title: Functional and pathological improvements of the hearts in diabetes model by the combined therapy of bFGF-loaded nanoparticles with ultrasound-targeted microbubble destruction.
abstract: Diabetic cardiomyopathy (DCM) is the leading cause of morbidity and mortality among the diabetic patients and currently there is no effective means to reverse its pathological progress. Basic fibroblast growth factor (bFGF) has shown promise as a molecular therapy for DCM, but its delivery is inefficient and non-specific. In the present study, a therapy combining nanoparticle (NP) carrier and ultrasound-targeted microbubble destruction (UTMD) was reported the first time for bFGF delivery to the heart of diabetic rats. bFGF-loaded NP (bFGF-NP) were prepared with Poloxamer 188-grafted heparin copolymer using water-in-water technique, and the morphology, encapsulation efficiency, and bioactivity of bFGF-NP were studied. The cellular uptake and cytotoxicity of bFGF-NP were evaluated with primary cultures of the left ventricular (LV) cardiomyocytes in vitro. Therapeutic effects of bFGF-NP/UTMD on the heart of DCM rats were studied by measuring LV systolic and diastolic functions, hemodynamic characteristics and indicators of cardiac remodeling including myocardial collagen volume fraction and capillary density. Results demonstrated that bFGF-NP showed good round morphology, efficient bFGF encapsulation and stable bioactivity of bFGF in vitro. bFGF-NP/UTMD combined treatment significantly enhanced the efficiency of bFGF cellular uptake (P<0.05) without obvious cytotoxicity. Significant improvements (P<0.05) in both cardiac functions and tissue morphology in the DCM rats were observed in bFGF-NP/UTMD group. These were not achievable using free bFGF, bFGF-NP or UTMD treatment alone. Our results show that combining a non-viral vector with UTMD technique is an effective strategy to deliver bFGF to the heart, and the resulting growth factor therapy has demonstrated potential to reverse the progress of DCM by restoring the cardiac functions and even the structure of damaged cardiac tissues.
authors.affiliation: Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
authors.forename: Ying-Zheng
authors.initials: YZ
authors.lastname: Zhao
authors.affiliation: Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Xin-Qiao
authors.initials: XQ
authors.lastname: Tian
authors.affiliation: Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: The KCHRI at the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
authors.affiliation: Ultrasound Department, The First People's Hospital of Huzhou, Huzhou City, Zhejiang Province 313000, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Ru
authors.affiliation: Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Shen
authors.affiliation: Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Jin
authors.affiliation: Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.affiliation: The KCHRI at the Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Hawkins
authors.affiliation: Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Subrata
authors.initials: S
authors.lastname: Charkrabarti
authors.affiliation: Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Li
authors.affiliation: Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
authors.forename: Wen-Ze
authors.initials: WZ
authors.lastname: Yu
authors.affiliation: St. Christopher's Hospital for Children/Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Ge
authors.affiliation: Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China; Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Cui-Tao
authors.initials: CT
authors.lastname: Lu
authors.affiliation: School of Pharmacy, Temple University, Philadelphia, PA 19140, USA. Electronic address: ho-lun.wong@temple.edu.
authors.forename: Ho Lun
authors.initials: HL
authors.lastname: Wong
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000737:chemistry; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006493:Heparin / Q000737:chemistry; D045423:Microbubbles; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D020442:Poloxamer / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D014465:Ultrasonics; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D016222:Fibroblast Growth Factor 2; D020442:Poloxamer; D006493:Heparin; D003094:Collagen
keywords: Basic fibroblast growth factor; Diabetic cardiomyopathy; Nanoparticle; Targeted delivery; Ultrasound-targeted microbubble destruction