8 research outputs found
Automatic evaluation of the sinus of Valsalva from cine-MRI in patients with dilated aortic root
Tumor-associated macrophages, nanomedicine and imaging: the axis of success in the future of cancer immunotherapy
Correction to Cancer-Targeting Ultrasmall Silica Nanoparticles for Clinical Translation: Physicochemical Structure and Biological Property Correlations
Residual Tumor Volume, Cell Volume Fraction, and Tumor Cell Kill During Fractionated Chemoradiation Therapy of Human Glioblastoma using Quantitative Sodium MR Imaging
Correction to Melanocortin-1 Receptor-Targeting Ultrasmall Silica Nanoparticles for Dual-Modality Human Melanoma Imaging
Cancer-Targeting Ultrasmall Silica Nanoparticles for Clinical Translation: Physicochemical Structure and Biological Property Correlations
Although
a large body of literature exists on the potential use
of nanoparticles for medical applications, the number of probes translated
into human clinical trials is remarkably small. A major challenge
of particle probe development and their translation is the elucidation
of safety profiles associated with their structural complexity, not
only in terms of size distribution and heterogeneities in particle
composition but also their effects on biological activities and the
relationship between particle structure and pharmacokinetics. Here,
we report on the synthesis, characterization, and long-term stability
of ultrasmall (<10 nm diameter) dual-modality (optical and positron
emission tomography) and integrin-targeting silica nanoparticles (cRGDY–PEG–Cy5–C′
dots and <sup>124</sup>I-(or <sup>131</sup>I-) cRGDY–PEG–Cy5–C′dots)
and the extent to which their surface ligand density differentially
modulates key in vitro and in vivo biological activities in melanoma
models over a range of ligand numbers (i.e., ∼6–18).
Gel permeation chromatography, established as an important particle
characterization tool, revealed a two-year shelf life for cRGDY–PEG–Cy5–C′
dots. Radiochromatography further demonstrated the necessary radiochemical
stability for clinical applications. The results of subsequent ligand
density-dependent studies elucidate strong modulations in biological
response, including statistically significant increases in integrin-specific
targeting and particle uptake, cellular migration and adhesion, renal
clearance, and tumor-to-blood ratios with increasing ligand number.
We anticipate that nanoprobe characteristics and a better understanding
of the structure–function relationships determined in this
study will help guide identification of other lead nanoparticle candidates
for in vitro and in vivo biological assessments and product translation
Melanocortin‑1 Receptor-Targeting Ultrasmall Silica Nanoparticles for Dual-Modality Human Melanoma Imaging
The
poor prognosis associated with malignant melanoma has not changed
substantially over the past 30 years. Targeted molecular therapies,
such as immunotherapy, have shown promise but suffer from resistance
and off-target toxicities, underscoring the need for alternative therapeutic
strategies that can be used in combination with existing protocols.
Moreover, peptides targeting melanoma-specific markers, like the melanocortin-1
receptor (MC1-R), for imaging and therapy exhibit high renal uptake
that limits clinical translation. In the current study, the application
of ultrasmall fluorescent (Cy5) silica nanoparticles (C′ dots),
conjugated with MC1-R targeting alpha melanocyte stimulating hormone
(αMSH) peptides on the polyethylene glycol (PEG) coated surface,
is examined for melanoma-selective imaging. αMSH peptide sequences,
evaluated for conjugation to the PEG-Cy5-C′ dot nanoparticles,
bound to MC1-R with high affinity and targeted melanoma in syngenetic
and xenografted melanoma mouse models. Results demonstrated a 10-fold
improvement in MC1-R affinity over the native peptide alone following
surface attachment of the optimal αMSH peptide. Systematic in
vivo studies further demonstrated favorable in vivo renal clearance
kinetics as well as receptor-mediated tumor cell internalization of
as-developed radiolabeled particle tracers in B16F10 melanoma bearing
mice. These findings highlight the ability of αMSH-PEG-Cy5-C′
dots to overcome previous hurdles that prevented clinical translation
of peptide and antibody-based melanoma probes and reveal the potential
of αMSH-PEG-Cy5-C′ dots for melanoma-selective imaging,
image-guided surgery, and therapeutic applications