Optimization of dihydrosphingomyelin/cholesterol mol ratio in topotecan-loaded liposomes to enhance drug retention and plasma half-life by understanding physicochemical and thermodynamic properties of the lipid membrane

Kasagi, Noriyuki; Doi, Issei; Nakabayashi, Jun; Saito, Kenkichi; Tadakuma, Akiko; Muraki, Nanae; Hori, Ryusuke; Kimura, Takeshi; Okada, Ken; Yamada, Naoki; Makita-Suzuki, Keiko; Tanisaka, Hiroki; Shimoyama, Susumu; Mori, Mikinaga

doi:10.1016/j.molstruc.2023.135333

Cited by 6 publications

(3 citation statements)

References 45 publications

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“…FF-10850 was prepared according to a previously described method [ 26 ]. Topotecan was purchased from ScinoPharm Taiwan (Tainan, Taiwan) and topotecan-d6 was purchased from Toronto Research Chemicals (Toronto, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…Considering its cytotoxicity, particularly on cells in the S-phase, topotecan damages rapidly renewing healthy tissues such as hematopoietic cells. To overcome these limitations, FF-10850, a pegylated topotecan liposomal injection, approximately 110 nm in diameter, with encapsulation efficiency exceeding 99.8%, and storage stability for 24 months under refrigeration, has been recently developed [ 26 ]. FF-10850 stably encapsulates topotecan within the dihydrosphingomyelin-based liposomal shell and has demonstrated prolonged plasma circulating time, greater antitumor activity, and milder hematological toxicities than the non-liposomal TPT in mice [ 26 , 27 ] and is currently under clinical investigation (NCT04047251).…”

Section: Introductionmentioning

confidence: 99%

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Quantification of Unencapsulated Drug in Target Tissues Demonstrates Pharmacological Properties and Therapeutic Effects of Liposomal Topotecan (FF-10850)

Kimura,

Okada,

Morohashi

et al. 2024

Pharm Res

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Purpose Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen. Methods We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments. The ratios of the area under the concentration–time curves (AUCs) between tumor and BM-ISF were calculated for total and unencapsulated topotecan. DNA damage and antitumor effects of FF-10850 or non-liposomal topotecan (TPT) were evaluated in an ES-2 mice xenograft model. Results FF-10850 exhibited a much larger AUC ratio between tumor and BM-ISF for unencapsulated topotecan (2.96), but not for total topotecan (0.752), than TPT (0.833). FF-10850 promoted milder DNA damage in the bone marrow than TPT; however, FF-10850 and TPT elicited comparable DNA damage in the tumor. These findings highlight the greater tumor exposure to unencapsulated topotecan and lower bone marrow exposure to FF-10850 than TPT. The dosing regimen was successfully improved based on the kinetics of unencapsulated topotecan and DNA damage. Conclusions Tissue pharmacokinetics of unencapsulated topotecan elucidated the favorable pharmacological properties of FF-10850. Evaluation of tissue exposure to an unencapsulated drug with appropriate pharmacodynamic markers can be valuable in optimizing liposomal drugs and dosing regimens.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantification of Unencapsulated Drug in Target Tissues Demonstrates Pharmacological Properties and Therapeutic Effects of Liposomal Topotecan (FF-10850)

Kimura,

Okada,

Morohashi

et al. 2024

Pharm Res

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“…Reports clarified that a stable liposome has to include the appropriate amount of membrane fluidity and cholesterol (about 50 mol %) [10]. As a result, cholesterol is essential for the fluidity and rigidity of the liposome bilayer.…”

Section: Conventional and Stealth Liposomesmentioning

confidence: 99%

An Updated Review of Stealth Liposomes and Its Ability to Evade the Immune System: A New Frontier in Cancer Chemotherapy

SIVADASAN

2024

Int J App Pharm

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Liposomes have been the delivery of choice for the cancer targeting therapy for the last few decades. Since the 1990s, the development of sterically stabilized (stealth) liposomes has garnered interest for their long circulating half-life. PEGylated (Polyethylene Glycol) liposomes are most extensively studied for delivering cancer therapeutics in a sustained manner. Stealth liposomes are having a less intrinsic toxicity with higher efficacy in cancer treatment. There are numerous clinical trials on the liposomes in tackling cancer is evident for the better outcome of the delivery system. Stealth liposomes are extensively studied for their improved circulation time and better pharmacokinetic profile in cancer treatment. The steric hindrance of the stealth liposomes bypasses the reticuloendothelial system clearance. Further the ligands conjugation in the surface of the liposomes able to achieve better target to the cancer cells. The vascularization nature of the cancerous cells is readily making the liposomal delivery of the cancer drugs accumulate in the cancerous cells rather than healthy cells. There is an utmost need to understand the possible mechanism of stealth liposomes and the basic science behind the development of liposomal delivery system in advancing the cancer treatment with less toxicity. The present review addresses the various modalities of the liposomal development, liposome characterization, mechanism of PEGylated liposomes, the advancements and results of the liposomes in the treatment of various diseases, and the clinical trials and regulatory considerations of liposomal drug delivery system.

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Advances in liposome-based delivery of RNA therapeutics for cancer treatment

Sanati,

Afshari,

Ahmadi

et al. 2024

Progress in Molecular Biology and Translational Science

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Optimization of dihydrosphingomyelin/cholesterol mol ratio in topotecan-loaded liposomes to enhance drug retention and plasma half-life by understanding physicochemical and thermodynamic properties of the lipid membrane

Cited by 6 publications

References 45 publications

Quantification of Unencapsulated Drug in Target Tissues Demonstrates Pharmacological Properties and Therapeutic Effects of Liposomal Topotecan (FF-10850)

Quantification of Unencapsulated Drug in Target Tissues Demonstrates Pharmacological Properties and Therapeutic Effects of Liposomal Topotecan (FF-10850)

An Updated Review of Stealth Liposomes and Its Ability to Evade the Immune System: A New Frontier in Cancer Chemotherapy

Advances in liposome-based delivery of RNA therapeutics for cancer treatment

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