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TRACK 1 Technical Program

TRACK 1 NANOIMAGING non-invasively in the absence of drug labeling. The future success of molec-
ular medicine will, in part, rest upon our ability to offer improved clinical trial
designs addressing the foregoing issues. In conclusion, the adoption of such
MONDAY, FEBRUARY, 22 an approach for image-directed drug delivery in clinical settings will have
far-reaching implications for personalizing cancer care in terms of treatment
planning, stratification to appropriate trial arms, and response monitoring.
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TRANSLATIONAL NANOPARTICLES 10:00am Intrinsically Radiolabeled Nanoparticles: An Emerging
Paradigm
Sam Houston 9:30am - 11:00am Technical Presentation. NEMB2016-5904

Session Organizer: Weibo Cai, University of Wisconsin-Madison, Weibo Cai, University of Wisconsin-Madison, Madison, WI, United
Madison, WI, United States States

9:30am Translational Ultrasmall Particle Imaging Tools for Mo- With the rapid growing interests in using radioisotopes for nanooncology,
lecular Cancer Imaging and Intraoperative Treatment a broad spectrum of radiotracers has been generated for positron emis-
sion tomography (PET) and single photon emission computed tomography
(SPECT) imaging in different diseases. To date, different radioisotopes
Keynote. NEMB2016-5920 have been labeled to carriers, such as antibodies, peptides, nanoparticles,
etc., for in vivo biomarker expression level imaging, early tumor detection,
Michelle Bradbury, Memorial Sloan Kettering Cancer Center, New drug biodistribution pattern studies, and so on. The most widely used ra-
York, NY, United States diolabeling strategy involves the use of exogenous chelators which could
coordinate with certain radioisotopes to form stable complexes. Well-estab-
Despite recent advances in imaging probe development for biomedicine, lished chelators, such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA),
the translation of targeted diagnostic platforms remains challenging. Nano- 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), p-isothiocy-
materials platforms currently under evaluation in oncology clinical trials are anatobenzyl-desferrioxamine (Df-Bz-NCS) and diethylene triamine penta-
largely non-targeted drug delivery vehicles or devices to thermally treat acetic acid (DTPA), etc., have been employed for radiolabeling of copper-64
tissue; these are typically not surface modified for targeted detection by ( Cu, t =12.7 h), zirconium-89 ( Zr, t1/2=78.4 h), and indium-111 ( In, t =2.8 d)
64
89
111
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clinical imaging tools. New tumor-selective platforms need to satisfy critical for imaging in preclinical studies.
safety benchmarks, in addition to assaying targeted interactions with the
microenvironment and their effects on biological systems. Coupled with met- Different isotopes vary significantly in their coordination chemistry, making
abolic imaging and analysis tools, such as PET, complete and quantitatively selection of the right chelator for a specific isotope vital. However, this could
accurate data sets for whole body distributions, targeting kinetics, and clear- be tricky and even impossible to achieve in some cases. For example, it is
ance profiles of new diagnostic platforms undergoing preclinical testing or still a major challenge to radiolabel certain isotopes such as arsenic-72 ( As,
72
69
transitioning into early-phase clinical trials can be acquired. t =26 h) and germanium-69 ( Ge, t =39.1 h). In addition, although most of
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the radiolabeling could be done under mild conditions, in some cases suc-
In the operating theatre, there is also an urgent need for implementing new cessful radiolabeling might require very harsh conditions (e.g. high reaction
image-directed visualization tools that can enhance surgical vision, facili- temperature with prolonged incubation time) which limit their use.
tate minimally invasive surgical procedures, and dramatically alter surgical
outcomes of oncological patients. The lack of clear surgical vision impacts The other concerns of using traditional radiolabeling strategies include the
the ability of the operating surgeon to accurately and specifically identify possible alteration of pharmacokinetics of carriers and potential detachment
the extent of malignancy, microscopic tumor burden, or remnant disease. of radioisotopes, which could lead to problems such as off-targeting and
Collectively, these factors affect therapeutic outcome, prognosis, and treat- false positives. Since the carrier itself is not labeled and PET (or SPECT) only
ment management. Newer molecular imaging probe designs coupled with detects signals from the radioisotope, the integrity (or stability) of the radio-
state-of-the-art device technologies, may enhance cancer care, provide labeled system in the complicated physiological environment should always
real-time imaging guidance, and lead to new, more efficient approaches for be thoroughly investigated before in vivo imaging applications. Detachment
early-stage detection and treatment. of the radioisotopes from the carriers can also lead to potential transchela-
tion to proteins, causing erroneous interpretation of the results. Therefore,
Advances in nanotechnology have also fueled a paradigm shift in targeting successful chelator-based radiolabeling requires in-depth knowledge of the
and safely delivering drugs in conjunction with image-directed approaches. coordination chemistry and selection of the best chelator for every radioiso-
The size, architecture, and chemical composition of particle-based drug tope.
delivery vehicles can be fine-tuned to achieve properties optimal for loading
and controlled release of therapeutic agents, patient safety/compliance, To address these concerns, recent research has been focusing on devel-
favorable kinetic profiles, and reducing unwanted side effects. By combining oping more reliable chelator-free radiolabeling techniques, which could
therapeutic particle tracer preparations with quantitative bioimaging ap- fully take advantage of the unique physical and chemical properties of
proaches, drug delivery, lesion localization, and the extraction of key tumor well-selected inorganic or organic nanoparticles for radiolabeling, and more
biologic properties can be achieved for individualizing treatment planning. importantly, offer an easier, faster, and more specific radiolabeling possi-
In turn, dosage regimens needed to achieve therapeutic efficacy might be bility. Therefore, intrinsically radiolabeled nanoparticles have becoming an
estimated based on knowledge of drug specific activity and dose, uptake increasingly more important research topic, which could be achieved mainly
kinetics, and IC50 values. via four different methods. The four major categories for intrinsically radiola-
beled nanoparticles include: 1) hot-plus-cold precursors, 2) specific trapping,
The ability to flexibly adapt the formulation of clinically-promising drugs to 3) cation exchange, and 4) proton beam activation.
improve their physicochemical and/or biological properties, in combination
with metabolic imaging tools, will be important to quantify and establish Representative examples of each category will be briefly illustrated. The
suitable clinical trial endpoints. Issues relating to solubility, transport, barrier main focus of this talk will be on our own recent work that involves the
penetration, time-dependent changes in drug uptake, and intratumoral dis- radiolabeling of a variety of nanomaterials via “specific trapping”, and the
tribution are additional considerations. These properties are often not gen- nanomaterials investigated in our laboratory include iron oxide nanoparti- 15
erally evaluated in the context of drug delivery due to the complexity of the cles, micelles, silica-based nanoparticles, multifunctional/multimodal hybrid
biological systems involved and the inability to serially monitor this process nanomaterials, among others. Although still in the early stages, design and