title: Sustained delivery by a cyclodextrin material-based nanocarrier potentiates antiatherosclerotic activity of rapamycin via selectively inhibiting mTORC1 in mice.
abstract: Increasing evidence has demonstrated special advantages of the nanomedicinal approach for the management of cardiovascular disease. We hypothesize that sustained delivery of rapamycin (RAP) may provide more desirable therapeutic effects than traditional oral administration by selectively inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. To evidence this assumption and develop an effective, safe, and translational nanotherapy for atherosclerosis, this study was designed to examine antiatherosclerotic efficacy of a RAP nanotherapy based on an acetalated β-cyclodextrin (Ac-bCD) material in apolipoprotein E-deficient (ApoE(-/-)) mice. First, biodegradable and biocompatible materials of Ac-bCDs were synthesized by kinetically controlled acetalation, giving rise to carrier materials that may not generate acidic byproducts after hydrolysis. Then RAP-loaded nanoparticles base on various Ac-bCDs were prepared by a nanoemulsion technique, which can sustain drug release for different periods of time, depending on the composition of Ac-bCDs. For a RAP/Ac-bCD180-derived nanotherapy (RAP-NP) that may continue RAP release for up to 20days in vitro, it afforded constant drug levels in both the blood and aortic tissue after subcutaneous injection, while orally administered free RAP showed typical peak-valley profiles with remarkably high peak concentrations. Therapeutic studies conducted in an experimental model of atherosclerosis established in ApoE(-/-) mice revealed that RAP-NP significantly reduced the formation of atherosclerotic lesions and dramatically enhanced the stability of plaques, which was more efficacious than orally delivered free RAP. Moreover, rupture-prone proinflammatory factors in both serum and aortas were significantly decreased after treatment. Whereas oral administration of RAP simultaneously inhibited mTORC1 and mTORC2 in the aorta, sustained delivery by RAP-NP selectively suppressed mTORC1, agreeing with in vitro results in smooth muscle cells. These findings demonstrated that antiatherosclerotic activity of RAP may be considerably improved by sustained release via the Ac-bCD material-derived nanocarrier, which was achieved through selectively inhibiting mTORC1.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Songling
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Youcai
authors.initials: Y
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China.
authors.forename: Ruibing
authors.initials: R
authors.lastname: Wang
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China. Electronic address: lpsh008@aliyun.com.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China. Electronic address: jxzhang1980@gmail.com.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000627:therapeutic use; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D065546:Drug Liberation; D004357:Drug Synergism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors*; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D047392:beta-Cyclodextrins; D000076222:Mechanistic Target of Rapamycin Complex 1; D020123:Sirolimus
keywords: Atherosclerosis; Cyclodextrin; Nanomedicine; Rapamycin; Sustained delivery; mTOR