title: Antiproliferative effect of ASC-J9 delivered by PLGA nanoparticles against estrogen-dependent breast cancer cells.
abstract: Among polymeric nanoparticles designed for cancer therapy, PLGA nanoparticles have become one of the most popular polymeric devices for chemotherapeutic-based nanoformulations against several kinds of malignant diseases. Promising properties, including long-circulation time, enhanced tumor localization, interference with "multidrug" resistance effects, and environmental biodegradability, often result in an improvement of the drug bioavailability and effectiveness. In the present work, we have synthesized 1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one (ASC-J9) and developed uniform ASC-J9-loaded PLGA nanoparticles of about 120 nm, which have been prepared by a single-emulsion process. Structural and morphological features of the nanoformulation were analyzed, followed by an accurate evaluation of the in vitro drug release kinetics, which exhibited Fickian law diffusion over 10 days. The intracellular degradation of ASC-J9-bearing nanoparticles within estrogen-dependent MCF-7 breast cancer cells was correlated to a time- and dose-dependent activity of the released drug. A cellular growth inhibition associated with a specific cell cycle G2/M blocking effect caused by ASC-J9 release inside the cytosol allowed us to put forward a hypothesis on the action mechanism of this nanosystem, which led to the final cell apoptosis. Our study was accomplished using Annexin V-based cell death analysis, MTT assessment of proliferation, radical scavenging activity, and intracellular ROS evaluation. Moreover, the intracellular localization of nanoformulated ASC-J9 was confirmed by a Raman optical imaging experiment designed ad hoc. PLGA nanoparticles and ASC-J9 proved also to be safe for a healthy embryo fibroblast cell line (3T3-L1), suggesting a possible clinical translation of this potential nanochemotherapeutic to expand the inherently poor bioavailability of hydrophobic ASC-J9 that could be proposed for the treatment of malignant breast cancer.
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca , Piazza della Scienza 2, 20126 Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Verderio
authors.forename: Laura
authors.initials: L
authors.lastname: Pandolfi
authors.forename: Serena
authors.initials: S
authors.lastname: Mazzucchelli
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Marinozzi
authors.forename: Renzo
authors.initials: R
authors.lastname: Vanna
authors.forename: Furio
authors.initials: F
authors.lastname: Gramatica
authors.forename: Fabio
authors.initials: F
authors.lastname: Corsi
authors.forename: Miriam
authors.initials: M
authors.lastname: Colombo
authors.forename: Carlo
authors.initials: C
authors.lastname: Morasso
authors.forename: Davide
authors.initials: D
authors.lastname: Prosperi
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D017209:Apoptosis; D001672:Biocompatible Materials / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003474:Curcumin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004967:Estrogens / Q000737:chemistry*; D005260:Female; D016166:Free Radical Scavengers; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D061986:MCF-7 Cells; D051379:Mice; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017382:Reactive Oxygen Species; D013056:Spectrophotometry, Ultraviolet; D013059:Spectrum Analysis, Raman; D013997:Time Factors
chemical_list: D001672:Biocompatible Materials; D003474:Curcumin; D004967:Estrogens; D016166:Free Radical Scavengers; D019344:Lactic Acid; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017382:Reactive Oxygen Species; C471106:ASC-J9 compound