Anti-tumor activity of liposomal glucocorticoids: The relevance of liposome-mediated drug delivery, intratumoral localization and systemic activity.
Abstract
Tumor-associated inflammation has been recognized as an important tumor growth propagator and, therefore, represents an attractive target for anti-cancer therapy. In the current study, inspired by recent findings on the anti-tumor activity of liposomal glucocorticoids, we introduce paramagnetic and fluorescent liposomes, encapsulating prednisolone phosphate (PLP), to evaluate the local delivery of liposomal glucocorticoids to the tumor and its importance for the therapeutic response. The new multifunctional liposomes (Gd-PLP-L) (120nm diameter, 5.8mg PLP/60μmol lipid, bioexponential blood-clearance kinetics (T(1/2α)=2.4±0.5h, T(1/2β)=42.0±12.4h), drug leakage of 15%/72h (in vitro)), containing 25mol% Gd-DTPA-lipid and 0.1mol% of rhodamine-lipid, were tested in B16F10 melanoma subcutaneously inoculated in C57BL/6 mice, and compared to the original PLP formulation (PLP-L). A single dose of Gd-PLP-L (20mgPLP/kg/week, i.v.) was found to significantly inhibit tumor growth compared to non-treated mice (P<0.05), similarly to PLP-L. The accumulation efficacy of the liposomal agent in the tumor was assessed with MRI, using the increase in the longitudinal relaxation rate (ΔR(1)) as a marker. Interestingly, large inter-tumor differences in ΔR(1) (0.009-0.063s(-1), 24h post-administration), corresponding to highly variable intratumoral Gd-PLP-L levels, did not correlate to the effectiveness of tumor growth inhibition. Uptake of liposomes by tumor-associated macrophages (TAM), determined by ex-vivo fluorescence microscopy, was limited to only 5% of the TAM population. Furthermore, the therapy did not lead to TAM depletion. Importantly, a 90% drop in white blood cell count both after Gd-PLP-L and PLP-L administration was observed. This depletion may reduce tumor infiltration of monocytes, which stimulate angiogenesis, and, thus, possibly co-contributes to the anti-tumor effects. In conclusion, MRI provides a powerful instrument to monitor the delivery of liposomal therapeutics to tumors and guided us to reveal that the activity of liposomal glucocorticoids is not limited to the tumor site only.
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Storm and coworkers described successful treatment of B6F10 murine melanoma by nano-liposomes passively loaded with prednisolone phosphate, with the underlying mechanism described as inhibition of angiogenesis.
“Recently, Storm and coworkers [15], [48] described a successful treatment of B6F10 murine melanoma by nano-liposomes passively loaded with the GC water-soluble prodrug prednisolone phosphate, where the underlying mechanism was described as inhibition of angiogenesis [15].”
From Fabrication Principles and Their Contribution to the Superior In Vivo Therapeutic Efficacy of Nano-Liposomes Remote Loaded with Glucocorticoids (2011) · cites this paper as [48]
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- Authors
- Kluza, E., Yeo, S. Y., Schmid, S., van der Schaft, D. W. J., Boekhoven, R. W., Schiffelers, R. M., Storm, G., Strijkers, G. J., & Nicolay, K.
- Affiliations
- Eindhoven University of Technology (NL)
- Utrecht University (NL)
- Corresponding author
- Kluza, Ewelina
- ORCID
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 151
- Issue
- 1
- Pages
- 10-17
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2105467096
- Cited by
- 54
- References
- 25
- Citations by year
- 2025: 1 · 2022: 1 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 6 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 8
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- TU/e Research Portal (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- European Commission
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- paramagnetic liposomes, fluorescent liposomes, intratumoral drug delivery, tumor-associated macrophages, tumor inflammation, B16F10 melanoma, tumor growth inhibition, tumor angiogenesis, liposomal drug delivery, tumor microenvironment
- MeSH terms
- Animals, Anti-Inflammatory Agents, Antineoplastic Agents, Glucocorticoids, Humans, Inflammation, Liposomes, Macrophages, Melanoma, Experimental, Mice, Inbred C57BL, Neoplasms, Prednisolone, Cell Line, Tumor, Mice
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