Simulation of Stimuli-Responsive and Stoichiometrically Controlled Release Rate of Doxorubicin from Liposomes in Tumor Interstitial Fluid
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.
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.
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.
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.
KEY WORDSDoxil® drug release liposomes tumor interstitial fluid simulation
Drug delivery system
High performance liquid chromatography
Hydrogenated soy phosphatidylcholine
In vitro and in vivo correlation
PEGylated liposomal doxorubicin
Tumor interstitial fluid
- 4.Yang M, Lai SK, Wang Y-Y, Zhong W, Happe C, Zhang M, et al. Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus. Angew Chem Int Ed. 2011;50(11):2597–600.Google Scholar
- 7.Eng CH, Yu K, Lucas J, White E, Abraham RT. Ammonia Derived from Glutaminolysis Is a Diffusible Regulator of Autophagy. Science Signaling. 2010;3(119):ra31–1.Google Scholar
- 8.Gabizon A, Martin F. Polyethylene glycol-coated (Pegylated) liposomal doxorubicin. Drugs. 2012;54(4):15–21.Google Scholar
- 12.Fugit KD, Xiang T-X, Choi DH, Kangarlou S, Csuhai E, Bummer PM, et al. Mechanistic model and analysis of doxorubicin release from liposomal formulations. J Control Release. 2015;217:82–91.Google Scholar
- 13.Csuhai E, Kangarlou S, Xiang T-X, Ponta A, Bummer P, Choi D, et al. Determination of key parameters for a mechanism-based model to predict doxorubicin release from actively loaded liposomes. J Pharm Sci. 2015;104(3):1087–98.Google Scholar
- 16.Yuan W, Kuai R, Dai Z, Yuan Y, Zheng N, Jiang W, et al. Development of a flow-through USP-4 apparatus drug release assay to evaluate doxorubicin liposomes. AAPS J. 2016:1–11.Google Scholar
- 18.Anchordoquy TJ, Barenholz Y, Boraschi D, Chorny M, Decuzzi P, Dobrovolskaia MA, et al. Mechanisms and barriers in cancer nanomedicine: addressing challenges, looking for solutions. ACS Nano. 2017;11(1):12–8.Google Scholar
- 19.Yamamoto E, Hyodo K, Ohnishi N, Suzuki T, Ishihara H, Kikuchi H, et al. Direct, simultaneous measurement of liposome-encapsulated and released drugs in plasma by on-line SPE–SPE–HPLC. J Chromatogr B Anal Technol Biomed Life Sci. 2011;879(30):3620–5.Google Scholar
- 22.Itoh N, Kimoto A, Yamamoto E, Higashi T, Santa T, Funatsu T, et al. High performance liquid chromatography analysis of 100-nm liposomal nanoparticles using polymer-coated, silica monolithic columns with aqueous mobile phase. J Chromatogr A. 2017;1484:34–40.Google Scholar
- 29.Gref R, Luck M, Quellec P, Marchand M, Dellacherie E, Harnisch S, et al. 'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids Surf, B. 2000;18:301–13.Google Scholar
- 30.Andriyanov AV, Koren E, Barenholz Y, Goldberg SN. Therapeutic efficacy of combining PEGylated liposomal doxorubicin and radiofrequency (RF) ablation: comparison between slow-drug-releasing, non-thermosensitive and fast-drug-releasing, thermosensitive Nano-liposomes. PLoS One. 2014;9(5):e92555.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res. 1994;54(4):987–92.Google Scholar
- 34.O'Brien M, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, et al. Breast cancer study group: reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004;15(3):440–9.Google Scholar
- 38.Schellekens H, Stegemann S, Weinstein V, Vlieger JSB, Flühmann B, Mühlebach S, et al. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J. 2013;16(1):15–21.Google Scholar