title: Augmented anticancer efficacy of doxorubicin-loaded polymeric nanoparticles after oral administration in a breast cancer induced animal model.
abstract: The present investigation reports an extensive evaluation of in vitro and in vivo anticancer efficacy of orally administered doxorubicin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Dox-NPs) in a breast cancer induced animal model. Spherically shaped Dox-NPs were prepared with an entrapment efficiency and particle size of 55.40 ± 2.30% and 160.20 ± 0.99 nm, respectively, and freeze-dried with 5% trehalose using stepwise freeze-drying. Cytotoxicity, as investigated on C127I cell line, revealed insignificant differences between the IC(50) of free Dox and Dox-NPs treated cells in the first 24 h, while higher cytotoxicity was demonstrated by Dox-NPs, following 72 h of incubation. Confocal laser scanning microscopy (CLSM) imaging corroborated that nanoparticles were efficiently localized into the nuclear region of C127I cells. The cellular uptake profile of Dox-NPs revealed both time and concentration dependent increases in the Caco-2 cell uptake as compared to the free Dox solution. Further, Dox-NPs significantly suppressed the growth of breast tumor in female Sprague-Dawley (SD) rats upon oral administration. Finally, orally administered Dox-NPs showed a marked reduction in cardiotoxicity when compared with intravenously injected free Dox as also evident by the increased level of malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine phosphokinase (CK-MB) and reduced levels of glutathione (GSH) and superoxide dismutase (SOD). The reduced cardiotoxicity of orally administered Dox-NPs was also confirmed by the major histopathological changes in the heart tissue after the treatments of intravenously injected free Dox and orally delivered Dox-NPs.
authors.affiliation: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar (Mohali), Punjab 160062, India.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Jain
authors.forename: Nitin K
authors.initials: NK
authors.lastname: Swarnakar
authors.forename: Manasmita
authors.initials: M
authors.lastname: Das
authors.forename: Chandraiah
authors.initials: C
authors.lastname: Godugu
authors.forename: Raman Preet
authors.initials: RP
authors.lastname: Singh
authors.forename: Poduri Rama
authors.initials: PR
authors.lastname: Rao
authors.forename: Sanyog
authors.initials: S
authors.lastname: Jain
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003402:Creatine Kinase / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018625:Microscopy, Atomic Force; D053758:Nanoparticles / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D008315:Malondialdehyde; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D003402:Creatine Kinase; D005978:Glutathione