title: Development of innovative paclitaxel-loaded small PLGA nanoparticles: study of their antiproliferative activity and their molecular interactions on prostatic cancer cells.
abstract: Taxanes, including paclitaxel, are anti-cancer drugs approved for the treatment of prostate cancer but which have limited clinical application due to their hydrophobicity, their low therapeutic index and the emergence of chemoresistance. These side effects may be avoided through the use of new drug delivery systems such as nanoparticles, and paclitaxel-loaded PLGA nanoparticles up to 200 nm in size have shown encouraging results. As it is known that size affects the tissular penetration and distribution of tumors via the enhanced permeability and retention effect, so nanoparticles smaller than 100 nm are potentially interesting vehicles for improving paclitaxel delivery and efficacy. In this work, new paclitaxel-loaded small PLGA nanoparticles, between 49 nm and 95 nm in size and with positive or negative surface charges, were prepared without detergent. They were stable in the presence of serum, and HPLC showed that high paclitaxel loading and stability were achieved. Intracellular uptake of these nanoparticles was studied in PC3 cells by flow cytometry. Confocal studies confirmed a high tubulin destructuration at very low dose with these nanoparticles. This study suggests that both positively and negatively charged paclitaxel-loaded small PLGA nanoparticles deliver this drug into PC3 cells, and that this nanoparticle mode of delivery highly improves paclitaxel efficiency by up to two log-increase. These results also highlight the importance of small nanoparticles for drug delivery in cancer applications and are extremely promising for in vivo studies.
authors.affiliation: Université Lille Nord de France, F-59000 Lille, France.
authors.forename: D
authors.initials: D
authors.lastname: Le Broc-Ryckewaert
authors.forename: R
authors.initials: R
authors.lastname: Carpentier
authors.forename: E
authors.initials: E
authors.lastname: Lipka
authors.forename: S
authors.initials: S
authors.lastname: Daher
authors.forename: C
authors.initials: C
authors.lastname: Vaccher
authors.forename: D
authors.initials: D
authors.lastname: Betbeder
authors.forename: C
authors.initials: C
authors.lastname: Furman
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004705:Endocytosis; D006801:Humans; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry*; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013499:Surface Properties
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D017239:Paclitaxel
keywords: 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate; 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide; BCA; BSA; CTAB; Chemoresistance; DiI; EP; FBS; HPLC; MTT; NP; P-gp; PBS; PDI; PLGA; PMSF; Paclitaxel; Prostate cancer; Ptx; R effectenhanced and permeability retention effect; SDS; Small-PLGA nanoparticles; bicinchoninic acid; bovine serum albumin; foetal bovine serum; hexadecyltrimethylammonium bromide; high performance liquid chromatography; nanoparticles; p-glycoprotein; paclitaxel; phenylmethanesulfonylfluoride; phosphate buffer saline; poly(lactic-co-glycolic) acid; polydispersity index; sodium dodecyl sulfate