title: Surface decorated nanoparticles as surrogate carriers for improved transport and absorption of epirubicin across the gastrointestinal tract: Pharmacokinetic and pharmacodynamic investigations.
abstract: Epirubicin (EPI) is a P-gp substrate antracycline analogue which elicits poor oral bioavailability. In the present work, EPI loaded poly-lactide-co-glycolic acid nanoparticles (PLGA-NPs) were prepared by double emulsion approach and superficially decorated with polyethylene glycol (EPI-PNPs) and mannosamine (EPI-MNPs). Average hydrodynamic particle size of EPI-PNPs and EPI-MNPs was found 248.63 ± 12.36 and 254.23 ± 15.16 nm, respectively. Cytotoxicity studies were performed against human breast adenocarcinoma cell lines (MCF-7) confirmed the superiority of EPI-PNPs and EPI-MNPs over free epirubicin solution (EPI-S). Further, confocal laser scanning microscopy (CLSM) and flow cytometric analysis (FACS) demonstrated enhanced drug uptake through EPI-PNPs and EPI-MNPs and elucidated dominance of caveolae mediated endocytosis for NPs uptake. Cellular transport conducted on human colon adenocarcinoma cell line (Caco-2) showed 2.45 and 3.17 folds higher permeability of EPI through EPI-PNPs and EPI-MNPs when compared with EPI-S (p<0.001) while permeability of EPI was found 5.23 and 5.67 folds higher across rat ileum, respectively. Furthermore, pharmacokinetic studies demonstrated 4.7 and 5.57 folds higher oral bioavailability through EPI-PNPs and EPI-MNPs when compared with EPI-S. In addition, both, EPI-PNPs and EMNPs showed tumor suppression comparable to indicated route (i.v. injection). EPI-MNPs showed 1.18 folds higher bioavailability and better tumor suppression than EPI-PNPs.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tariq
authors.affiliation: Department Pharmacy, Galgotia University, Greater Noida, India.
authors.forename: Md Aftab
authors.initials: MA
authors.lastname: Alam
authors.affiliation: Dabur Research Foundation, 22, Site IV, Sahibabad, Ghaziabad, Uttar Pradesh, India.
authors.forename: Anu T
authors.initials: AT
authors.lastname: Singh
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Road, New Delhi, India.
authors.forename: Amulya K
authors.initials: AK
authors.lastname: Panda
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India. Electronic address: stalegaonkar@gmail.com.
authors.forename: Sushama
authors.initials: S
authors.lastname: Talegaonkar
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065546:Drug Liberation; D015251:Epirubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D041981:Gastrointestinal Tract; D006595:Hexosamines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017208:Rats, Wistar; D013499:Surface Properties
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D006595:Hexosamines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; C008322:mannosamine; D019344:Lactic Acid; D011092:Polyethylene Glycols; D015251:Epirubicin
keywords: 1 - (3 - Dimethylaminopropyl) - 3 - ethylcarbodiimide hydrochloride (PubChem CID: 2723939); 3 - (4,5 - dimeth ylthiazol - 2 - yl) - 2, 5 - diphenyl tetrazolium bromide (PubChem CID: 64965); Anti tumor activity; Chlorpromazine Hydrochloride (PubChemCID: 6240); Coumarin 6 (PubChem CID: 100334); EAT induced tumor; Epirubicin hydrochloride (PubChem CID: 65348); Mannosamine hydrochloride (PubChem CID: 9964480); Mannosylated NPs; Methoxypolyethylene glycol amine (PubChem SID: 24845958); Oral bioavailability; Oral delivery; Pegylated NPs; Poly(DL - lactic - co - glycolic acid) (PubChem CID: 23111554); Polyvinyl alcohol (Pubchem CID: 11199); Sodium Azide (PubChem CID: 33557)