antibodies was measured in mouse models, and recently even in humanized FcRn
mouse models [62]. Findings in mouse models were extrapolated to humans taking
the inter-species differences into account with further modification than simple
allometry. Once physiologically-based pharmacokinetic model (PBPK) was
established [51, 60], predictive projection to human pharmacokinetics using mouse
data and PBPK has been highly recommended [46].
Radiolabeled PEGylated nanomaterials will enhance the predictability of human
pharmacokinetics while they allow single-photon emission computed tomography
(SPECT) or positron emission tomography (PET) acquisition which enable to
elucidate the exact biodistribution and its temporal changes. Target-mediated drug
disposition (TMDD) model which was originally developed and used for
small-molecule drugs such as tyrosine kinase inhibitors, was further used for
understanding target disposition of biologics (therapeutic monoclonal antibodies) in
small animals [51, 60]. Recently again, like PBPK, TMDD model was also used for
projection to predict human target disposition of therapeutic monoclonal antibodies
such as rituximab [60].
If we bind rituximab upon the surface of PEGylated nanomaterials, we are going
to measure the biodistribution and thus understand pharmacokinetics of new therapeutic nanomaterials, and then the projection to human pharmacokinetics will be
tried using inter-species scaling methods, allometry, PBPK and TMDD models [46,
60]. Though physiological differences between mouse and human are considered
with these models, immunogenicity and its difference between species will still cast
a great ambiguity in this projection. We think that we need to know the confounding variables for the determination of in vivo fates of radionanomaterials and
devise how to remove the effect of these variables to grossly-correct prediction of
the estimated amount of antibody-bound PEGylated nanomaterials in humans.
Of course, the exact amount of nanomaterials in the target tissues can only be
obtained from the human imaging studies using PET or SPECT [63, 64]. Cupper-64
(
64 Cu) or zirconium-89 (
89 Zr) are for PET and indium-111 (
111
In) is for SPECT
studies with appropriate physical half-lives. The amount of nanomaterials is not
important for therapeutic radioisotopes as the beta radiation is usually used for the
treatment. When we are able to increase the specific activity (Bq/g for radionuclides, Bq/mole for radiopharmaceutical or nanomaterials), the radioactivity really
counts but not the antibody or ligand on the nanomaterials’ surfaces, which originally was used for targeting. Nanomaterials would be less than 30 nmole/injection
for microdosing study in humans according to the rules announced by the each
country’s agency for nanomaterials as well as biomacromolecules. If 1 mCi is
going to be injected to human, 3.7 Â 10
7 Bq/30 Â 10
−9
 6  10
23 is allowed
and thus theoretically 10
16 particles can be given.
In summary, in case of therapeutic radioisotope-labeled nanomaterials, we need
to examine the biodistribution of radioactivity using PET or SPECT in small animals or monkeys and project the preclinical findings the human pharmacokinetics
[46, 60]. The target disposition is also to be projected. To keep in mind, the
therapeutic effect is not from the biological action of target-cumulated biologics, but
instead, from the radioactivity of nanomaterials’ surface-bound chelator labeled
21 Innate Immunity to Nanomaterials
403
mouse models [62]. Findings in mouse models were extrapolated to humans taking
the inter-species differences into account with further modification than simple
allometry. Once physiologically-based pharmacokinetic model (PBPK) was
established [51, 60], predictive projection to human pharmacokinetics using mouse
data and PBPK has been highly recommended [46].
Radiolabeled PEGylated nanomaterials will enhance the predictability of human
pharmacokinetics while they allow single-photon emission computed tomography
(SPECT) or positron emission tomography (PET) acquisition which enable to
elucidate the exact biodistribution and its temporal changes. Target-mediated drug
disposition (TMDD) model which was originally developed and used for
small-molecule drugs such as tyrosine kinase inhibitors, was further used for
understanding target disposition of biologics (therapeutic monoclonal antibodies) in
small animals [51, 60]. Recently again, like PBPK, TMDD model was also used for
projection to predict human target disposition of therapeutic monoclonal antibodies
such as rituximab [60].
If we bind rituximab upon the surface of PEGylated nanomaterials, we are going
to measure the biodistribution and thus understand pharmacokinetics of new therapeutic nanomaterials, and then the projection to human pharmacokinetics will be
tried using inter-species scaling methods, allometry, PBPK and TMDD models [46,
60]. Though physiological differences between mouse and human are considered
with these models, immunogenicity and its difference between species will still cast
a great ambiguity in this projection. We think that we need to know the confounding variables for the determination of in vivo fates of radionanomaterials and
devise how to remove the effect of these variables to grossly-correct prediction of
the estimated amount of antibody-bound PEGylated nanomaterials in humans.
Of course, the exact amount of nanomaterials in the target tissues can only be
obtained from the human imaging studies using PET or SPECT [63, 64]. Cupper-64
(
64 Cu) or zirconium-89 (
89 Zr) are for PET and indium-111 (
111
In) is for SPECT
studies with appropriate physical half-lives. The amount of nanomaterials is not
important for therapeutic radioisotopes as the beta radiation is usually used for the
treatment. When we are able to increase the specific activity (Bq/g for radionuclides, Bq/mole for radiopharmaceutical or nanomaterials), the radioactivity really
counts but not the antibody or ligand on the nanomaterials’ surfaces, which originally was used for targeting. Nanomaterials would be less than 30 nmole/injection
for microdosing study in humans according to the rules announced by the each
country’s agency for nanomaterials as well as biomacromolecules. If 1 mCi is
going to be injected to human, 3.7 Â 10
7 Bq/30 Â 10
−9
 6  10
23 is allowed
and thus theoretically 10
16 particles can be given.
In summary, in case of therapeutic radioisotope-labeled nanomaterials, we need
to examine the biodistribution of radioactivity using PET or SPECT in small animals or monkeys and project the preclinical findings the human pharmacokinetics
[46, 60]. The target disposition is also to be projected. To keep in mind, the
therapeutic effect is not from the biological action of target-cumulated biologics, but
instead, from the radioactivity of nanomaterials’ surface-bound chelator labeled
21 Innate Immunity to Nanomaterials
403