Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy

Our plain-English summary of Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy, by F. El Bahhaj, I. Denis, L. Pichavant, et al (Theranostics, 2016).

The study

• Authors: F. El Bahhaj, I. Denis, L. Pichavant, R. Delatouche, F. Collette, C. Linot, D. Pouliquen, M. Grégoire, V. Héroguez, C. Blanquart, P. Bertrand
• Journal: Theranostics
• Published: 2016;6(6):795-807
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Fast clearance, metabolism and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo model of cancers. Specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. In this work, we describe a simple and flexible polymeric nanoparticle platform highly targeting the tumor in vivo and triggering impressive tumor weight reduction when functionalized with HDACi. Our nanoparticles were produced by Ring-Opening Metathesis Polymerization of azido-polyethylene oxide-norbornene macromonomers and functionalized using click chemistry. Using an orthotopic model of peritoneal invasive cancer, a highly selective accumulation of the particles in the tumor was obtained. A combination of epigenetic drugs involving a pH-responsive histone deacetylase inhibitor (HDACi) polymer conjugated to these particles gave 80% reduction of tumor weight without toxicity whereas the free HDACi has no effect. Our work demonstrates that the use of a nanovector with theranostic properties leads to an optimized delivery of potent HDACi in tumor and then, to an improvement of their anti-tumor properties in vivo.

In plain English

This laboratory and animal study tested nanoparticles made by Ring-Opening Metathesis Polymerization of azido-polyethylene oxide-norbornene macromonomers as carriers for a histone deacetylase inhibitor (HDACi), in mesothelioma, described by the authors as an asbestos exposure-related cancer. A pH-responsive prodrug (4b) of the trichostatin A analogue compound 2 was clicked onto azide macromonomer 6 to give macromonomer 7, which was then copolymerized with norbornene to form nanoparticles 8. Prodrug 4b had half-lives of 3h at pH 3.0, 13h at pH 4.3, 21h at pH 5.0 and 3.2 days at pH 7.3; particle diameter was 380 nm in water. In cell assays the HDAC-inhibition IC50 was 500 nM for compounds 2 or 4b; for NPs 8 the Results text gives 0.125 µg/mL and the figure legend 0.125 mg/mL (6 µM compound 2). In C57Bl/6 mice bearing intraperitoneal AK7 murine mesothelioma tumours, fluorescent NPs 11 accumulated selectively in tumour over 96h; all treated groups received decitabine, and NPs 8 reduced tumour weight by 80%, whereas free compound 2 and bare NPs 10 had no anti-tumour effect, with no apparent toxicity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Experimental study combining chemical synthesis, in vitro cell assays and in vivo mouse experiments (orthotopic peritoneal mesothelioma model)
• Who was studied: Human pleural mesothelial cell line MeT-5A and mesothelioma cell lines Meso13, Meso34, Meso56 established from patients' pleural fluids; C57Bl/6 mice given intraperitoneal AK7 murine mesothelioma cells (five mice per group; five groups for biodistribution, four groups of five for treatment)
• Exposure: Drug treatments: free HDACi compound 2 (racemic trichostatin A analogue), its pH-responsive prodrug 4b, prodrug-functionalized nanoparticles NPs 8, bare NPs 10, rhodamine-labelled NPs 11, with decitabine given intraperitoneally to all treated groups
• Main results:
  • Prodrug 4b half-lives: 3h at pH 3.0, 13h at pH 4.3, 21h at pH 5.0 and 3.2 days at pH 7.3; prodrug 4a was stable at the pHs tested
  • Nanoparticle size: 305 nm in organic solvent and 380 nm in water by DLS, confirmed by TEM
  • HDAC inhibition (BRET assay in MeT-5A cells): IC50 500 nM for compounds 2 or 4b; for NPs 8 the Results text prints 0.125 µg/mL (equivalent to 6.0 µM compound 2), while the Figure 3 legend prints 0.125 mg/mL NPs 8 for the same 6 µM compound 2 equivalent
  • Figure 3 legend wording of the same nanoparticle dose, in mg/mL
  • In tumour-bearing mice given fluorescent NPs 11 intravenously, fluorescence accumulated in tumours over the first 24h, plateaued at 72h and remained stable to 96h
  • Tumour weight, in mice all receiving decitabine: NPs 8 reduced tumour weight by 80%, significantly; free compound 2 and bare NP 10 showed no anti-tumour effect
  • All three treated groups received decitabine in combination
  • In NP 8-treated mice, absence of tumour cells in pancreas in 4 of 5 mice, versus large and numerous pancreatic invasion areas in untreated and free compound 2 mice
  • No apparent toxicity in any tested condition, judged by liver, kidney and spleen weight and blood formula
• The authors' conclusion: The authors concluded that loading the HDACi onto their pH-responsive delivery system gave improved activity of compound 2 in vivo, suggesting effective and specific delivery to the tumour site by the EPR effect followed by acid-mediated release, with optimal antitumoral effect and no apparent toxicity despite very low drug loading
• Limitations the authors state:
  • The nanoparticle composition was calculated under the assumption that both macromonomers are consumed at the same rate, an approximation made by the authors

Related studies

• Design of pH responsive clickable prodrugs applied to histone deacetylase inhibitors: a new strategy for anticancer therapy — R. Delatouche, I. Denis, et al. (2013)
• The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy — P. Bertrand, C. Blanquart, et al. (2019)
• Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma — R. Liu, A.H. Colby, et al. (2016)
• New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells — F. Gueugnon, P.F. Cartron, et al. (2014)
• Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles — A.H. Colby, R. Liu, et al. (2016)
• Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors — J.J. Sacco, J. Kenyani, et al. (2015)

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