[24, 25]. Although numerous pre-clinical research papers on the PK of nanoparticles with varied sizes have been published during the last 30 years, conclusions
drawn by a specific nanoplatform (or in a specific animal model) might not be easily
applied to the others. Researchers still rely on extensive experiments to select the
best size or size range for their given project. Considering that most of the previous
review articles only covered the general PK of nanoparticles with an HD size
greater than 10 nm [22], and multi-functional renal clearable nanoparticles have
attracted increasing interests recently [26, 27], PK of radiolabeled nanoparticles
with a less than 10 nm HD size will be our main focus in the following sections.
17.2.1 Radiolabeled Silica Nanoparticles
Silica (or silicon dioxide) is “generally recognized as safe” by the US Food and
Drug Administration (FDA) (ID Code: 14808-60-7) [28]. For more than 30 years,
scientists all over the world have been focusing on the engineering pre-clinical
applications of silica-based nanoparticles in cancer detection and treatment [29–32].
However, it was not until year 2014 that the nanomedicine community started to
celebrate the first-in-human clinical trial of ultrasmall fluorescent dye-encapsulated
silica PET-optical hybrid nanoparticles (also known as Cornell dots, or C dots) [33].
The clinical translation history of C dot involved great efforts in optimizing the
particle size, surface functionalities, surface charge, particle manufacturing and
stability (shelf-life), radiolabeling techniques, PK (especially minimizing the liver/
spleen uptake and maintaining bulk renal clearance) study, toxicity, in vitro/in vivo
(small and large animal) tumor targeting efficacy studies, etc. [33–36], and should
serve a great example when explaining how the size, surface chemistry could affect
the PK of silica nanoparticles and their clinical translation.
Developed by Wiesner and co-workers in 2005, the first dye-encapsulated silica
nanoparticles were created by using a modified Stöber method, and had a physical
size of 20–30 nm [37]. Although no in vivo PK study was mentioned in that early
work, high liver, spleen uptake and no renal clearance were expected due to the
>10 nm particle size. Great efforts were later devoted in engineering of
dye-encapsulated silica nanoparticle with efficient urinary excretion by introducing
two major upgrades [34] (Fig. 17.1a). Firstly, the hydrodynamic (HD) size was
tuned down to <10 nm. Secondly, nanoparticles were covalently coated with
methoxy-terminated poly(ethylene glycol) chains (PEG, *0.5 kDa) to prevent
aggregation and opsonization in vivo. Dramatic difference in nanoparticle biodistribution after i.v. injection was observed for particle with and without PEGylation
(Fig. 17.1b). Results showed a dominant liver and spleen uptake for silica
nanoparticles with no PEGylation (highly negatively charged surface), while bulk
renal clearance and significant bladder uptake was observed for the same particle
with a PEGylation (neutral surface charge) (Fig. 17.1b). The study further compared the whole body biodistribution pattern and clearance rate of silica nanoparticles with two different HD sizes. As expected, smaller sized silica particle showed
17 Size-, Shape- and Charge-Dependent Pharmacokinetics …
315
drawn by a specific nanoplatform (or in a specific animal model) might not be easily
applied to the others. Researchers still rely on extensive experiments to select the
best size or size range for their given project. Considering that most of the previous
review articles only covered the general PK of nanoparticles with an HD size
greater than 10 nm [22], and multi-functional renal clearable nanoparticles have
attracted increasing interests recently [26, 27], PK of radiolabeled nanoparticles
with a less than 10 nm HD size will be our main focus in the following sections.
17.2.1 Radiolabeled Silica Nanoparticles
Silica (or silicon dioxide) is “generally recognized as safe” by the US Food and
Drug Administration (FDA) (ID Code: 14808-60-7) [28]. For more than 30 years,
scientists all over the world have been focusing on the engineering pre-clinical
applications of silica-based nanoparticles in cancer detection and treatment [29–32].
However, it was not until year 2014 that the nanomedicine community started to
celebrate the first-in-human clinical trial of ultrasmall fluorescent dye-encapsulated
silica PET-optical hybrid nanoparticles (also known as Cornell dots, or C dots) [33].
The clinical translation history of C dot involved great efforts in optimizing the
particle size, surface functionalities, surface charge, particle manufacturing and
stability (shelf-life), radiolabeling techniques, PK (especially minimizing the liver/
spleen uptake and maintaining bulk renal clearance) study, toxicity, in vitro/in vivo
(small and large animal) tumor targeting efficacy studies, etc. [33–36], and should
serve a great example when explaining how the size, surface chemistry could affect
the PK of silica nanoparticles and their clinical translation.
Developed by Wiesner and co-workers in 2005, the first dye-encapsulated silica
nanoparticles were created by using a modified Stöber method, and had a physical
size of 20–30 nm [37]. Although no in vivo PK study was mentioned in that early
work, high liver, spleen uptake and no renal clearance were expected due to the
>10 nm particle size. Great efforts were later devoted in engineering of
dye-encapsulated silica nanoparticle with efficient urinary excretion by introducing
two major upgrades [34] (Fig. 17.1a). Firstly, the hydrodynamic (HD) size was
tuned down to <10 nm. Secondly, nanoparticles were covalently coated with
methoxy-terminated poly(ethylene glycol) chains (PEG, *0.5 kDa) to prevent
aggregation and opsonization in vivo. Dramatic difference in nanoparticle biodistribution after i.v. injection was observed for particle with and without PEGylation
(Fig. 17.1b). Results showed a dominant liver and spleen uptake for silica
nanoparticles with no PEGylation (highly negatively charged surface), while bulk
renal clearance and significant bladder uptake was observed for the same particle
with a PEGylation (neutral surface charge) (Fig. 17.1b). The study further compared the whole body biodistribution pattern and clearance rate of silica nanoparticles with two different HD sizes. As expected, smaller sized silica particle showed
17 Size-, Shape- and Charge-Dependent Pharmacokinetics …
315