(678e) Ultrafast Post-Formulation Core Radiolabeling of Biodegradable Nanoparticles for PET Contrast Agents

Wang, L. Z., Princeton University
Lim, T. L., Princeton University
Padakanti, P., University of Pennsylvania
Lu, H. D., Princeton University
Alavi, A., Hospital of the University of Pennsylvania, Perelman School of Medicine
Mach, R., University of Pennsylvania
Prud'homme, R. K., Princeton University

Among almost all cancers cases,
diagnostic accuracy and speed remains one of the major factors for patient
prognosis. Positron emission tomography (PET) is among the most sensitive of
imaging modalities but requires accumulation of radionuclide at the targeted
site. 18F-FDG (Fludeoxyglucose) is the
current gold standard for PET diagnostics but still has challenges with
accessibility, sensitivity and specificity. The short half-life of 18F
limits PET usage to only institutions with easy access to a cyclotron.
Furthermore, since resolution is dependent on concentration of positron
emitters at the imaging site, smaller and low metabolism cancers might not be
detectable using FDG. Lastly, non-tumor areas with high metabolism, such as brain
tissue or inflammation sites, produce high background signals that limit the
specificity of FDG-PET. Nanoparticle-based PET modality has the potential to
overcome all these limitations. Targeted particles can both localize PET signal
and drastically improve sensitivity by clustering the PET imaging agents in one
place. Additionally, nanoparticles have more flexibility in labeling with
longer half-life PET isotopes such as Cu-64 (12.7 hrs)
and Zr-89 (3.3 days), suitable for long-time imaging and drug biodistribution
studies. However, the lack of a clinically relevant formulation and
radiolabeling method is the current bottleneck for nanoparticle contrast agent
development. Traditional surface labeling methods are not industrially scalable
and can lead to off target effects in
. Alternatively, radiolabeling the nanoparticle core requires careful
selection of biocompatible chelators that can rapidly bind to radionuclides to
form stable complexes. To this end, we here present the use of Flash
Nanoprecipitation (FNP), a continuous and scalable self-assembly process, to
form porphyrin encapsulated polymeric nanoparticles (NPs) at various sizes
ranging from 50 to 200 nm. The core component, hematoporphyrin derivative, is a
biocompatible small molecule that has been FDA approved for photodynamic
therapy (Photofrin). Its iron(III) complex precursor
is Heme, a major component of hemoglobin. When
incubated in a solution of [64Cu]CuCl2, a
long half-life positron emitter, the porphyrin core rapidly chelated copper in a
stable and irreversible manner, generating PET active nanoparticles. Under very
mild temperature and pH conditions (25C and pH 5.5), the porphyrin
nanoparticles’ chelation to 64Cu was complete in less than 15
minutes with essentially all the initial 64Cu activity (1.1 MBq) localized within the nanoparticle core. This core
radiolabeling method is comparable or even faster than currently used
nanoparticle surface labeling methods. Additionally, the porphyrin:64Cu
complex in the nanoparticle core was found to be stable for at least 24 hours
and resistant to leaching from external chelators such as
ethylenediaminetetraacetic acid (EDTA). Chelation rate modeling was done based
on absorbance changes of the porphyrin nanoparticles when incubated with
non-radioactive copper and was found to be consistent with experimental
results. Drugs could also be encapsulated into the core of these nanoparticles
to facilitate a theranostic approach to cancer
diagnostic and treatment. This development of a formulation and rapid radiolabeling
method to generate stable and biocompatible PET nanoparticles facilitates more
accessible, sensitive and specific cancer diagnostics.

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