The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy

Our plain-English summary of The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy, by P. Bertrand, C. Blanquart, V. Héroguez (Biomolecules, 2019).

The study

• Authors: P. Bertrand, C. Blanquart, V. Héroguez
• Journal: Biomolecules
• Published: 2019;9(2)
• Type of article: Review
• Cited by: 11 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 models of cancer. The 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. This paper deals with the synthesis of the polymeric nanoparticle platform, which was produced by Ring-Opening Metathesis Polymerization (ROMP), able to release anti-cancer drugs in dispersion, such as histone deacetylase inhibitors, into mesothelioma tumors. The core-shell nanoparticles (NPs) have stealth properties due to their poly(ethylene oxide) shell and can be viewed as universal nano-carriers on which any alkyne-modified anti-cancer molecule can be grafted by click chemistry. A cleavage reaction of the chemical bond between NPs and drugs through the contact of NPs with a medium presenting an acidic pH, which is typically a cancer tumor environment or an acidic intracellular compartment, induces a controlled release of the bioactive molecule in its native form. In our in vivo syngeneic model of mesothelioma, a highly selective accumulation of the particles in the tumor was obtained. The release of the drugs led to an 80% reduction of tumor weight for the best compound without toxicity. Our work demonstrates that the use of theranostic nanovectors leads to an optimized delivery of epigenetic inhibitors in tumors, which improves their anti-tumor properties in vivo.

In plain English

This article is a review in which the authors described their own earlier laboratory and mouse work on a drug-delivery system for mesothelioma, a cancer the article links to asbestos exposure. It did not study asbestos exposure itself. The authors made tiny polymer particles (nanoparticles, 300 to 380 nm across) coated with poly(ethylene oxide). They attached anti-cancer drugs called histone deacetylase inhibitors (vorinostat, tacedinaline and a compound called NODH) using a chemical link designed to break in acidic conditions. In mouse models of mesothelioma, fluorescent particles injected into a vein built up in tumors more than in liver, spleen, kidneys, ovaries and brain. Particles carrying vorinostat increased markers of drug activity in tumors but had no effect on tumor mass. In mice with mesothelioma in the abdomen, which according to a figure legend also received decitabine, particles carrying NODH were reported to decrease tumor weight by 80% compared with control mice and mice given free NODH. No toxicity was observed in blood cells, liver, spleen or kidneys. The authors concluded that this approach appears to be an interesting strategy, but that combination with standard chemotherapy needs to be considered.

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: Review of the authors' own previous chemistry, cell and animal studies
• Who was studied: Lung adenocarcinoma and mesothelioma cell lines, and syngeneic mice (C57Bl/6) with subcutaneous or intraperitoneal AK7 mesothelioma tumors. The number of mice is not given in this review.
• Exposure: Not an asbestos exposure study. The treatments were polymer nanoparticles carrying pH-sensitive pro-drugs of the histone deacetylase inhibitors vorinostat, tacedinaline (CI-994) and NODH, given intravenously. Mesothelioma is described as associated with asbestos exposure.
• Main results:
  • The nanoparticles produced were spherical and measured 300 to 380 nm in diameter.
  • In the subcutaneous mesothelioma mouse model, fluorescent nanoparticles accumulated in tumor tissue more than in other organs.
  • Nanoparticles carrying vorinostat (NPs 24) increased apoptosis and histone H3 acetylation in tumors, but did not affect tumor mass.
  • In the intraperitoneal mesothelioma model, nanoparticles carrying NODH (NPs 23) led to an 80% decrease in tumor weight and less invasion of the pancreas, compared with control and free NODH groups.
  • In this experiment, the figure legend states that mice received decitabine before the nanoparticle or NODH injections, and that the control group G1 received no treatment.
  • No toxicity of NPs 23 was observed on blood cells or on the liver, spleen and kidneys.
• The authors' conclusion: The authors concluded that delivering HDAC inhibitors with nanoparticles appears to be an interesting strategy to improve their activity in living animals, but that combination with classical chemotherapy needs to be considered to obtain efficient anti-tumor activity.
• Limitations the authors state:
  • The vorinostat nanoparticles had a poor anti-tumor effect, despite improved acetylation in tumors.
  • The authors did not know whether the lack of effect on tumor mass was due to the drug's insufficient activity or to too low a level of drug loading.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

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• Curcumin loaded PLGA-poloxamer blend nanoparticles induce cell cycle arrest in mesothelioma cells — L. Mayol, C. Serri, et al. (2015)
• Efficacy of piroxicam plus cisplatin-loaded PLGA nanoparticles in inducing apoptosis in mesothelioma cells — C. Menale, M.T. Piccolo, et al. (2015)
• Nanoparticle drug-delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle — A.H. Colby, N.H. Oberlies, et al. (2017)
• 3D Culture Models of Malignant Mesothelioma Reveal a Powerful Interplay Between Photodynamic Therapy and Kinase Suppression Offering Hope to Reduce Tumor Recurrence — B.Q. Spring, D. Kessel (2019)

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