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

Bahhaj, Fatima el; Denis, Iza; Pichavant, Loïc; Delatouche, Régis; Collette, Floraine; Linot, Camille; Pouliquen, Daniel; Grégoire, Marc; Héroguez, Valérie; Blanquart, Christophe; Bertrand, Philìppe

doi:10.7150/thno.13725

Cited by 33 publications

(21 citation statements)

References 42 publications

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“…Multiple investigators have identified HDAC inhibitors as drugs of interest for treating cancer, including GBM [ 1 , 8 , 17 , 41 – 43 ]. While in vitro results have been promising, little success has been observed in vivo [ 20 , 44 , 45 ]. As a monotherapy, quisinostat and other HDIs have shown the greatest in vivo efficacy against hematological cancers [ 17 , 19 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma

Householder

DiPerna

Chung

et al. 2018

Colloids and Surfaces B: Biointerfaces

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Histone deacetylases (HDACs) are known to be key enzymes in cancer development and progression through their modulation of chromatin structure and the expression and post-translational modification of numerous proteins. Aggressive dedifferentiated tumors, like glioblastoma, frequently overexpress HDACs, while HDAC inhibition can lead to cell cycle arrest, promote cellular differentiation and induce apoptosis. Although multiple HDAC inhibitors, such as quisinostat, are of interest in oncology due to their potent in vitro efficacy, their failure in the clinic as monotherapies against solid tumors has been attributed to poor delivery. Thus, we were motivated to develop quisinostat loaded poly(D,L-lactide)-b-methoxy poly(ethylene glycol) nanoparticles (NPs) to test their ability to treat orthotopic glioblastoma. In developing our NP formulation, we identified a novel, pH-driven approach for achieving over 9% (w/w) quisinostat loading. We show quisinostat-loaded NPs maintain drug potency in vitro and effectively slow tumor growth in vivo, leading to a prolonged survival compared to control mice.

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Section: Resultsmentioning

confidence: 99%

pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma

Householder

DiPerna

Chung

et al. 2018

Colloids and Surfaces B: Biointerfaces

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“…Hence, we shifted our attention to HDAC1 in our subsequent analysis. In epigenetic regulation, HDAC1 always forms a complex at the promoter region with DNA methyltransferase 3 alpha (DNMT3a, ~100 kD), which is reported to mediate DNA de novo methylation 51 . The complex blocks the binding of transcription factors and leads to gene silencing 52 , 53 .…”

Section: Resultsmentioning

confidence: 99%

Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression

Chen

Xu³

et al. 2018

Theranostics

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Many plant-specialized metabolites have remedial properties and provide an endless chemical resource for drug discovery. However, most of these metabolites have promiscuous binding targets in mammalian cells and elicit a series of responses that collectively change the physiology of the cells. To explore the potential of these multi-functional and multi-targeted drugs, it is critical to understand the direct relationships between their key chemical features, the corresponding binding targets and the relevant biological effects, which is a prerequisite for future drug modification and optimization.Methods: We introduced and demonstrated a general workflow, called Comparative Profiling of Analog Targets (CPAT), to connect specific biological effects with defined chemical structures of drugs. Using resveratrol (RSV) as an example, we have synthesized and characterized a series of partial functional analogs of RSV. An analog (named RSVN) that specifically lost the inhibitory effect of RSV in cell migration was identified. The binding targets of RSVN and RSV was profiled and compared.Results: Comparative profiling of the RSV and RSVN binding targets showed that, unlike RSV, RSVN failed to target specific components involved in DNA methylation (histone deacetylase 1 [HDAC1] and DNA methyltransferase 3 alpha [DNMT3a]), suggesting that RSV suppresses cell migration through epigenetic regulation. Indeed, RSV treatment recruited HDAC1 and DNMT3a to the promoter region of the focal adhesion kinase (FAK), a key factor involved in cell adhesion, enhanced the promoter methylation, and thus attenuated the protein expression. The inhibitory effect of RSV in cell migration was diminished once FAK expression was restored. Thus, the mechanism of RSV in inhibiting cell migration could be largely accounted to epigenetically control of FAK expression.Conclusion: Our results showed that even though RSV exhibits promiscuous binding, its inhibitory effect on cell migration can be mechanistically understood. First, the presence of 4'-hydroxystilbene within the RSV structure is essential for this activity. Second, it inhibits cell migration through epigenetically based downregulation of FAK expression. Taken together, we propose that CPAT might also be adapted to delineate the specific function of other natural products (NPs) that exhibit binding promiscuity.

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“…Some studies have described the synthesis and applications for the delivery of HDACi by nanoformulations including PLGA-based NPs for the delivery of vorinostat to prostate and colorectal cancers 37 and a polyethylene oxidenorbornene macromonomer platform for the delivery of different HDACi prodrugs for mesothelioma models. 38 In another study, lipid-polymer conjugated based NPs were utilized for the delivery of two HDACi, vorinostat and quisinostat, as radiosensitizers to investigate their therapeutic potentials in xenograft models of colorectal and prostate carcinomas. 39 The studies outlined here represent the first study using polymeric starch NPs prepared using standard emulsification methods for the delivery of therapeutic drugs to breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

<p>Starch nanoparticles for delivery of the histone deacetylase inhibitor CG-1521 in breast cancer treatment</p>

Alp¹,

Damkaci²,

Güven³

et al. 2019

IJN

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Background:The efficacy of epigenetic drugs, such as histone deacetylase inhibitors, is often diminished by poor aqueous solubility resulting in limited bioavailability and a low therapeutic index. To overcome the suboptimal therapeutic index, we have developed a biocompatible starch nanoparticle formulation of CG-1521, a histone deacetylase inhibitor in preclinical development for hard-to-treat breast cancers, which improves its bioavailability and half-life. Methods: The physicochemical parameters (size, zeta potential, morphology, loading, and release kinetics) of these nanoparticles (CG-NPs) have been optimized and their cytotoxic and apoptotic capacities measured in MCF-7 breast cancer cell line. The mechanism of action of the encapsulated drug was compared with the free drug at molecular level. Results: We show that encapsulation of CG-1521 substantially reduces the release rate of drug and provides a significantly enhanced cytotoxic ability of nanoparticles compared with equivalent dose of free CG-1521. CG-NPs induced cell cycle arrest and significant apoptosis in MCF-7 cells in vitro. The biological action of encapsulated drug has the similar impact with free drug on gene expression. Conclusion: The findings suggest that encapsulation of CG-1521 into starch nanoparticles can improve drug delivery of histone deacetylase inhibitors for breast cancer therapy without interfering with the mechanism of action of the drug.

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

Cited by 33 publications

References 42 publications

pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma

pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma

Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression

<p>Starch nanoparticles for delivery of the histone deacetylase inhibitor CG-1521 in breast cancer treatment</p>

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