Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging

EJNMMI Research, Feb 2018

Elisabeth Eppard, Ana de la Fuente, Nicole Mohr, Mareli Allmeroth, Rudolf Zentel, Matthias Miederer, Stefanie Pektor, Frank Rösch

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Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging

Eppard et al. EJNMMI Research Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging Elisabeth Eppard 3 Ana de la Fuente 2 Nicole Mohr 1 Mareli Allmeroth 1 Rudolf Zentel 1 Matthias Miederer 0 Stefanie Pektor 0 Frank Rösch 2 0 Clinic for Nuclear Medicine, University Medical Center Mainz , Langenbeckstraße 1, 55131 Mainz , Germany 1 Institute of Organic Chemistry, Johannes Gutenberg University Mainz , Mainz , Germany 2 Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz , Mainz , Germany 3 Clinic for Nuclear Medicine, University Medical Center Bonn , Bonn , Germany Background: In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177. Results: Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h. Conclusions: This study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy. DOTA-HPMA conjugates; Theranostic; Radiolabeling; Gallium-68; Scandium-44; Lutetium-177; PET; Biodistribution Background One of the major problems in current chemotherapy is the lack of selectivity of the utilized anticancer drugs. Conventional chemotherapeutic drugs suffer from a narrow therapeutic index as a consequence of affecting not only cancer cells but basically all cells with high proliferation rates. The therapeutic index of a drug can be improved by increasing the accumulation at the target site, e.g., the tumor [ 1, 2 ]. Nanomaterials (< 100 nm) can often improve pharmacokinetics due to their particle size, charge, and shape and may passively and/or actively accumulate in tumor tissue. Since the early 1970s, N-(2-hydroxypropyl)methacrylamide (HPMA) is investigated as drug delivery system based on the enhanced permeability and retention (EPR) effect [ 3–5 ]. HPMA-based copolymers are hydrophilic, biocompatible, and non-immunogenic [ 6, 7 ], and selection as drug carrier is based on detailed studies of the relationship between structure and biocompatibility of hydrophilic polymers [ 8–13 ]. HPMA-copolymer conjugates have been successfully utilized in the delivery of miscellaneous drugs (e.g., doxorubicin [14], paclitaxel [ 15 ], camptothecin [ 16 ]). Modification can be achieved through activated comonomers leading to biocompatible polymers with functionalities for polymer analogue reaction. This strategy is very flexible in the choice of ligands, type of activation, and occupancy rate and was already used in various studies [ 17 ]. As it was shown before, nanomaterials like HPMAbased nanocarriers are able to combine both imaging agents and drugs within one formulation [ 8, 18, 19 ] for the in vivo analysis by positron emission tomography (PET) [ 20, 21 ]. Those studies include information about the early pharmacology of fluorine-18-radiolabelled HPMA derivatives, yielding information of excretion pathways, blood retention, and organ distribution. According to the physical half-life of fluorine-18 of 110 min, those data only cover a period of 2 to 4 h post injection. For an investigation of later time points, in particular when drug accumulation in tumors is of interest, radionuclides of longer physical half-life are needed. Here, we intent to introduce a radiolabeling concept based on a chelator being (i) adequate to the coordination chemistry of trivalent metals, namely DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10tetraacetic acid), and being (ii) covalently attachable to the HPMA structure. Two generator-produced positron emitters of choice are gallium-68 and scandium-44, which can be applied to quantitative in vivo imaging via PET. Gallium-68 is a positron emitter (89%) with a half-life of 67.71 min and average positron energy of 1.899 MeV. Its physical halflife is adequate to allow the preparation and purification of gallium-68-labeled radiopharmaceuticals and for imaging biological processes with short half-life. The major advantage of gallium-68 is its availability via a 68Ge/ 68Ga-generator system, which provides a cyclotronindependent and cost-effective source of the isotope in suitable conditions for labeling after its post-processing [ 22–27 ]. Scandium-44 (94% posi (...truncated)


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Elisabeth Eppard, Ana de la Fuente, Nicole Mohr, Mareli Allmeroth, Rudolf Zentel, Matthias Miederer, Stefanie Pektor, Frank Rösch. Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging, EJNMMI Research, 2018, pp. 16, Volume 8, Issue 1, DOI: 10.1186/s13550-018-0372-x