[Frontiers In Bioscience, Landmark, 24, 1097-1157, March 1, 2019]

Nano-engineered flavonoids for cancer protection

Neha Bunkar1, Ruchita Shandilya1, Arpit Bhargava1, Ravindra M. Samarth1, Rajnarayan Tiwari1, Dinesh Kumar Mishra2, Rupesh Kumar Srivastava3, Radhey Shyam Sharma4, Nirmal Kumar Lohiya5, Pradyumna Kumar Mishra1

1Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bhopal, India, 2School of Pharmacy and Technology Management, Narsee Moonjee Institute of Management Studies, Shirpur, India, 3Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India, 4Division of Reproductive Biology, Maternal and Child Health, Indian Council of Medical Research, New Delhi, India, 5Centre for Advanced Studies, University of Rajasthan, Jaipur, India

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Epigenetic modification: Reversible codes
3.1. DNA methylation: Covalent cytosine methylation patterns
3.2. Histone modification: Covalent tags on amino tails
3.2.1. Histone acetylation
3.2.2. Histone methylation
3.2.3. Histone phosphorylation
3.2.4. Histone ubiquitination
3.3. microRNA (miRNA) expression profiling
4. Flavonoids as promising nutraceuticals
5. Nutri-epigenetics: flavonoids as epigenetic modifiers
6. Molecular mechanism of flavonoids: Epigenetic modulation through mitochondria
7. Preclinical studies of mitochondria targeted flavonoids for anti-cancer action
8. Challenges in flavonoids mediated-anti-cancer therapeutic strategy
8.1. Isolation and purification challenges
8.2. Pharmacokinetic (PK) challenges
9. Approaches to surmount pharmacokinetic/pharmacodynamic and other barriers for flavonoids delivery
9.1. Improving isolation, purification and yield
9.2. Overcoming PK challenges
9.3. Nanocarriers for efficient delivery of flavonoids
9.3.1. Polymer-based nanocarriers
9.3.1.1. Polymeric nanoparticles (PNPs)
9.3.1.2. Polymeric micelles
9.3.2. Lipid-based nanocarriers
9.3.2.1. Micelles
9.3.2.2. Microemulsions, nanoemulsions and self-emulsifying drug delivery systems
9.3.3. Solid lipid nanoparticles (SLN)
9.3.4. Nanostructured lipid carriers (NLC)
9.3.5. Molecular inclusion complexes
9.3.5.1. Cyclodextrins inclusion complexes
9.3.5.2. Phytosomes®
10. Mitochondrial targeting nano-engineered strategies for bio-therapeutics
10.1. Liposomal nanocarriers for mitochondrial targeting
10.2. DQAsomes
10.3. MITO-Porter
10.4. Delocalized lipophilic cations (DLCs)
10.4.1. TPP-conjugates
10.5. Polymeric NPs
10.6. Mitochondrial targeting peptide
10.7. Carbon nanostructures
10.8. Blended nanoparticles
10.8.1. Metal nanoparticles
10.8.2. Mesoporous silica nanoparticles
11. Nano-engineered flavonoids targeting mitochondrial-induced epigenetic modifications
12. Concluding remarks
13. Acknowledgments
14. References

1. ABSTRACT

Diet and environment are two critical regulators that influence an individual’s epigenetic profile. Besides the anterograde signaling, mitochondria act as a key regulator of epigenetic alterations in cancer either by controlling the concentration of the cofactors, activity of vital enzymes or by affecting the transcription of NF-kappaB and associated signaling molecules. As epigenetic modifications are the major drivers of aberrant gene expression, designing novel nutri-epigenomic strategies to modulate reversible epigenetic modifications will be important for effective cancer protection. In this regard, nutraceuticals such as flavonoids holds significant promise to modulate the epigenome through a network of interconnected anti-redox mechanisms. However, low solubility, rapid metabolism and poor absorption of flavonoids in gastrointestinal tract hinder their use in clinical settings. Therefore, it is imperative to develop nano-engineered systems which could considerably improve the targeted delivery of these bioactive compounds with better efficacy and pharmacokinetic properties. Concerted efforts in nano-engineering of flavonoids using polymer, lipid and complexation based approaches could provide successful bench-to-bedside translation of flavonoids as broad spectrum anti-cancer agents.

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Abbreviations: ADMET, absorption, distribution, metabolism, excretion, and toxicity; ATM, ataxia telangiectasia-mutated; sATP, adenosine triphosphate; Bcl-2, B-cell lymphoma 2; BNIP3, BCL2 Interacting Protein 3; BRCT, BRCA1 C Terminus; CMC, critical micelle concentration; CSCs, cancer stem cells; DLCs, Delocalized lipophilic cations; DNMTs, DNA methyltransferases; DUBs, deubiquitinases; EGCG, epigallocatechin gallate; EMT, epithelial-mesenchymal transition; EZH2, enhancer of zeste homolog 2; GALT, Gut-associated lymphoid tissue; GATA4, GATA Binding Protein 4; H2Bub, 1monoubiquitination of histone H2B at lysine 120; H3K4, histone H3 lysine 4; HAT, histone acetyl transferase; HDAC1, histone deacetylase 1; HMT, histone methyl transferase; IUIM, inverted ubiquitin interaction motif; KDM, histone methyl transferase; LSD1, lysine demethylates; M cells, specialized microfold cells; MeCP, methyl CpG binding protein; miRNA microRNA; MOF, males absent on the first; MYST, Moz-Ybf2/Sas3-Sas2-Tip60; NAD+, nicotinamide adenine dinucleotide; NICD, Notch1 intracellular domain; NLC, nanostructured lipid carriers; NP.SB, nano-engineered flavonoid rich fraction from Selaginella bryopteris; PARP-1, poly (ADP-ribose) polymerase 1; PD, Pharmacodynamics; PK, Pharmacokinetics; PLGA, poly(lactic-co-glycolic acid; PNP, polymeric nanoparticles; RASSF1A, Ras association domain family 1 isoform A; RNF20, RING finger proteins; RNF40, RING finger proteins; ROS, reactive oxygen species; SAH, S-adenosylhomocystein; SAM, S-adenosylmethionine; SAM/SAH ratio, SAM to SAH ratios; SB.Fr., flavonoid rich fraction from Selaginella bryopteris; SLN, solid lipid nanoparticles; TET, ten eleven translocation; γH2AX, phosphorylated histone 2AX

Key Words: Nutriepigenomics, Epigenetic modifiers, Anti-cancer agents, Nanomedicine, Translational research, Review

Send correspondence to: Prof. (Dr.) Pradyumna Kumar Mishra, Head, Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Kamla Nehru Hospital Building, Gandhi Medical College Campus), Bhopal - 462001, India, Tel: +91-9479983943, Fax: 91-755-2533976, E-mail: pkm_8bh@yahoo.co.uk