title: Synthesis of PLGA nanoparticles of tea polyphenols and their strong in vivo protective effect against chemically induced DNA damage.
abstract: In spite of proficient results of several phytochemicals in preclinical settings, the conversion rate from bench to bedside is not very encouraging. Many reasons are attributed to this limited success, including inefficient systemic delivery and bioavailability under in vivo conditions. To achieve improved efficacy, polyphenolic constituents of black (theaflavin [TF]) and green (epigallocatechin-3-gallate [EGCG]) tea in poly(lactide-co-glycolide) nanoparticles (PLGA-NPs) were entrapped with entrapment efficacy of ~18% and 26%, respectively. Further, their preventive potential against 7,12-dimethylbenzanthracene (DMBA)-induced DNA damage in mouse skin using DNA alkaline unwinding assay was evaluated. Pretreatment (topically) of mouse skin with either TF or EGCG (100 μg/mouse) doses exhibits protection of 45.34% and 28.32%, respectively, against DMBA-induced DNA damage. However, pretreatment with TF-loaded PLGA-NPs protects against DNA damage 64.41% by 1/20th dose of bulk, 71.79% by 1/10th dose of bulk, and 72.46% by 1/5th dose of bulk. Similarly, 51.28% (1/20th of bulk), 57.63% (1/10th of bulk), and 63.14% (1/5th of bulk) prevention was noted using EGCG-loaded PLGA-NP doses. These results showed that tea polyphenol-loaded PLGA-NPs have ~30-fold dose-advantage than bulk TF or EGCG doses. Additionally, TF- or EGCG-loaded PLGA-NPs showed significant potential for induction of DNA repair genes (XRCC1, XRCC3, and ERCC3) and suppression of DNA damage responsive genes (p53, p21, MDM2, GADD45α, and COX-2) as compared with respective bulk TF or EGCG doses. Taken together, TF- or EGCG-loaded PLGA-NPs showed a superior ability to prevent DMBA-induced DNA damage at much lower concentrations, thus opening a new dimension in chemoprevention research.
authors.affiliation: Proteomics Laboratory, Indian Institute of Toxicology Research (CSIR), Lucknow, India.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Srivastava
authors.forename: Priyanka
authors.initials: P
authors.lastname: Bhatnagar
authors.forename: Madhulika
authors.initials: M
authors.lastname: Singh
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mishra
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.forename: Yogeshwer
authors.initials: Y
authors.lastname: Shukla
authors.forename: Kailash Chand
authors.initials: KC
authors.lastname: Gupta
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D044946:Biflavonoids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012867:Skin / Q000187:drug effects; D013662:Tea / Q000737:chemistry*
chemical_list: D000975:Antioxidants; D044946:Biflavonoids; D013662:Tea; C056068:theaflavin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D002392:Catechin; C045651:epigallocatechin gallate
keywords: DNA alkaline unwinding assay; DNA repair; mouse skin