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J Pharm Sci. 2018 Sep;107(9):2497-2508. doi: 10.1016/j.xphs.2018.05.020. Epub 2018 Jun 6.

PEGylation of Carbonate Apatite Nanoparticles Prevents Opsonin Binding and Enhances Tumor Accumulation of Gemcitabine.

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Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3800, Australia.
Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3800, Australia. Electronic address:


pH sensitives carbonate apatite (CA) has emerged as a targeted delivery vehicle for chemotherapeutics agent with tremendous potential to increase the effectivity of breast cancer treatment. The major challenge for intravenous delivery of drug-incorporated nanoparticles is their rapid opsonization, resulting in accumulation within the organs of reticuloendothelial system, such as liver and spleen. Therefore, surface modification by polyethylene glycol was implemented to improve the half-life of drug-particle complexes and enhance their uptake by target tissues. A simple, rapid, and sensitive triple quadrupole liquid chromatography-mass spectrometry method was developed and validated for quantification of gemcitabine in plasma, various organs and tumor tissues of mice with breast carcinoma, whereas sodium dodecyl sulfate-polyacrylamide gel electrophoresis, quadrupole-time of flight liquid chromatography-mass spectrometry and analysis by SwissProt.Mus_musculus database were performed for protein separation, identification, and homology search by comparing the de novo sequence tag. PEGylated CA exhibited almost 6-fold increase in gemcitabine accumulation in tumor with significant reduction in other organs within 1 h of intravenous administration, compared to free drug. In addition, plasma drug amount was found to be higher in PEGylated particles, implying their role in prolonging blood circulation time of particle-bound gemcitabine. Investigation of protein corona composition demonstrated notable reduction in opsonin interactions after PEGylation of CA particles. Overall, the results indicate that the composition and dynamics of protein corona subjected to alteration by PEGylation play crucial roles in affecting successful nanoparticle-based targeted delivery of a cytotoxic drug.


LC/MS; PEGylation; carbonate apatite; cytotoxicity; gemcitabine; nanoparticle; opsonin; pharmacokinetics; protein corona; proteomics

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