title: Simultaneous diagnosis and gene therapy of immuno-rejection in rat allogeneic heart transplantation model using a T-cell-targeted theranostic nanosystem.
abstract: As the final life-saving treatment option for patients with terminal organ failure, organ transplantation is far from an ideal solution. The concomitant allograft rejection, which is hardly detectable especially in the early acute rejection (AR) period characterized by an intense cellular and humoral attack on donor tissue, greatly affects the graft survival and results in rapid graft loss. Based on a magnetic resonance imaging (MRI)-visible and T-cell-targeted multifunctional polymeric nanocarrier developed in our lab, effective co-delivery of pDNA and superparamagnetic iron oxide nanoparticles into primary T cells expressing CD3 molecular biomarker was confirmed in vitro. In the heart transplanted rat model, this multifunctional nanocarrier showed not only a high efficiency in detecting post-transplantation acute rejection but also a great ability to mediate gene transfection in T cells. Upon intravenous injection of this MRI-visible polyplex of nanocarrier and pDNA, T-cell gathering was detected at the endocardium of the transplanted heart as linear strongly hypointense areas on the MRI T(2)*-weighted images on the third day after cardiac transplantation. Systematic histological and molecular biology studies demonstrated that the immune response in heart transplanted rats was significantly suppressed upon gene therapy using the polyplex bearing the DGKα gene. More excitingly, the therapeutic efficacy was readily monitored by noninvasive MRI during the treatment process. Our results revealed the great potential of the multifunctional nanocarrier as a highly effective imaging tool for real-time and noninvasive monitoring and a powerful nanomedicine platform for gene therapy of AR with high efficiency.
authors.affiliation: Lab of Liver Disease Hospital, Medical Research Center, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.forename: Wenjie
authors.initials: W
authors.lastname: Chen
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Ruomi
authors.initials: R
authors.lastname: Guo
authors.forename: Faming
authors.initials: F
authors.lastname: Gong
authors.forename: Shudong
authors.initials: S
authors.lastname: Lin
authors.forename: Du
authors.initials: D
authors.lastname: Cheng
authors.forename: Guihua
authors.initials: G
authors.lastname: Chen
authors.forename: Xintao
authors.initials: X
authors.lastname: Shuai
mesh_terms: D000818:Animals; D019852:Diacylglycerol Kinase / Q000235:genetics; D005290:Ferric Compounds / Q000737:chemistry; D015316:Genetic Therapy / Q000379:methods*; D006084:Graft Rejection / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016027:Heart Transplantation / Q000009:adverse effects*; D007167:Immunotherapy; D008279:Magnetic Resonance Imaging; D008297:Male; D049329:Nanostructures / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D051381:Rats; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D005290:Ferric Compounds; D057127:Single-Chain Antibodies; C000499:ferric oxide; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D019852:Diacylglycerol Kinase