title: New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53-/- mice by delaying carcinogenesis.
abstract: The nutrient-sensing mTOR (mammalian Target of Rapamycin) pathway regulates cellular metabolism, growth functions, and proliferation and is involved in age-related diseases including cancer, type 2 diabetes, neurodegeneration and cardiovascular disease. The inhibition of mTOR by rapamycin, or calorie restriction, has been shown to extend lifespan and delays tumorigenesis in several experimental models suggesting that rapamycin may be used for cancer prevention. This requires continuous long-term treatment making oral formulations the preferred choice of administration route. However, rapamycin by itself has very poor water solubility and low absorption rate. Here we describe pharmacokinetic and biological properties of novel nanoformulated micelles of rapamycin, Rapatar. Micelles of Rapatar were rationally designed to increase water solubility of rapamycin to facilitate oral administration and to enhance its absorption. As a result, bioavailability of Rapatar was significantly increased (up to 12%) compared to unformulated rapamycin, which concentration in the blood following oral administration remained below level of detection. We also demonstrated that the new formulation does not induce toxicity during lifetime administration. Most importantly, Rapatar extended the mean lifespan by 30% and delayed tumor development in highly tumor-prone p53-/- mice. Our data demonstrate that water soluble Rapatar micelles represent safe, convenient and efficient form of rapamycin suitable for a long-term treatment and that Rapatar may be considered for tumor prevention.
authors.affiliation: Departments of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Comas
authors.forename: Ilia
authors.initials: I
authors.lastname: Toshkov
authors.forename: Karen K
authors.initials: KK
authors.lastname: Kuropatwinski
authors.forename: Olga B
authors.initials: OB
authors.lastname: Chernova
authors.forename: Alexander
authors.initials: A
authors.lastname: Polinsky
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Blagosklonny
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Marina P
authors.initials: MP
authors.lastname: Antoch
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D005260:Female; D016158:Genes, p53; D006720:Homozygote; D008136:Longevity / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D049329:Nanostructures; D009369:Neoplasms / Q000235:genetics / Q000517:prevention & control*; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000903:Antibiotics, Antineoplastic; D020123:Sirolimus