Simulation of Stimuli-Responsive and Stoichiometrically Controlled Release Rate of Doxorubicin from Liposomes in Tumor Interstitial Fluid

• Published in: Pharmaceutical research Vol. 35; no. 5; pp. 103 - 9
• Main Authors: Yamamoto, Eiichi, Hyodo, Kenji, Suzuki, Takuya, Ishihara, Hiroshi, Kikuchi, Hiroshi, Kato, Masaru
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.05.2018; Springer; Springer Nature B.V
• Subjects: Ammonia; Ammonia - chemistry; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood plasma; Controlled release; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - pharmacokinetics; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacokinetics; Drug Liberation; Encapsulation; Extracellular Fluid - metabolism; High performance liquid chromatography; Hydrogen ions; Hydrogen-Ion Concentration; Incubation; Liposomes; Liquid chromatography; Medical Law; Models, Biological; Neoplasms - drug therapy; Neoplasms - pathology; pH effects; Pharmacology/Toxicology; Pharmacy; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - pharmacokinetics; Product introduction; Research Paper; Tumors; Doxil; drug release; liposomes; simulation; tumor interstitial fluid
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-018-2380-y

Purpose To simulate the stimuli-responsive and stoichiometrically controlled doxorubicin (DOX) release from liposomes in in vivo tumor interstitial fluid (TIF), the effect of ammonia concentration and pH on the DOX release from liposomes in human plasma at 37°C was quantitatively evaluated in vitro and the release rate was calculated as a function of ammonia concentration and pH. Methods Human plasma samples spiked with DOX-loaded PEGylated liposomes (PLD) or Doxil ® , containing ammonia (0.3–50 mM) at different pH values, were incubated at 37°C for 24 h. After incubation, the concentration of encapsulated DOX in the samples was determined by validated solid-phase extraction (SPE)-SPE-high performance liquid chromatography. Results Accelerated DOX release (%) from liposomes was observed as the increase of ammonia concentration and pH of the matrix, and the decrease of encapsulated DOX concentration. The release rate was expressed as a function of the ammonia concentration and pH by using Henderson-Hasselbalch equation. Conclusions The DOX release from PLD in TIF was expressed as a function ammonia concentration and pH at various DOX concentrations. Further, it was found that the DOX release from liposomes in a simulated TIF was more than 15 times higher than in normal plasma.