non-targeted group (in M21L tumor mice). In vivo optical imaging was also performed to show their potential in local and regional lymph node mapping.
In 2010, FDA approved C dots as the Investigational New Drug (IND) for
first-in-human clinical trial studies (Fig. 17.1c). The Phase 1 safety study of
124 I–
cRGDY–PEG–C dots in five human patients with metastatic melanoma was led by
Dr. Michelle Bradbury of Memorial Sloan Kettering Cancer Center [33].
Systematic investigation showed relatively low tissue activities in most of the
patients. Whole body tracer clearance half-life was estimated to range from 13 to
21 h with no notable accumulation observed in the Reticuloendothelial system
(RES) (Fig. 17.1d). Radiation dosimetry study further showed an average effective
dose of 0.183 ± 0.065 mSv/MBq, which was comparable to the estimated values
from their previous preclinical data (*0.157 mSv/MBq) [35]. Although the tracer
was not yet optimized for active tumor targeting, lesion uptake and localization
were seen in several patients. Specific tracer localization in liver metastasis was also
observed in one of the patients. Multimodality (PET/MRI) imaging also showed the
accumulation of
124 I–cRGDY–PEG–C dots in a pituitary lesion in one patient. The
same tracer also showed high and retained uptake in both renal cortices over several
days in one patient. Renal function assessment study showed no substantially
change of average blood urea nitrogen and creatinine concentrations over the
2-week study interval, indicating that renal function was unaffected by the C dot
tracer. No changes in liver function were found either. These first-in-human results
clearly suggest safe use and great potential of
124 I–cRGDY–PEG–C dots in human
cancer diagnostics. Besides optimizing the clearance profiles and the in vivo targeting efficacy, great efforts have also been devoted to the manufacturing of a newer
generation Cornell prime dots, or C′ dots, with better reproducibility in a
water-based environment [38, 39]. Both the pre-clinical and clinical translation of
the newer generation C′ dots are actively ongoing.
For radiolabeled silica nanoparticles with a HD size greater than 10 nm, they
usually share a quite similar biodistribution pattern with a rapid, high and non-specific
particle accumulation in mouse RES organs (e.g., liver and spleen). For example, in
2013, Cai and his group reported the first example of in vivo tumor vasculaturetargeting TRC105-conjugated and
64 Cu-labeled MSN (HD: >150 nm, surface charge:
about-3 mV) in a murine breast cancer model (4T1) [40]. MSN was surface
modified step-by-step with PEG, radio-chelator ((S)-2-(4-isothiocyanatobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid, or p-SCN–Bn–NOTA), and vasculature
targeting full antibody (i.e., TRC105) before radiolabeled with copper-64
(
64 Cu, t 1/2 = 12.6 h). Systematic in vivo tumor targeting studies demonstrated the
specific accumulation of
64 Cu–NOTA–MSN–PEG–TRC105 at 4T1 tumor site
(*5%ID/g) with the liver uptake estimated to be the highest of 16%ID/g (Fig. 17.2a).
In a follow-up study, water-soluble photothermally sensitive copper sulfide
nanoparticles were encapsulated in biocompatible mesoporous silica shells, followed
by multi-step surface engineering to form theranostic nanoparticles named
64 Cu–NOTA–CuS@MSN–PEG–TRC105 [41]. The newly designed multifunctional nanoplatform showed a slightly improved active 4T1 tumor targeting
efficacy and two times higher liver uptake than the pure MSN structure [40], possibly
17 Size-, Shape- and Charge-Dependent Pharmacokinetics …
317
In 2010, FDA approved C dots as the Investigational New Drug (IND) for
first-in-human clinical trial studies (Fig. 17.1c). The Phase 1 safety study of
124 I–
cRGDY–PEG–C dots in five human patients with metastatic melanoma was led by
Dr. Michelle Bradbury of Memorial Sloan Kettering Cancer Center [33].
Systematic investigation showed relatively low tissue activities in most of the
patients. Whole body tracer clearance half-life was estimated to range from 13 to
21 h with no notable accumulation observed in the Reticuloendothelial system
(RES) (Fig. 17.1d). Radiation dosimetry study further showed an average effective
dose of 0.183 ± 0.065 mSv/MBq, which was comparable to the estimated values
from their previous preclinical data (*0.157 mSv/MBq) [35]. Although the tracer
was not yet optimized for active tumor targeting, lesion uptake and localization
were seen in several patients. Specific tracer localization in liver metastasis was also
observed in one of the patients. Multimodality (PET/MRI) imaging also showed the
accumulation of
124 I–cRGDY–PEG–C dots in a pituitary lesion in one patient. The
same tracer also showed high and retained uptake in both renal cortices over several
days in one patient. Renal function assessment study showed no substantially
change of average blood urea nitrogen and creatinine concentrations over the
2-week study interval, indicating that renal function was unaffected by the C dot
tracer. No changes in liver function were found either. These first-in-human results
clearly suggest safe use and great potential of
124 I–cRGDY–PEG–C dots in human
cancer diagnostics. Besides optimizing the clearance profiles and the in vivo targeting efficacy, great efforts have also been devoted to the manufacturing of a newer
generation Cornell prime dots, or C′ dots, with better reproducibility in a
water-based environment [38, 39]. Both the pre-clinical and clinical translation of
the newer generation C′ dots are actively ongoing.
For radiolabeled silica nanoparticles with a HD size greater than 10 nm, they
usually share a quite similar biodistribution pattern with a rapid, high and non-specific
particle accumulation in mouse RES organs (e.g., liver and spleen). For example, in
2013, Cai and his group reported the first example of in vivo tumor vasculaturetargeting TRC105-conjugated and
64 Cu-labeled MSN (HD: >150 nm, surface charge:
about-3 mV) in a murine breast cancer model (4T1) [40]. MSN was surface
modified step-by-step with PEG, radio-chelator ((S)-2-(4-isothiocyanatobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid, or p-SCN–Bn–NOTA), and vasculature
targeting full antibody (i.e., TRC105) before radiolabeled with copper-64
(
64 Cu, t 1/2 = 12.6 h). Systematic in vivo tumor targeting studies demonstrated the
specific accumulation of
64 Cu–NOTA–MSN–PEG–TRC105 at 4T1 tumor site
(*5%ID/g) with the liver uptake estimated to be the highest of 16%ID/g (Fig. 17.2a).
In a follow-up study, water-soluble photothermally sensitive copper sulfide
nanoparticles were encapsulated in biocompatible mesoporous silica shells, followed
by multi-step surface engineering to form theranostic nanoparticles named
64 Cu–NOTA–CuS@MSN–PEG–TRC105 [41]. The newly designed multifunctional nanoplatform showed a slightly improved active 4T1 tumor targeting
efficacy and two times higher liver uptake than the pure MSN structure [40], possibly
17 Size-, Shape- and Charge-Dependent Pharmacokinetics …
317