title: Accelerated blood clearance of PEGylated PLGA nanoparticles following repeated injections: effects of polymer dose, PEG coating, and encapsulated anticancer drug.
abstract: OBJECTIVE
  To investigate accelerated blood clearance (ABC) induction upon repeated injections of PLGA-PEG nanoparticles as a commonly used polymeric drug carrier.
  
  
  METHODS
  Etoposide-loaded PLGA-PEG NPs were developed and administered as the test dose to rats pre-injected with various NP treatments at certain time intervals. Pharmacokinetic parameters of etoposide and production of anti-PEG IgM antibody were evaluated.
  
  
  RESULTS
  A notable ABC effect was induced by a wide range of polymer doses (0.1 to 20 mg) of empty NPs, accompanied by IgM secretion. However, a further increase in polymer dose resulted not only in the abrogation of the observed ABC induction but also in distinctly a higher value for AUC of the NPs relative to the control. The data from the PEG-negative group verified the fundamental role of PEG for ABC induction. The first injection of etoposide-containing PEGylated nanoparticles (a cell cycle phase-specific drug) produced a strong ABC phenomenon. Three sequential administrations of etoposide-loaded NPs abolished ABC, although a high level of IgM was still detected, which suggests saturation with insignificant poisoning of immune cells.
  
  
  CONCLUSIONS
  The presented results demonstrate the importance of clinical evaluations for PLGA-PEG nanocarriers that consider the administration schedule in multiple drug delivery, particularly in cancer chemotherapy.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, PO Box 14155-6153, Tehran, Iran.
authors.forename: Roonak
authors.initials: R
authors.lastname: Saadati
authors.forename: Simin
authors.initials: S
authors.lastname: Dadashzadeh
authors.forename: Zahra
authors.initials: Z
authors.lastname: Abbasian
authors.forename: Hoorieh
authors.initials: H
authors.lastname: Soleimanjahi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000097:blood*; D004337:Drug Carriers / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D005047:Etoposide / Q000008:administration & dosage* / Q000097:blood*; D007075:Immunoglobulin M / Q000276:immunology; D007275:Injections, Intravenous; D019344:Lactic Acid / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000032:analysis; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000906:Antibodies; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D007075:Immunoglobulin M; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D005047:Etoposide