Amphipathic weak acid glucocorticoid prodrugs remote-loaded into sterically stabilized nanoliposomes evaluated in arthritic rats and in a Beagle dog: a novel approach to treating autoimmune arthritis.
Abstract
OBJECTIVE: The use of glucocorticoids (GCs) in rheumatoid arthritis is limited by side effects related to unfavorable pharmacokinetics and biodistribution. Liposomal GC formulations have been studied since the 1970s in an attempt to overcome this obstacle, but none has entered clinical use. We undertook this study to determine whether a novel approach could overcome the limitations that have thus far prevented the clinical use of these formulations: low drug:lipid ratio, low encapsulation efficiency, and lack of controlled release. METHODS: We used approximately 80-nm sterically stabilized (pegylated) nanoliposomes (NSSLs), which were remote-loaded with an amphipathic weak acid GC (such as methyl prednisolone hemisuccinate) utilizing an intraliposome (aqueous compartment)-high/extraliposome (bulk medium)-low transmembrane calcium acetate gradient. This unique method actually "traps" the GC in the liposomal aqueous phase as a calcium-GC precipitate. RESULTS: Our liposome formulation exhibited high encapsulation efficiency (94%) and a high drug:lipid mole ratio (0.41) and demonstrated controlled release of the encapsulated GC during systemic circulation and in inflamed paws in rats with adjuvant-induced arthritis. In addition, both in arthritic rats and in a Beagle dog, we showed the pharmacokinetic advantage of using liposomes as GC carriers. Finally, we demonstrated the superior therapeutic efficacy of our liposome formulation over that of free GCs in arthritic rats, both in early and in peak disease stages. CONCLUSION: Amphipathic weak acid GCs remote-loaded into approximately 80-nm NSSLs overcome past limitations of liposomal GC formulations. The unique loading method, which also leads to controlled release, improves the therapeutic effect both systemically and locally. Such a development has great potential for improving GC therapy.
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nSSL-GC based on high (>37°C) Tm liposome-forming phosphatidylcholines exhibit zero-order slow drug release in vitro in human plasma and inflamed synovial fluid, and in vivo in rat systemic circulation and inflamed paw.
“nSSL-GC based on high (>37°C) Tm “liposome-forming phosphatidylcholines” are characterized by the unique property of being a zero-order, slow drug release DDS, as shown in vitro in human plasma and inflamed synovial fluid, and in vivo in the rat's systemic circulation and inflamed paw [27].”
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 [27]
MPS uptake into nSSL leads to appearance of a precipitate in the intraliposome aqueous phase.
“In addition, previously we have published cryo-transmission electron microscopy (Cryo-TEM) images of nSSL remote loaded with MPS (nSSL-MPS) and nSSL [27], [31] ( Fig. 2c ), and the nSSL-MPS image indicated that MPS uptake into the nSSL leads to the appearance of a precipitate in the intraliposome aqueous phase.”
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 [27]
A transmembrane calcium acetate gradient is most suitable for loading amphipathic weak acids.
“Overall, from our own experience, we concluded that a transmembrane ammonium sulfate gradient is most suitable for stable encapsulation of amphipathic weak bases [16]–[19], [25], [26], while a transmembrane calcium acetate gradient is most suitable for loading amphipathic weak acids [16], [27], [28].”
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 [27]
MPS release from HSPC/CHOL/2000-PEG-DSPE nSSL in human plasma was not accompanied by loss of liposome calcium ions or change in liposome size distribution, indicating controlled release not membrane destruction.
“Moreover, as we have reported in our previous study [27], the release of MPS from nSSL based on HSPC/CHOL/2000-PEG-DSPE when incubated in human plasma was neither accompanied by loss of liposome calcium ions nor by change in liposome size distribution (data not shown), indicating that MPS release is not a result of a destructive effect on membrane barrier properties, but rather a controlled”
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 [27]
The features of optimized nSSL-MPS lead to superior therapeutic efficacy in mouse and rat models of diseases with inflammatory components (rheumatoid arthritis, EAE, cerebral malaria) and in two types of mouse tumor models (MPS-sensitive BCL-1 B-cell leukemia and MPS-insensitive J6456 T-cell lymphoma).
“All these lead to superior therapeutic efficacy in mouse and rat models of diseases with inflammatory components (rheumatoid arthritis [27], EAE (this study), and cerebral malaria (Waknine-Grinberg et al., in preparation) and in two types of mouse tumor models (the MPS-sensitive BCL-1 B-cell leukemia and the MPS-insensitive J6456 T-cell lymphoma).”
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 [27]
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Self-citation
- Authors
- Avnir, Y., Ulmansky, R., Wasserman, V., Even‐Chen, S., Broyer, M., Barenholz, Y., & Naparstek, Y.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Hadassah Medical Center (IL)
- ORCID
- Barenholz, Yechezkel
- Venue
- Arthritis & Rheumatism
- Publisher
- Wiley
- Published
- 2007-12-28
- Volume
- 58
- Issue
- 1
- Pages
- 119-129
- ISSN
- 0004-3591 (ISSN-L)
- 1529-0131
- OpenAlex
- W2038827900
- Cited by
- 99
- References
- 37
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 5 · 2020: 12 · 2019: 6 · 2018: 6 · 2017: 3 · 2016: 7 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 7
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arthritis & Rheumatism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- liposomal drug delivery, PEGylated liposomes, remote loading, rheumatoid arthritis, adjuvant-induced arthritis, controlled release, encapsulation efficiency, pharmacokinetics, autoimmune arthritis, local drug delivery
- MeSH terms
- Acids, Animals, Arthritis, Experimental, Delayed-Action Preparations, Dogs, Female, Glucocorticoids, Liposomes, Prodrugs, Rats, Inbred Lew, Tissue Distribution, Drug Delivery Systems, Nanostructures, Rats
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