Project/scholarship details

Several drawbacks (such as short imaging time, nonspecificity, and renal toxicity) of the small molecule-based computed tomography (CT) contrast agents (e.g., Omnipaque) lead to the extensive development of various nanoparticle (NP)-based CT imaging probes. Recently, Gold NPs (AuNPs) have been used as contrast agents for X-ray CT imaging due to their strong X-ray attenuation characteristics [1-3]. Although a few of the studies have proven that targeting ligand-modified Au NPs enable the targeted CT imaging of cancer cells [4-6], development of various NP-based CT contrast agents that can overcome the drawbacks of nonspecificity, short blood circulation time, low sensitivity, and cytotoxicity at a higher dose still remains a great challenge. In the mean time, for accurate molecular imaging-based cancer diagnosis, it is essential to combine different imaging elements within one NP system for dual mode or multimode imaging. Literature data have shown that thiolated gadolium (III) (Gd(III)) chelator can be used to stabilize AuNPs for dual mode CT and magnetic resonance (MR) imaging [7]. However, this technique has difficulty to modify targeting ligands onto the particle surfaces for targeted imaging applications. Our team member’s previous work has shown that by entrapping AuNPs within the interior of poly(amidoamine) (PAMAM) dendrimers [8], followed by covalently attaching imaging dyes and targeting ligands onto the dendrimer periphery, a multifunctional dendrimer-entrapped AuNPs (Au DENPs) can be generated for targeted imaging of cancer cells [9]. Very recently, we have shown that Au DENPs have a high X-ray attenuation property, allowing them to be used for CT imaging of blood pool in mice after an acetylation reaction to neutralize the dendrimer periphery amines [10]. Using acetylated Au DENPs or Au DENPs modified by both acetyl groups or PEG moieties, the Au DENPs are able to be used for tumor imaging in vivo via enhanced permeation retention (EPR) effect [11, 12]. Development of an Au DENP-based CT imaging nanoprobe with targeting specificity has scarcely been reported in literature. In addition, using Au DENPs as a platform to develop for dual mode CT/MR imaging probes has never been reported in literature before. Thus, the original idea and main purpose of this project is the synthesis and characterization of Au DENPs with cell targeting capability for CT imaging of cancer cells and with dual mode CT/MR imaging capability for accurate targeted cancer imaging. The PEGylation of dendrimers is expected to expand the periphery of dendrimers, allowing for more loading of AuNPs with enhanced colloidal stability, thus promoting the sensitivity of CT imaging and improving the biocompatibility of Au DENPs at a higher dose. Simultaneously, with the tunable dendrimer chemistry that allows easy conjugation of Gd(III) chelator and the convenient manipulation of the PEG linking strategy that allows targeting ligands (e.g., FA and arginine-glycine-aspartic acid (RGD) peptide) to be modified onto the dendrimer surfaces, the designed PEGylated Au DENPs should be able to act as novel CT or dual mode CT/MR imaging agents for targeted tumor imaging with prolonged blood circulation time. Briefly, the following questions will be answered: a) Are the targeting ligand-modified PEGylated Au DENPs able to target cancer cells overexpressing the specific receptors in vitro? b) Can the targeted PEGylated Au DENPs be used for CT imaging of cancer cells in vitro and in vivo? c) How the incorporation of the two imaging elements within one NP system affects the X-ray attenuation and T1-relaxation rate of the final particle system? d) Can the Gd(III)-loaded PEGylated Au DENPs be used for dual mode CT and MR imaging of cancer cells in vitro and in vivo? This multidisciplinary project has a support research team of 7 PhDs and two full time researchers (a young researcher with a master degree (BI grant, 24 months) and one post-doc (BPD grant, 24 months) to be contracted. The research proposal which is based on the expertise acquired by the research team through previous projects and collaborations and is organized in 4 related tasks will be mainly developed at the CQM/Univ. of Madeira, also having the collaboration of two Chinese research groups: M. Shen Group with expertise in nanobiotechnology (Donghua University, Shanghai, China) and the Molecular Imaging Group headed by G. Zhang from Shanghai First People’s Hospital (Shanghai, China).

  • Funder

    FCT - Fundação para a Ciência e a Tecnologia, I.P.

  • Funder's country

    Portugal

  • Funding program

    3599-PPCDT

  • Funding amount

    197,616.00 €

  • Start date

    2013-04-03

  • End date

    2015-08-02

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