4 research outputs found
The uptake of soluble and nanoparticulate imaging isotope in model liver tumours after intra-venous and intra-arterial administration
Delivery of chemotherapeutic drugs to tumours by reformulation as nanoparticles has often been proposed as a means of facilitating increased selective uptake, exploiting the increased permeability of the tumour vasculature. However realisation of this improvement in drug delivery in cancer patients has met with limited success. We have compared tumour uptake of soluble Tc99m-pertechnetate and a colloid of nanoparticles with a Tc99m core, using both intra-venous and intra-arterial routes of administration in a rabbit liver VX2 tumour model. The radiolabelled nanoparticles were tested both in untreated and cationised form. The results from this tumour model in an internal organ show a marked advantage in intra-arterial administration over the intra-venous route, even for the soluble isotope. Tumour accumulation of nanoparticles from arterial administration was augmented by cationisation of the nanoparticle surface with histone proteins, which consistently facilitated selective accumulation within microvessels at the periphery of tumours.Sources of support for this research: Sirtex Medical Ltd, Sydney
Australia
In vivo tumour imaging employing regional delivery of novel gallium radiolabelled polymer composites
Background: Understanding the regional vascular delivery of particles to tumour sites is a prerequisite for
developing new diagnostic and therapeutic composites for treatment of oncology patients. We describe a novel
imageable 67Ga-radiolabelled polymer composite that is biocompatible in an animal tumour model and can be
used for preclinical imaging investigations of the transit of different sized particles through arterial networks of
normal and tumour-bearing organs.
Results: Radiolabelling of polymer microspheres with 67Ga was achieved using a simple mix and wash method,
with tannic acid as an immobilising agent. Final in vitro binding yields after autoclaving averaged 94.7%. In vivo
stability of the composite was demonstrated in New Zealand white rabbits by intravenous administration, and
intrahepatic artery instillations were made in normal and VX2 tumour implanted rabbit livers. Stability of radiolabel
was sufficient for rabbit lung and liver imaging over at least 3 hours and 1 hour respectively, with lung retention of
radiolabel over 91%, and retention in both normal and VX2 implanted livers of over 95%. SPECT-CT imaging of
anaesthetised animals and planar imaging of excised livers showed visible accumulation of radiolabel in tumours.
Importantly, microsphere administration and complete liver dispersal was more easily achieved with 8 μm diameter
MS than with 30 μm MS, and the smaller microspheres provided more distinct and localised tumour imaging.
Conclusion: This method of producing 67Ga-radiolabelled polymer microspheres is suitable for SPECT-CT imaging
of the regional vascular delivery of microspheres to tumour sites in animal models. Sharper distinction of model
tumours from normal liver was obtained with smaller MS, and tumour resolution may be further improved by the
use of 68Ga instead of 67Ga, to enable PET imaging.The ANU authors acknowledge the collaborative research project support
generously provided to ANU by Sirtex Medical Ltd. (Sydney), including
donation of a GE Hawkeye Infinia SPECT/CT scanner and a Xeleris image
processing system
Evidence for a link between translocation and processing during protein import into soybean mitochondria
AbstractThe effect of metal chelators on protein import was investigated using isolated soybean mitochondria and soybean precursor proteins. Adding 1,10-phenanthroline, a metal chelator that can cross both mitochondrial membranes abolished import of both the alternative oxidase, and the FAd subunit of the ATP synthase, a matrix located protein. Other metal chelators such as EDTA, 1,7-phenanthroline and 4,7-phenanthroline, which cannot cross the mitochondrial membranes, had no effect on import. When processing, a known metal-dependent step inside mitochondria, was inhibited using a mutagenesis approach (changing a - 2 arginine to a - 2 glycine in the pre-piece of the precursor), so was import. Thus it would appear that in soybean, at least, translocation of proteins across the mitochondrial membrane, as well as processing, relies on a metal dependent step. Taken together, the data suggest that the two processes may be directly connected in these mitochondria
Tc-99m-radiolabeled composites enabling in vivo imaging of arterial dispersal and retention of microspheres in the vascular network of rabbit lungs, liver, and liver tumors.
Purpose: Selective internal radiation therapy (SIRT) is an effective treatment option for liver
tumors, using Y-90-loaded polymer microspheres that are delivered via catheterization of the
hepatic artery. Since Y-90 is a beta emitter and not conveniently imaged by standard clinical
instrumentation, dosimetry is currently evaluated in each patient using a surrogate particle,
99mTechnetium-labeled macroaggregated albumin (99mTc-MAA). We report a new composite
consisting of 99mTc-labeled nanoparticles attached to the same polymer microspheres as used
for SIRT, which can be imaged with standard SPECT.
Methods: Carbon nanoparticles with an encapsulated core of 99mTc were coated with the polycation
protamine sulfate to provide electrostatic attachment to anionic polystyrene sulfonate
microspheres of different sizes (30, 12, and 8 µm). The in vivo stability of these composites was
determined via intravenous injection and entrapment in the capillary network of normal rabbit
lungs for up to 3 hours. Furthermore, we evaluated their biodistribution in normal rabbit livers,
and livers implanted with VX2 tumors, following intrahepatic artery instillation.
Results: We report distribution tests for three different sizes of radiolabeled microspheres and
compare the results with those obtained using 99mTc-MAA. Lung retention of the radiolabeled
microspheres ranged from 72.8% to 92.9%, with the smaller diameter microspheres showing
the lowest retention. Liver retention of the microspheres was higher, with retention in normal
livers ranging from 99.2% to 99.8%, and in livers with VX2 tumors from 98.2% to 99.2%. The
radiolabeled microspheres clearly demonstrated preferential uptake at tumor sites due to the
increased arterial perfusion produced by angiogenesis.
Conclusion: We describe a novel use of radiolabeled carbon nanoparticles to generate an
imageable microsphere that is stable in vivo under the shear stress conditions of arterial
networks. Following intra-arterial instillation in the normal rabbit liver, they distribute in a
distinct segmented pattern, with the smaller microspheres extending throughout the organ in
finer detail, while still being well retained within the liver. Furthermore, in livers hosting an
implanted VX2 tumor, they reveal the increased arterial perfusion of tumor tissue resulting from
angiogenesis. These novel composites may have potential as a more representative mimic of
the vascular distribution of therapeutic microspheres in patients undergoing SIRTThe ANU authors acknowledge the collaborative project support generously provided to ANU by Sirtex Medical Limited
(Sydney), including donation of a GE Hawkeye Infinia SPECT/
CT scanner and a Xeleris image processing system. This work
was funded through a collaborative research agreement with
Sirtex Medical Limited, Sydney, Australia