Biomedical Engineering Reference
In-Depth Information
are that of the dose rate effect [
32
]. Low dose rates are less damaging than high
dose rates, as with fractionated external beam therapy, the total dose from continues
low dose radionuclide therapy is less biologically effective than a single dose of
the same magnitude. Therefore, the most suitable physical half-live should vary
between a few hours to that of a few days when targeting disseminated cancer cells.
On the other hand, longer physical half-lives might be desirable in the treatment
of solid tumors where high uptake is required. Furthermore, stable non-toxic decay
products are desirable to minimize normal tissue toxicity.
28.2.4
Suitable chemistry for the radiolabelling process
Production of Auger electron emitters for therapy should be economically viable
and allow preparation to high specific activity and purity. Efficient incorporation
into a selective carrier molecule is also a prerequisite. Once inside the target tissue,
the selective carrier molecule should be able to associate with the DNA complex
for a time corresponding to the radionuclide half-life [
33
]. Prolonged intracellular
retention can be achieved by using various residualizing agents for indirect halogen
labeling [
34
]. In addition, cellular excretion can be limited if the radionuclides are
of metal type, e.g. indium or platinum, this is due to the intracellular retention of
metal containing catabolic products [
35
,
36
].
28.3
Targeting strategies - the clinical experience
The first requirement for the delivery of Auger emitting nuclides is the definition of
suitable tumor-selective delivery vehicles to avoid normal tissue toxicity [
17
]. The
explosive growth of antibody targeted cancer therapy has expanded the development
of novel pharmaceuticals for targeted radionuclide therapy. After the FDA approval
of the first monoclonal antibodies for clinical use [
37
] many other targeting
strategies have been explored for targeted radionuclide therapy. Molecules and
molecular targets that have been used in the past can be classified according to the
carrier molecule used to deliver the Auger-electron-emitting radionuclide. These
include (1) antibodies, (2) peptides, (3) small molecules, (4) oligonucleotides and
peptide nucleic acids (PNAs), (5) proteins, and (6) nanoparticles. A schematic
overview of the trafficking and nuclear localization of Auger-electron-emitters
isshowninFig.
28.1
. Auger electron emitters can only be considered as an
effective compliment to other treatment modalities or a possible alternative to
chemotherapy if targeted delivery of the radionuclide complex could accomplish
total eradication of disseminated tumor cells and micro-metastasis. From the
vast number of cell culture studies performed it has been shown that nuclear
localization of the radionuclide is a key factor for the induction of high LET type
cytotoxicity in mammalian cells [
38
]. Therefore, only targets on cancer cells that
