3 research outputs found
Ultrasmall Silica-Based Bismuth Gadolinium Nanoparticles for Dual Magnetic Resonance–Computed Tomography Image Guided Radiation Therapy
Selective
killing of cancer cells while minimizing damage to healthy tissues
is the goal of clinical radiation therapy. This therapeutic ratio
can be improved by image-guided radiation delivery and selective radiosensitization
of cancer cells. Here, we have designed and tested a novel trimodal
theranostic nanoparticle made of bismuth and gadolinium for on-site
radiosensitization and image contrast enhancement to improve the efficacy
and accuracy of radiation therapy. We demonstrate in vivo magnetic
resonance (MR), computed tomography (CT) contrast enhancement, and
tumor suppression with prolonged survival in a non-small cell lung
carcinoma model during clinical radiation therapy. Histological studies
show minimal off-target toxicities due to the nanoparticles or radiation.
By mimicking existing clinical workflows, we show that the bismuth–gadolinium
nanoparticles are highly compatible with current CT-guided radiation
therapy and emerging MR-guided approaches. This study reports the
first in vivo proof-of-principle for image-guided radiation therapy
with a new class of theranostic nanoparticles
Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer
Human pancreatic ductal adenocarcinoma
(PDAC) contains a distinctively
dense stroma that limits the accessibility of anticancer drugs, contributing
to its poor overall prognosis. Nanoparticles can enhance drug delivery
and retention in pancreatic tumors and have been utilized clinically
for their treatment. In preclinical studies, various mouse models
differentially recapitulate the microenvironmental features of human
PDAC. Here, we demonstrate that through utilization of different organic
cosolvents and by doping of a homopolymer of poly(ε-caprolactone),
a diblock copolymer composition of poly(ethylene oxide)-<i>block</i>-poly(ε-caprolactone) may be utilized to generate biodegradable
and nanoscale micelles with different physical properties. Noninvasive
optical imaging was employed to examine the pharmacology and biodistribution
of these various nanoparticle formulations in both allografted and
autochthonous mouse models of PDAC. In contrast to the results reported
with transplanted tumors, spherical micelles as large as 300 nm in
diameter were found to extravasate in the autochthonous model, reaching
a distance of approximately 20 μm from the nearest tumor cell
clusters. A lipophilic platinum(IV) prodrug of oxaliplatin was further
able to achieve a ∼7-fold higher peak accumulation and a ∼50-fold
increase in its retention half-life in pancreatic tumors when delivered
with 100 nm long worm-like micelles as when compared to the free drug
formulation of oxaliplatin. Through further engineering of nanoparticle
properties, as well as by widespread adoption of the autochthonous
tumor model for preclinical testing, future therapeutic formulations
may further enhance the targeting and penetration of anticancer agents
to improve survival outcomes in PDAC
Nanoparticle Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy
More than 50% of all cancer patients
receive radiation therapy. The clinical delivery of curative radiation
dose is strictly restricted by the proximal healthy tissues. We propose
a dual-targeting strategy using <i>vessel</i>-<i>targeted</i>-radiosensitizing gold nanoparticles and <i>conformal</i>-image guided radiation therapy to specifically amplify damage in
the tumor neoendothelium. The resulting tumor vascular disruption
substantially improved the therapeutic outcome and subsidized the
radiation/nanoparticle toxicity, extending its utility to intransigent
or nonresectable tumors that barely respond to standard therapies