Characterization of PEGylated nanoliposomes co-remotely loaded with topotecan and vincristine: relating structure and pharmacokinetics to therapeutic efficacy.
Recently, developing drug delivery systems exhibiting controlled drug release at the tumor sites emerged as an attractive option for enhancing anticancer therapeutic efficacy. It seems, however, unlikely that single agent therapies will prove effective enough against the myriad cells present within the malignancy. Therefore, next generation nanotherapeutics must not only find their way to the solid tumor but also must effectively destroy the diverse populations of cells promoting tumor growth. Nanoliposomes offer an important advantage in the delivery of a combination of drugs acting synergistically in cancer treatment. They allow controlling the pharmacokinetics and biodistribution of the drugs by uniform time and spatial co-delivery of the agents. However, successful translation of such complex formulations into the clinic relies on understanding critical physicochemical characteristics. These include: liposomes' membrane phase and dynamics, size distribution, state of encapsulated drug, internal environment of liposome, state of grafted polyethylene glycol at the liposome surface, and in-vivo drug release rate. They determine the pharmacokinetics of the formulation and the bioavailability of the drugs. We encapsulated the combination of vincristine (VCR) and topotecan (TPT) in the same nanoliposome (LipoViTo). Our in-vitro and in-vivo characterization of LipoViTo provides an explanation for the good therapeutic efficacy that was previously reported by us. Moreover, we have described how to study these critical features for a two-drug in one nanoliposome formulation. This characterization is an important step for a rational clinical development and for how to ensure liposome product quality of LipoViTo and other liposomal formulations alike.
Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Daniel
D
Zucker
Alexander V
AV
Andriyanov
Ariel
A
Steiner
Uri
U
Raviv
Yechezkel
Y
Barenholz
D000818:Animals; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D004338:Drug Combinations; D004339:Drug Compounding; D004355:Drug Stability; D004356:Drug Storage; D008055:Lipids / Q000737:chemistry; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014018:Tissue Distribution; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D014750:Vincristine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004338:Drug Combinations; D008055:Lipids; D008081:Liposomes; D011092:Polyethylene Glycols; D014750:Vincristine; D019772:Topotecan