Optimization of vincristine-topotecan combination--paving the way for improved chemotherapy regimens by nanoliposomes.
Abstract
There is an opportunity to improve the therapeutic potential of a combination of two drugs using nanoliposomes. The combination of topotecan (TPT) and vincristine (VCR) was selected. The ratio-dependent synergy between these two drugs was evaluated, in an attempt to improve the therapeutic efficacy of this combination in vivo. The interaction between the drugs was evaluated in tissue culture by the median-effect analysis. Certain ratios of combined drugs were synergistic, whereas, others were antagonistic, implying that the most efficacious combinations should be at a specific fixed drug ratio. For in vivo evaluation, nanoliposomes co-remotely loaded simultaneously with both drugs by transmembrane ammonium sulfate gradient were developed. VCR and TPT were successfully co-encapsulated at therapeutically relevant levels in the same nanoliposome (LipoViTo). The nanoliposomes controlled the drugs' "biofate" and maintained a fixed drug ratio in vivo, allowing one to compare the therapeutic efficacy of various predefined drug ratios. Pharmacokinetics and biodistribution studies showed that LipoViTo delivers the two drugs simultaneously to the tumors, where they are released at a predefined ratio. LipoViTo was more efficacious than the free drugs and liposomes with one agent, singly or in combination, in two tumor models in mice. LipoViTo co-loaded with both drugs corresponding to their maximal tolerated dose (MTD) ratio resulted in the best therapeutic efficacy. To summarize: liposomal co-encapsulation of anticancer drug combinations can profoundly influence therapeutic outcomes. Drug combinations can be optimized preclinically through pharmacokinetic control by remote loading into nanoliposomes.
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The MPS release profile resembles that of a few other remotely loaded substances such as Doxil, vincristine, and topotecan.
“MPS release profile resembles that of a few other remotely loaded substances such as DoxilTM, vincristine, and topotecan [16]–[19], [54].”
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 [54]
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Self-citationTargeted delivery of anticancer drugs: new trends in lipid nanocarriers
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- Authors
- Zucker, D., & Barenholz, Y.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Barenholz, Yechezkel
- ORCID
- Barenholz, Yechezkel
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2010-09-15
- Volume
- 146
- Issue
- 3
- Pages
- 326-333
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2062238282
- Cited by
- 77
- References
- 45
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 7 · 2017: 9 · 2016: 8 · 2015: 5 · 2014: 4 · 2013: 6 · 2012: 4
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hebrew University of Jerusalem
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Keywords
- vincristine, topotecan, combination chemotherapy, nanoliposomes, drug synergy, pharmacokinetics, tissue distribution, tumor models, anticancer drug delivery
- MeSH terms
- Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Drug Synergism, Humans, Liposomes, Mice, Nude, Neoplasms, Vincristine, Topotecan, Mice, Topoisomerase I Inhibitors
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