title: Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles.
abstract: Cellular senescence, a state of irreversible growth arrest and altered cell function, causes aging-related diseases. Hence, treatment modalities that could target aging cells would provide a robust therapeutic avenue. Herein, for the first time, we utilized CD9 receptors (overexpressed in senescent cells) for nanoparticle targeting in addition to the inherent β-galactosidase activity. In our study, CD9 monoclonal antibody-conjugated lactose-wrapped calcium carbonate nanoparticles loaded with rapamycin (CD9-Lac/CaCO3/Rapa) were prepared for targeted rapamycin delivery to senescent cells. The nanoparticles exhibited an appropriate particle size (~130 nm) with high drug-loading capacity (~20%). In vitro drug release was enhanced in the presence of β-galactosidase suggesting potential cargo drug delivery to the senescent cells. Furthermore, CD9-Lac/CaCO3/Rapa exhibited high uptake and anti-senescence effects (reduced β-galactosidase and p53/p21/CD9/cyclin D1 expression, reduced population doubling time, enhanced cell proliferation and migration, and prevention of cell cycle arrest) in old human dermal fibroblasts. Importantly, CD9-Lac/CaCO3/Rapa significantly improved the proliferation capability of old cells as suggested by BrdU staining along with significant reductions in senescence-associated secretory phenotypes (IL-6 and IL-1β) (P < 0.05). Altogether, our findings suggest the potential applicability of CD9-Lac/CaCO3/Rapa in targeted treatment of senescence.
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongsanbuk-do, 712-749, Republic of Korea.
authors.forename: Raj Kumar
authors.initials: RK
authors.lastname: Thapa
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongsanbuk-do, 712-749, Republic of Korea.
authors.forename: Hanh Thuy
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongsanbuk-do, 712-749, Republic of Korea.
authors.forename: Jee-Heon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, 705-717, Republic of Korea.
authors.forename: Jae Ryong
authors.initials: JR
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea.
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongsanbuk-do, 712-749, Republic of Korea.
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Yong
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongsanbuk-do, 712-749, Republic of Korea.
authors.forename: Jong Oh
authors.initials: JO
authors.lastname: Kim
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism*; D002119:Calcium Carbonate / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007785:Lactose / Q000378:metabolism*; D053758:Nanoparticles / Q000378:metabolism*; D020123:Sirolimus / Q000378:metabolism*; D060245:Tetraspanin 29 / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C554869:CD9 protein, human; D060245:Tetraspanin 29; D002119:Calcium Carbonate; D007785:Lactose; D020123:Sirolimus