Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Investigational New Drugs
Published in: Investigational New Drugs 5/2019

Open Access 01-10-2019 | PRECLINICAL STUDIES

The availability of drug by liposomal drug delivery

Individual kinetics and tissue distribution of encapsulated and released drug in mice after administration of PEGylated liposomal prednisolone phosphate

Authors: Evelien A. W. Smits, José A. Soetekouw, Ebel H. E. Pieters, Coen J. P. Smits, Nicolette de Wijs-Rot, Herman Vromans

Published in: Investigational New Drugs | Issue 5/2019

Login to get access

Summary

Lately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied. However, drug release in the tumor seems more extended than in the other tissues and the non-encapsulated drug concentration decreases more slowly in the tumor than in the liver and spleen. The spleen shows a high affinity for the uptake of encapsulated drug as well as the release of drug from the liposomes. Subsequently, released drug in the spleen, and possibly also in other tissues, is probably quickly redistributed towards the blood and other tissues. This also impairs the drug delivery effect of the liposomes. In contrast to the released drug in the central circulation, liver and spleen, the released drug concentration in the tumor remains at a fairly constant level likely due to the extended release kinetics from the liposomes. These extended release characteristics in the tumor most probably contribute to the beneficial effect. Nevertheless, it should be noted that larger released drug concentrations are formed in healthy tissues.
Appendix
Available only for authorised users
Literature
1.
Allen TM, Cullis PR (2013) Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev 65:36–48CrossRefPubMed
2.
Qian S, Li C, Zuo Z (2012) Pharmacokinetics and disposition of various drug loaded liposomes. Curr Drug Metab 13:372–395CrossRefPubMed
3.
Ngoune R, Peters A, von Elverfeldt D, Winkler K, Pütz G (2016) Accumulating nanoparticles by EPR: a route of no return. J Control Release 238:58–70CrossRefPubMed
4.
5.
Maeda H (2015) Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv Drug Deliv Rev 91:3–6CrossRefPubMed
6.
Park K (2017) The drug delivery field at the inflection point: time to fight its way out of the egg. J Control Release 267:2–14CrossRefPubMed
7.
Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of Pegylated liposomal doxorubicin. Clin Pharmacokinet 42:419–436CrossRefPubMed
8.
Liu X, Situ A, Kang Y, Villabroza KR, Liao Y, Chang CH, Donahue T, Nel AE, Meng H (2016) Irinotecan delivery by lipid-coated mesoporous silica nanoparticles shows improved efficacy and safety over liposomes for pancreatic Cancer. ACS Nano 10:2702–2715CrossRefPubMedPubMedCentral
9.
Schiffelers RM, Metselaar JM, Fens MHAM, Janssen APCA, Molema G, Storm G (2005) Liposome-encapsulated prednisolone phosphate inhibits growth of established tumors in mice. Neoplasia 7:118–127CrossRefPubMedPubMedCentral
10.
Druckmann S, Gabizon A, Barenholz Y (1989) Separation of liposome-associated doxorubicin from non-liposome-associated doxorubicin in human plasma: implications for pharmacokinetic studies. Biochim Biophys Acta 980:381–384CrossRefPubMed
11.
Srigritsanapol AA, Chan KK (1994) A rapid method for the separation and analysis of leaked and liposomal entrapped phosphoramide mustard in plasma. J Pharm Biomed Anal 12:961–968CrossRefPubMed
12.
Mayer LD, St-Onge G (1995) Determination of free and liposome-associated doxorubicin and vincristine levels in plasma under equilibrium conditions employing ultrafiltration techniques. Anal Biochem 232:149–157CrossRefPubMed
13.
Krishna R, Webb MS, St-Onge G, Mayer LD (2001) Liposomal and nonliposomal drug pharmacokinetics after Administration of Liposome-Encapsulated Vincristine and Their Contribution to drug tissue distribution properties. J Pharmacol Exp Ther 298:1206–1212PubMed
14.
Bellott R, Pouna P, Robert J (2001) Separation and determination of liposomal and non-liposomal daunorubicin from the plasma of patients treated with Daunoxome. J Chromatogr B 757:257–267CrossRef
15.
Deshpande NM, Gangrade MG, Kekare MB, Vaidya VV (2010) Determination of free and liposomal amphotericin B in human plasma by liquid chromatography–mass spectroscopy with solid phase extraction and protein precipitation techniques. J Chromatogr B 878:315–326CrossRef
16.
Xie Y, Shao N, Jin Y, Zhang L, Jiang H, Xiong N, Su F, Xu H (2018) Determination of non-liposomal and liposomal doxorubicin in plasma by LC–MS/MS coupled with an effective solid phase extraction: in comparison with ultrafiltration technique and application to a pharmacokinetic study. J Chromatogr B 1072:149–160CrossRef
17.
Schorzman AN, Lucas AT, Kagel JR, Zamboni WC (2018) Methods and study designs for characterizing the pharmacokinetics and pharmacodynamics of carrier-mediated agents. In: Sirianni RW, Behkam B (eds) Targeted drug delivery methods and protocols. Humana Press, New York, pp 201–228CrossRef
18.
Laginha KM, Verwoert S, Charrois GJR, Allen TM (2005) Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer tumors. Clin Cancer Res 11:6944–6949CrossRefPubMed
19.
Zamboni WC, Strychor S, Joseph E, Walsh DR, Zamboni BA, Parise RA, Tonda ME, Yu NY, Engbers C, Eiseman JL (2007) Plasma, tumor, and tissue disposition of STEALTH liposomal CKD-602 (S-CKD602) and nonliposomal CKD-602 in mice bearing A375 human melanoma xenografts. Clin Cancer Res 13:7217–7223CrossRefPubMed
20.
Charrois GJR, Allen TM (2004) Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. Biochim Biophys Acta 1663:167–177CrossRefPubMed
21.
Gabizon A, Horowitz AT, Goren D, Tzemach D, Shmeeda H, Zalipsky S (2003) In Vivo fate of folate-targeted polyethylene-glycol liposomes in tumor-bearing mice. Clin Cancer Res 9:6551–6559PubMed
22.
Metselaar JM, Wauben MHM, Wagenaar-Hilbers JPA, Boerman OC, Storm G (2003) Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes. Arthritis Rheum 48:2059–2066CrossRefPubMed
23.
Smits EAW, Soetekouw JA, Vromans H (2014) In vitro confirmation of the quantitative differentiation of liposomal encapsulated and non-encapsulated prednisolone (phosphate) tissue concentrations by murine phosphatases. J Liposome Res 24:130–135CrossRefPubMed
24.
Kohli AG, Kieler-Ferguson HM, Chan D, Szoka FC (2014) A robust and quantitative method for tracking liposome contents after intravenous administration. J Control Release 176:86–93CrossRefPubMed
25.
Garg V, Jusko WJ (1994) Bioavailability and reversible metabolism of prednisone and prednisolone in man. Biopharm Drug Dispos 15:163–172CrossRefPubMed
26.
Möllmann H, Balbach S, Hochhaus G, Barth J, Derendorf H (1995) Pharmacokinetic-Pharmacodynamic correlations of corticosteroids. In: Derendorf H, Hochhaus G (eds) Handbook of pharmacokinetic/Pharmacodynamic correlation. CRC Press, Boca Raton, pp 323–361
27.
Smits EAW, Soetekouw JA, Bakker PFA, Baijens BJH, Vromans H (2015) Plasma, blood and liver tissue sample preparation methods for the separate quantification of liposomal-encapsulated prednisolone phosphate and non-encapsulated prednisolone. J Liposome Res 25:46–57CrossRefPubMed
28.
Motion JPM, Nguyen J, Szoka FC (2012) Phosphatase-triggered Fusogenic liposomes for cytoplasmic delivery of cell-impermeable compounds. Angew Chem 124:9181–9185CrossRef
29.
Crielaard BJ, Lammers T, Morgan ME, Chaabane L, Carboni S, Greco B, Zaratin P, Kraneveld AD, Storm G (2011) Macrophages and liposomes in inflammatory disease: friends or foes? Int J Pharm 416:499–506CrossRefPubMed
30.
Barrera P, Metselaar JM, van den Hoven JM, Mulder S, Nuijen B, Wortel C, Storm G, Beijnen JH, van Riel PLCM (2012) Long-circulating liposomal prednisolone versus pulse intramuscular methyl-prednisolone in patients with active rheumatoid arthritis. In: van den Hoven JM (2012). In: Liposomal glucocorticoids: pharmaceutical, preclinical and clinical aspects. Utrecht University, Dissertation
31.
Wong CW, Czarny B, Metselaar JM, Ho C, Ng SR, Barathi AV, Storm G, Wong TT (2018) Evaluation of subconjunctival liposomal steroids for the treatment of experimental uveitis. Sci Rep 8:6604CrossRefPubMedPubMedCentral
32.
Bull H, Murray PG, Thomas D, Fraser AM, Nelson PN (2002) Acid phosphatases. J Clin Pathol: Mol Pathol 55:65–72
33.
Cittadino E, Ferraretto M, Torres E, Maiocchi A, Crielaard BJ, Lammers T, Storm G, Aime S, Terreno E (2012) MRI evaluation of the antitumor activity of paramagnetic liposomes loaded with prednisolone phosphate. Eur J Pharm Sci 45:436–441CrossRefPubMed
34.
Smits EAW, Smits CJP, Vromans H (2013) The development of a method to quantify encapsulated and free prednisolone phosphate in liposomal formulations. J Pharm Biomed Anal 75:47–54CrossRefPubMed
35.
Smits EAW, Soetekouw JA, van Doormalen I, van den Berg BHJ, van der Woude MP, de Wijs-Rot N, Vromans H (2015) Quantitative LC–MS determination of liposomal encapsulated prednisolone phosphate and non-encapsulated prednisolone concentrations in murine whole blood and liver tissue. J Pharm Biomed Anal 115:552–561CrossRefPubMed
36.
Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP (1997) Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13:407–484CrossRefPubMed
37.
Maeda H, Nakamura H, Fang J (2013) The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev 65:71–79CrossRefPubMed
38.
Schmidt J, Metselaar JM, Wauben MHM, Toyka KV, Storm G, Gold R (2003) Drug targeting by long-circulating liposomal glucocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis. Brain 126:1895–1904CrossRefPubMed
39.
Ozbakir B, Crielaard BJ, Metselaar JM, Storm G, Lammers T (2014) Liposomal corticosteroids for the treatment of inflammatory disorders and cancer. J Control Release 190:624–636CrossRefPubMed
40.
Bertrand N, Leroux J-C (2012) The journal of a drug-carrier in the body: an anatomo-physiological perspective. J Control Release 161:152–163CrossRef
41.
Sarko D, Georges RB (2016) Kidney-specific drug delivery: review of opportunities, achievements, and challenges. J Analytical Pharm Res 2:33–38CrossRef
42.
43.
Kluza E, Yeo SY, Schmid S, van der Schaft DWJ, Boekhoven RW, Schiffelers RM, Storm G, Strijkers GJ, Nicolay K (2011) Anti-tumor activity of liposomal glucocorticoids: the relevance of liposome-mediated drug delivery, intratumoral localization and systemic activity. J Control Release 151:10–17CrossRefPubMed
44.
Lee SH, Starkey PM, Gordon S (1985) Quantitative analysis of Total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80. J Exp Med 161:475–489CrossRefPubMed
45.
Moghimi SM (1995) Mechanisms of splenic clearance of blood cells and particles: towards development of new splenotropic agents. Adv Drug Deliv Rev 17:103–115CrossRef
46.
Yates CR, Chang C, Kearbey JD, Yasuda K, Schuetz EG, Miller DD, Dalton JT, Swaan PW (2003) Structural determinants of P-glycoprotein-mediated transport of glucocorticoids. Pharm Res 20:1794–1803CrossRefPubMed
47.
Frey BM, Frey FJ (1990) Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharmacokinet 19:126–146CrossRefPubMed
48.
Xu J, Winkler J, Derendorf H (2007) A pharmacokinetic/pharmacodynamic approach to predict total prednisolone concentrations in human plasma. J Pharmacokinet Pharmacodyn 34:355–372CrossRefPubMed
49.
Czock D, Keller F, Rasche FM, Häussler U (2005) Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet 44:61–98CrossRefPubMed
50.
Bergmann TK, Barraclough KA, Lee KJ, Staatz CE (2012) Clinical pharmacokinetics and pharmacodynamics of prednisolone and prednisone in solid organ transplantation. Clin Pharmacokinet 51:711–741CrossRefPubMed
51.
Rocci ML Jr, Szefler SJ, Acara M, Jusko WJ (1981) Prednisolone metabolism and excretion in the isolated perfused rat kidney. Drug Metab Dispos 9:177–182PubMed
52.
Garg V, Jusko WJ (1991) Simultaneous analysis of prednisone, prednisolone and their major hydroxylated metabolites in urine by high-performance liquid chromatography. J Chromatogr Biomed Appl 567:39–47CrossRef
53.
Ahi S, Beotra A, Dubey S, Upadhyaym A, Jain S (2012) Simultaneous identification of prednisolone and its ten metabolites in human urine by high performance liquid chromatography-tandem mass spectrometry. Drug Test Anal 4:460–467CrossRefPubMed
54.
Rodchenkov GM, Vedenin AN, Uralets VP, Semenov VA (1991) Characterization of prednisone, prednisolone and their metabolites by gas chromatography-mass spectrometry. J Chromatogr Biomed Appl 565:45–51CrossRef
Metadata
Title
The availability of drug by liposomal drug delivery
Individual kinetics and tissue distribution of encapsulated and released drug in mice after administration of PEGylated liposomal prednisolone phosphate
Authors
Evelien A. W. Smits
José A. Soetekouw
Ebel H. E. Pieters
Coen J. P. Smits
Nicolette de Wijs-Rot
Herman Vromans
Publication date
01-10-2019
Publisher
Springer US
Published in
Investigational New Drugs / Issue 5/2019
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-018-0708-4

Other articles of this Issue 5/2019

Investigational New Drugs 5/2019 Go to the issue

PRECLINICAL STUDIES

A novel tetravalent bispecific antibody targeting programmed death 1 and tyrosine-protein kinase Met for treatment of gastric cancer

PRECLINICAL STUDIES

Lurbinectedin (PM01183), a selective inhibitor of active transcription, effectively eliminates both cancer cells and cancer stem cells in preclinical models of uterine cervical cancer

PRECLINICAL STUDIES

Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines

PRECLINICAL STUDIES

The novel PI3K inhibitor S1 synergizes with sorafenib in non-small cell lung cancer cells involving the Akt-S6 signaling

PHASE III STUDIES

Significant differences on submission lag following regulation reform for registration of novel therapeutic drugs in Taiwan

PHASE I STUDIES

A phase I study of the antibody drug conjugate ASG-5ME, an SLC44A4-targeting antibody carrying auristatin E, in metastatic castration-resistant prostate cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits