Introduction
In cancer discovery research, radiolabeled monoclonal antibodies
directed against tumor-associated antigens have been developed as
promising vectors to visualize or to treat tumors, mostly owing to their
high affinity and specificity [1], [2]. Since antibodies have a
long biological half-life, it takes a long time (in the order of days)
to clear the antibodies from plasma. The half-life of radionuclides that
are used to radiolabel antibodies should be sufficiently long
(>12h) to allow clearance of the radiolabeled antibody from
plasma prior to acquire high signal-to-noise ratio tumor PET images. The
use of long lived radionuclides (e.g. 64Cu,124I, 89Zr) will however result in
prolonged exposure to radiation and a high absorbed radiation dose.
Fluorine-18 (F-18) is the most frequently used radionuclide for
positron-emission tomography (PET) [3]–[5] radioisotopes due to
its favorable physical properties (e.g. half-life of 109.8 min) [6].
Application of shortlived F-18 for in vivo visualization of antibodies
can be achieved by pretargeting approaches based on high yield in vivo
click reaction using e.g. 18F-labeledtrans -cyclooctene (TCO) or tetrazine derivatives [7]. This
reaction strategy has been used for both in vitro and in
vivo applications [5], [8], [9].
Trans -cyclooctene has a high reactivity due to the release of
high strain energy upon the click reaction providing a well-defined
chiral structure which makes it interesting for stereocontrolled
synthesis. Therefore, radiolabeled TCOs are good candidates for
bio-orthogonal chemistry [10].
There are many routes to synthesize a trans- cyclooctene. A common
and elegant way is the photoisomerization of cis totrans -cyclooctene [11]. Yet, the photoisomerization is not
irreversible and thus removal of the trans -isomer from the
equilibrium cis and trans mixture is required to shift the
equilibrium. Fox et al. have proposed an elegant procedure for the
photochemical synthesis of TCO [12]. In this method, TCO was
produced via photoisomerisation of cis- cyclooctene by exposure to
UV light (254 nm) in a batch vessel. The reaction mixture was
continuously passed through a bed of silver nitrate impregnated on
silica gel. Subsequently, the TCO is selectively retained by silver
nitrate and the remaining cis -cyclooctene-containing solution is
recycled to the photochemistry batch vessel. This is a very unique
method yet the total yield was 66% and the total reaction time was
relatively long, i.e. 12 hrs.
Recently, the sustainable production of active pharmaceuticals and
excipients in a has received a lot of attention [13]. Novel
bioprocesses, continuous-flow processing, process integration and
intensification and green chemistry are the main assets of sustainable
processes. Flow chemistry, especially micro-flow technology, is a high
potential platform in terms of equipment size reduction, energy
efficiency , and reduced solvent usage to achieve process
intensification and thereby performing more sustainable processes in
fine chemistry [14], [15].
More specifically, for photochemical reactions, microreactors have
several advantages compared to batch processes such as improved photon
transport, energy efficiency and better mixing [16]–[18]. The
constricted diameter of the microreactors (shorter photon diffusion
pathway) allows better use of the irradiated light efficiently reducing
the total exposure time, which leads to shorter reaction time and
possibly reduced byproduct formation [19], [20].
Beyond microfabricated channels, and microcapillaries, mini-scale
packed-bed reactors allow to form micro-flow in their void spaces.
Indeed, enhanced reaction rates, higher conversions and selectivities
were found as well and can be attributed to the reduced mass-transfer
limitations [21], [22]. This, in combination with the high
surface-to-volume ratio, makes the packed-bed reactor suited for
performing biphasic reactions in multiple-repeated reentrance-flow mode
or for heterogeneous catalytic reactions [23]. Adsorption (and
desorption) is an essential step in heterogeneous catalysis. Hernández
Carucci et al. proposed a model based on the competitive adsorption of
ethylene and molecular oxygen over a silver surface of microchannels at
260 °C as part of a precise kinetic model for the ethylene oxide
formation [24].
Accordingly, it stands to reason that sole adsorption processes (without
catalysis) might be intensified in micro-flow. Microspheres have been
reported and termed as adsorption ‘microreactors’ and indeed use the
same transfer intensification by size reduction [25]. Rutin-Cr(III)
loaded alginate microspheres were designed to reduce Cr(VI) to Cr(III)
through adsorption and recover it. Yet, true micro(channel)reactors and
micro-flow packed bed reactors have been hardly applied for adsorption
so far.
Recently, we reported on the combination of a nucleophilic substitution
to the thermal-Claisen rearrangement and also to photo-Claisen
rearrangement in micro-flow [26], [27]. The motivation was to
integrate two processes and to address the resulted challenging issues
towards orthogonality. Also, here, we would like to design and integrate
two processes, photoreaction and adsorption, yet with more in depth
theoretical study for each process.
Therefore, the aim of this study is to develop a photo micro-flow
process for the photochemical isomerization of cis -cyclooctene to
TCO and its subsequent in-flow separation to isolate isomerically pure
TCO derivatives. Such a compact integration of small devices fed with
minute volumes provides opportunities for synergism between reaction and
separation, which is a means of process intensification and was termed
process-design intensification [28] as one arms of novel process
windows [29]–[31].
More specifically, we focus in this work on the experimental procedures
(batch as well as flow) for the photoisomerisation, and the design and
operation of the adsorption column. Furthermore, the theoretical
concepts behind these operations are explained and relevant models for
both sections are developed. Finally, the results of the experiments and
theoretical modeling are presented and discussed.