title: Mixed nanomicelles as potential carriers for systemic delivery of Z-GP-Dox, an FAPα-based doxorubicin prodrug: formulation and pharmacokinetic evaluation.
abstract: Z-GP-Dox, the FAPα (fibroblast activation protein-α)-based doxorubicin prodrug, demonstrates excellent tumor targeting effects and a favorable toxicokinetic profile. However, the insoluble nature of Z-GP-Dox becomes a significant barrier to drug administration, particularly when it comes to the clinical stage. Here we developed a nanomicelle system to facilitate the systemic delivery of Z-GP-Dox, and evaluated its disposition in rats following administration of the micelles using a physiologically-based pharmacokinetic model. Z-GP-Dox-loaded mixed nanomicelles (ZGD-MNs) were prepared by dispersion of an ethanol solution of Z-GP-Dox, lecithin, and sodium oleate in water. The obtained ZGD-MNs were 86.6 nm in size with a drug loading of 14.03%. ZGD-MNs were fairly stable in phosphate-buffered saline and showed satisfactory physical and chemical stability over a 2-week observation period. Accumulative drug release was more than 56% within 24 hours. Further, the physiologically-based pharmacokinetic rat model consisting of various organs (ie, heart, liver, spleen, lung, kidney, and intestine) was fitted to the experimental data following administration of ZGD-loaded cosolvent (control) or micelles. Derived partition coefficient values revealed that the nanomicelles significantly altered the biodistribution of Z-GP-Dox. Of note, drug distribution to the lung, liver, and spleen was greatly enhanced and the fold change ranged from 2.4 to 33. In conclusion, this is the first report of a mixed micelle system being a viable carrier for delivery of Z-GP-Dox. Also, the pharmacokinetic behavior of Z-GP-Dox was satisfactorily described by the physiologically-based pharmacokinetic model.
authors.affiliation: Department of Pharmacology, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Xingwang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Shaohui
authors.initials: S
authors.lastname: Cai
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Baojian
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D010450:Endopeptidases; D018093:Gelatinases / Q000737:chemistry / Q000493:pharmacokinetics; D008565:Membrane Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012697:Serine Endopeptidases / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D004317:Doxorubicin; D004337:Drug Carriers; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D008823:Micelles; D011355:Prodrugs; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
keywords: Z-GP-Dox; doxorubicin; micelles; pharmacokinetics; physiologically-based pharmacokinetic model; systemic delivery