Journal
ACS NANO
Volume 6, Issue 12, Pages 10646-10657Publisher
AMER CHEMICAL SOC
DOI: 10.1021/nn3037573
Keywords
nanoparticle; single-chain antibody; T-cell targeting; magnetic resonance imaging; heart allograft rejection
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Funding
- Natural Science Foundation of China [50830107, 81071208]
- 863 Programs of the Ministry of Science and Technology of China [2009AA03Z310]
- Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP) [20110171120091]
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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 DGK alpha 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.
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