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

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Abstract

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.

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Abbreviations

DDS:

Drug delivery system

DOX :

Doxorubicin

FLD:

Fluorescence detection

HPLC:

High performance liquid chromatography

HSPC:

Hydrogenated soy phosphatidylcholine

IVIVC:

In vitro and in vivo correlation

MPEG2000-DSPE:

N-(Carbonyl-methoxypolyethyleneglycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine

PLD :

PEGylated liposomal doxorubicin

SPE :

Solid-phase extraction

TIF:

Tumor interstitial fluid

UV:

Ultravioletcorrelation

References

  1. Bobo D, Robinson KJ, Islam J, Thurecht KJ, Corrie SR. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res. 2016;33(10):2373–87.

    Article  CAS  PubMed  Google Scholar 

  2. Barenholz Y. Doxil® — the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–34.

    Article  CAS  PubMed  Google Scholar 

  3. Asai T. Nanoparticle-mediated delivery of anticancer agents to tumor Angiogenic vessels. Biol Pharm Bull. 2012;35(11):1855–61.

    Article  CAS  PubMed  Google Scholar 

  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.

  5. Silverman L, Barenholz Y. In vitro experiments showing enhanced release of doxorubicin from Doxil® in the presence of ammonia may explain drug release at tumor site. Nanomedicine. 2015;11(7):1841–50.

    Article  CAS  PubMed  Google Scholar 

  6. Mariño G, Kroemer G. Ammonia: a diffusible factor released by proliferating cells that induces autophagy. Sci Signal. 2010;3(124):pe19.

    Article  PubMed  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.

  8. Gabizon A, Martin F. Polyethylene glycol-coated (Pegylated) liposomal doxorubicin. Drugs. 2012;54(4):15–21.

    Google Scholar 

  9. Maurer N, Wong KF, Hope MJ, Cullis PR. Anomalous solubility behavior of the antibiotic ciprofloxacin encapsulated in liposomes: a 1H-NMR study. Biochim Biophys Acta. 1998;1374(1–2):9–20.

    Article  CAS  PubMed  Google Scholar 

  10. Nakamura K, Yoshino K, Yamashita K, Kasukawa H. Designing a novel in vitro drug-release-testing method for liposomes prepared by pH-gradient method. Int J Pharm. 2012;430(1–2):381–7.

    Article  CAS  PubMed  Google Scholar 

  11. Zhigaltsev IV, Maurer N, Edwards K, Karlsson G, Cullis PR. Formation of drug–arylsulfonate complexes inside liposomes: a novel approach to improve drug retention. J Control Release. 2006;110(2):378–86.

    Article  CAS  PubMed  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.

  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.

  14. Gaber MH, Hong K, Huang SK, Papahadjopoulos D. Thermosensitive sterically stabilized liposomes: formulation and in vitro studies on mechanism of doxorubicin release by bovine serum and human plasma. Pharm Res. 1995;12(10):1407–16.

    Article  CAS  PubMed  Google Scholar 

  15. Shibata H, Izutsu K-i, Yomota C, Okuda H, Goda Y. Investigation of factors affecting in vitro doxorubicin release from PEGylated liposomal doxorubicin for the development of in vitro release testing conditions. Drug Dev Ind Pharm. 2015;41(8):1376–86.

    Article  CAS  PubMed  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.

  17. Snyder EL, Judge J. Plasma. In: Delves PJ, editor. Encyclopedia of immunology (Second Edition). Oxford: Elsevier; 1998. p. 1964–9.

    Chapter  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.

  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.

  20. Wibroe PP, Ahmadvand D, Oghabian MA, Yaghmur A, Moghimi SM. An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil®, Caelyx®, DOXOrubicin, and SinaDoxosome. J Control Release. 2016;221:1–8.

    Article  CAS  PubMed  Google Scholar 

  21. Schilt Y, Berman T, Wei X, Barenholz Y, Raviv U. Using solution X-ray scattering to determine the high-resolution structure and morphology of PEGylated liposomal doxorubicin nanodrugs. Biochim Biophys Acta Gen Subj. 2016;1860(1:108–19.

    Article  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.

  23. Howanitz JH, Howanitz PJ, Skrodzki CA, Iwanski JA. Influences of specimen processing and storage conditions on results for plasma ammonia. Clin Chem. 1984;30(6):906–8.

    CAS  PubMed  Google Scholar 

  24. Fugit KD, Jyoti A, Upreti M, Anderson BD. Insights into accelerated liposomal release of topotecan in plasma monitored by a non-invasive fluorescence spectroscopic method. J Control Release. 2015;197:10–9.

    Article  CAS  PubMed  Google Scholar 

  25. Olofsson G. Thermodynamic quantities for the dissociation of the ammonium ion and for the ionization of aqueous ammonia over a wide temperature range. J Chem Therm. 1975;7(6):507–14.

    Article  CAS  Google Scholar 

  26. Rhee JG, Kim TH, Levitt SH, Song CW. Changes in acidity of mouse tumor by hyperthermia. Int J Radiat Oncol Biol Phys. 1984;10(3):393–9.

    Article  CAS  PubMed  Google Scholar 

  27. Wiig H, Tenstad O, Iversen PO, Kalluri R, Bjerkvig R. Interstitial fluid: the overlooked component of the tumor microenvironment. Fibrogenesis Tissue Repair. 2010;3:12.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jiang W, Lionberger R, Yu LX. In vitro and in vivo characterizations of PEGylated liposomal doxorubicin. Bioanalysis. 2011;3(3):333–44.

    Article  CAS  PubMed  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.

  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.

    Article  PubMed  PubMed Central  Google 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.

  32. Jain RK, Shah SA, Finney PL. Continuous noninvasive monitoring of pH and temperature in rat Walker 256 carcinoma during Normoglycemia and hyperglycemia. J Natl Cancer Inst. 1984;73(2):429–36.

    Article  CAS  PubMed  Google Scholar 

  33. Stohrer M, Boucher Y, Stangassinger M, Jain RK. Oncotic pressure in solid tumors is elevated. Cancer Res. 2000;60(15):4251–5.

    CAS  PubMed  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.

  35. Petersen GH, Alzghari SK, Chee W, Sankari SS, La-Beck NM. Meta-analysis of clinical and preclinical studies comparing the anticancer efficacy of liposomal versus conventional non-liposomal doxorubicin. J Control Release. 2016;232(Supplement C):255–64.

    Article  CAS  PubMed  Google Scholar 

  36. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17(1):20–37.

    Article  CAS  PubMed  Google Scholar 

  37. Schellekens H, Klinger E, Mühlebach S, Brin J-F, Storm G, Crommelin DJA. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol. 2011;59(1):176–83.

    Article  CAS  PubMed  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.

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Authors and Affiliations

  1. Formulation Research, Pharmaceutical Science & Technology Core Function Unit, Eisai Product Creation Systems, Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan

    Eiichi Yamamoto, Kenji Hyodo, Takuya Suzuki & Hiroshi Ishihara

  2. Tsukuba Research Laboratories, Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan

    Hiroshi Kikuchi

  3. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Masaru Kato

  4. Department of Bioanalytical Chemistry, School of Pharmacy, Showa University, 1-5-8 Hatanodai Shinagawa-ku, Tokyo, 142-8555, Japan

    Masaru Kato

Authors
  1. Eiichi Yamamoto
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  2. Kenji Hyodo
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  3. Takuya Suzuki
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  4. Hiroshi Ishihara
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  5. Hiroshi Kikuchi
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  6. Masaru Kato
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Correspondence to Eiichi Yamamoto.

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Yamamoto, E., Hyodo, K., Suzuki, T. et al. Simulation of Stimuli-Responsive and Stoichiometrically Controlled Release Rate of Doxorubicin from Liposomes in Tumor Interstitial Fluid. Pharm Res 35, 103 (2018). https://doi.org/10.1007/s11095-018-2380-y

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  • DOI: https://doi.org/10.1007/s11095-018-2380-y

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