Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma

Anil K. Deshantri, Marcel H. Fens, Ruud W.J. Ruiter, Josbert M. Metselaar, Gert Storm, Louis van Bloois, Aida Varela-Moreira, Sanjay N. Mandhane, Tuna Mutis, Anton C.M. Martens, Richard W.J. Groen, Raymond M. Schiffelers (Corresponding Author)

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Glucocorticoids are the cornerstone in the clinic for treatment of hematological malignancies, including multiple myeloma. Nevertheless, poor pharmacokinetic properties of glucocorticoids require high and frequent dosing with the off-target adverse effects defining the maximum dose. Recently, nanomedicine formulations of glucocorticoids have been developed that improve the pharmacokinetic profile, limit adverse effects and improve solid tumor accumulation. Multiple myeloma is a hematological malignancy characterized by uncontrolled growth of plasma cells. These tumors initiate increased angiogenesis and microvessel density in the bone marrow, which might be exploited using nanomedicines, such as liposomes. Nano-sized particles can accumulate as a result of the increased vascular leakiness at the bone marrow tumor lesions. Pre-clinical screening of novel anti-myeloma therapeutics in vivo requires a suitable animal model that represents key features of the disease. In this study, we show that fluorescently labeled long circulating liposomes were found in plasma up to 24 h after injection in an advanced human-mouse hybrid model of multiple myeloma. Besides the organs involved in clearance, liposomes were also found to accumulate in tumor bearing human-bone scaffolds. The therapeutic efficacy of liposomal dexamethasone phosphate was evaluated in this model showing strong tumor growth inhibition while free drug being ineffective at an equivalent dose (4 mg/kg) regimen. The liposomal formulation slightly reduced total body weight of myeloma-bearing mice during the course of treatment, which appeared reversible when treatment was stopped. Liposomal dexamethasone could be further developed as monotherapy or could fit in with existing therapy regimens to improve therapeutic outcomes for multiple myeloma.

Original languageEnglish
Pages (from-to)232-240
Number of pages9
JournalJournal of controlled release
Volume296
DOIs
Publication statusPublished - 28 Feb 2019

Fingerprint

Multiple Myeloma
Dexamethasone
Growth
Neoplasms
Liposomes
Glucocorticoids
Nanomedicine
dexamethasone 21-phosphate
Hematologic Neoplasms
Therapeutics
Pharmacokinetics
Bone Marrow
Weight-Bearing
Microvessels
Plasma Cells
Blood Vessels
Animal Models
Body Weight
Bone and Bones
Injections

Keywords

  • UT-Hybrid-D
  • Dexamethasone
  • Drug delivery
  • EPR effect
  • Liposomes
  • Multiple myeloma
  • Tumor microenvironment
  • Bone marrow

Cite this

Deshantri, A. K., Fens, M. H., Ruiter, R. W. J., Metselaar, J. M., Storm, G., van Bloois, L., ... Schiffelers, R. M. (2019). Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma. Journal of controlled release, 296, 232-240. https://doi.org/10.1016/j.jconrel.2019.01.028
Deshantri, Anil K. ; Fens, Marcel H. ; Ruiter, Ruud W.J. ; Metselaar, Josbert M. ; Storm, Gert ; van Bloois, Louis ; Varela-Moreira, Aida ; Mandhane, Sanjay N. ; Mutis, Tuna ; Martens, Anton C.M. ; Groen, Richard W.J. ; Schiffelers, Raymond M. / Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma. In: Journal of controlled release. 2019 ; Vol. 296. pp. 232-240.
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abstract = "Glucocorticoids are the cornerstone in the clinic for treatment of hematological malignancies, including multiple myeloma. Nevertheless, poor pharmacokinetic properties of glucocorticoids require high and frequent dosing with the off-target adverse effects defining the maximum dose. Recently, nanomedicine formulations of glucocorticoids have been developed that improve the pharmacokinetic profile, limit adverse effects and improve solid tumor accumulation. Multiple myeloma is a hematological malignancy characterized by uncontrolled growth of plasma cells. These tumors initiate increased angiogenesis and microvessel density in the bone marrow, which might be exploited using nanomedicines, such as liposomes. Nano-sized particles can accumulate as a result of the increased vascular leakiness at the bone marrow tumor lesions. Pre-clinical screening of novel anti-myeloma therapeutics in vivo requires a suitable animal model that represents key features of the disease. In this study, we show that fluorescently labeled long circulating liposomes were found in plasma up to 24 h after injection in an advanced human-mouse hybrid model of multiple myeloma. Besides the organs involved in clearance, liposomes were also found to accumulate in tumor bearing human-bone scaffolds. The therapeutic efficacy of liposomal dexamethasone phosphate was evaluated in this model showing strong tumor growth inhibition while free drug being ineffective at an equivalent dose (4 mg/kg) regimen. The liposomal formulation slightly reduced total body weight of myeloma-bearing mice during the course of treatment, which appeared reversible when treatment was stopped. Liposomal dexamethasone could be further developed as monotherapy or could fit in with existing therapy regimens to improve therapeutic outcomes for multiple myeloma.",
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Deshantri, AK, Fens, MH, Ruiter, RWJ, Metselaar, JM, Storm, G, van Bloois, L, Varela-Moreira, A, Mandhane, SN, Mutis, T, Martens, ACM, Groen, RWJ & Schiffelers, RM 2019, 'Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma' Journal of controlled release, vol. 296, pp. 232-240. https://doi.org/10.1016/j.jconrel.2019.01.028

Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma. / Deshantri, Anil K.; Fens, Marcel H.; Ruiter, Ruud W.J.; Metselaar, Josbert M.; Storm, Gert; van Bloois, Louis; Varela-Moreira, Aida; Mandhane, Sanjay N.; Mutis, Tuna; Martens, Anton C.M.; Groen, Richard W.J.; Schiffelers, Raymond M. (Corresponding Author).

In: Journal of controlled release, Vol. 296, 28.02.2019, p. 232-240.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Fens, Marcel H.

AU - Ruiter, Ruud W.J.

AU - Metselaar, Josbert M.

AU - Storm, Gert

AU - van Bloois, Louis

AU - Varela-Moreira, Aida

AU - Mandhane, Sanjay N.

AU - Mutis, Tuna

AU - Martens, Anton C.M.

AU - Groen, Richard W.J.

AU - Schiffelers, Raymond M.

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N2 - Glucocorticoids are the cornerstone in the clinic for treatment of hematological malignancies, including multiple myeloma. Nevertheless, poor pharmacokinetic properties of glucocorticoids require high and frequent dosing with the off-target adverse effects defining the maximum dose. Recently, nanomedicine formulations of glucocorticoids have been developed that improve the pharmacokinetic profile, limit adverse effects and improve solid tumor accumulation. Multiple myeloma is a hematological malignancy characterized by uncontrolled growth of plasma cells. These tumors initiate increased angiogenesis and microvessel density in the bone marrow, which might be exploited using nanomedicines, such as liposomes. Nano-sized particles can accumulate as a result of the increased vascular leakiness at the bone marrow tumor lesions. Pre-clinical screening of novel anti-myeloma therapeutics in vivo requires a suitable animal model that represents key features of the disease. In this study, we show that fluorescently labeled long circulating liposomes were found in plasma up to 24 h after injection in an advanced human-mouse hybrid model of multiple myeloma. Besides the organs involved in clearance, liposomes were also found to accumulate in tumor bearing human-bone scaffolds. The therapeutic efficacy of liposomal dexamethasone phosphate was evaluated in this model showing strong tumor growth inhibition while free drug being ineffective at an equivalent dose (4 mg/kg) regimen. The liposomal formulation slightly reduced total body weight of myeloma-bearing mice during the course of treatment, which appeared reversible when treatment was stopped. Liposomal dexamethasone could be further developed as monotherapy or could fit in with existing therapy regimens to improve therapeutic outcomes for multiple myeloma.

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KW - UT-Hybrid-D

KW - Dexamethasone

KW - Drug delivery

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KW - Liposomes

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KW - Tumor microenvironment

KW - Bone marrow

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