title: Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension.
abstract: Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)-loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics.
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey, Monterrey, NL 64710, Mexico. Electronic address: vsegura-ibarra@houstonmethodist.org.
authors.forename: Victor
authors.initials: V
authors.lastname: Segura-Ibarra
authors.affiliation: Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX 77030, USA. Electronic address: jamioneguerra@houstonmethodist.org.
authors.forename: Javier
authors.initials: J
authors.lastname: Amione-Guerra
authors.affiliation: Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX 77030, USA. Electronic address: acruzsolbes@houstonmethodist.org.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Cruz-Solbes
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address: fcara@houstonmethodist.org.
authors.forename: Francisca E
authors.initials: FE
authors.lastname: Cara
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey, Monterrey, NL 64710, Mexico. Electronic address: A00815209@itesm.mx.
authors.forename: David A
authors.initials: DA
authors.lastname: Iruegas-Nunez
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address: swu@houstonmethodist.org.
authors.forename: Suhong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX 77030, USA. Electronic address: KAYouker@houstonmethodist.org.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Youker
authors.affiliation: Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX 77030, USA. Electronic address: ABhimaraj@houstonmethodist.org.
authors.forename: Arvind
authors.initials: A
authors.lastname: Bhimaraj
authors.affiliation: Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX 77030, USA; Catedra de Cardiología y Medicina Vascular, Tecnológico de Monterrey, Monterrey, NL 66278, Mexico. Electronic address: GTorre@houstonmethodist.org.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Torre-Amione
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: mferrari@houstonmethodist.org.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Harry.Karmouty@uth.tmc.edu.
authors.forename: Harry
authors.initials: H
authors.lastname: Karmouty-Quintana
authors.affiliation: Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX 77030, USA. Electronic address: gashrith@houstonmethodist.org.
authors.forename: Ashrith
authors.initials: A
authors.lastname: Guha
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address: eblanco@houstonmethodist.org.
authors.forename: Elvin
authors.initials: E
authors.lastname: Blanco
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D053758:Nanoparticles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D020123:Sirolimus
keywords: Drug delivery; Endothelial dysfunction; Polymer nanoparticles; Pulmonary arterial hypertension; Rapamycin; Vascular permeability