor growth. This was thought to be dependent on the Figure 3 Representative Romanowski stained blood smears collected following intravenous infusion and intrapleural injection of liposomal curcumin (16 mg/kg) (A) Echinocyte formation was observed in the blood 1.5 h after intravenous liposomal curcumin infusions (B) Normal erythrocyte morphology was observed at 1.5 h following the administration of intrapleural liposomal curcumin.…”

Section: Discussionmentioning

confidence: 99%

<p>The Safety and Exploration of the Pharmacokinetics of Intrapleural Liposomal Curcumin</p>

Hocking

Tommasi

Sordillo

et al. 2020

IJN

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Background: Malignant pleural effusion (MPE) is the accumulation of fluid in the pleural cavity as a result of malignancies affecting the lung, pleura and mediastinal lymph nodes. Curcumin, a compound found in turmeric, has anti-cancer properties that could not only treat MPE accumulation but also reduce cancer burden. To our knowledge, direct administration of curcumin into the pleural cavity has never been reported, neither in animals nor in humans. Purpose: To explore the compartmental distribution, targeted pharmacokinetics and the safety profile of liposomal curcumin following intrapleural and intravenous administration. Methods: Liposomal curcumin (16 mg/kg) was administered into Fischer 344 rats by either intrapleural injection or intravenous infusion. The concentration of curcumin in plasma and tissues (lung, liver and diaphragm) were measured using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Blood and tissues were examined for pathological changes. Results: No pleural or lung pathologies were observed following intrapleural liposomal curcumin administration. Total curcumin concentration peaked 1.5 hrs after the administration of intrapleural liposomal curcumin and red blood cell morphology appeared normal. A red blood cells abnormality (echinocytosis) was observed immediately and at 1.5 hrs after intravenous infusion of liposomal curcumin. Conclusion: These results indicate that liposomal curcumin is safe when administered directly into the pleural cavity and may represent a viable alternative to intravenous infusion in patients with pleural-based tumors.

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Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed

Cited by 33 publications

References 32 publications

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

A Unique Gene-Silencing Approach, Using an Intelligent RNA Expression Device (iRed), Results in Minimal Immune Stimulation When Given by Local Intrapleural Injection in Malignant Pleural Mesothelioma

<p>The Safety and Exploration of the Pharmacokinetics of Intrapleural Liposomal Curcumin</p>

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