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Meeting ReportMolecular Targeting Probes Track

Engineering of intrinsically zirconium-89 radiolabeled self-destructing mesoporous silica nanostructures for in vivo tumor vasculature targeting

Shreya Goel, Feng Chen, Sixiang Shi, Hector Valdovinos, Todd Barnhart and Weibo Cai
Journal of Nuclear Medicine May 2016, 57 (supplement 2) 1151;
Shreya Goel
3University of Wisconsin-Madison Madison WI United States
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Feng Chen
1University of Wisconsin - Madison Madison WI United States
2University of Wisconsin - Madison Madison WI United States
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Sixiang Shi
3University of Wisconsin-Madison Madison WI United States
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Hector Valdovinos
3University of Wisconsin-Madison Madison WI United States
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Todd Barnhart
3University of Wisconsin-Madison Madison WI United States
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Weibo Cai
1University of Wisconsin - Madison Madison WI United States
2University of Wisconsin - Madison Madison WI United States
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Abstract

1151

Objectives We present a systematic study of in vitro and in vivo behavior of biodegradable mesoporous silica nanoparticles (bMSN), designed to carry multiple cargos (both small and macro-molecular drugs) and subsequently self-destruct over time after release of their payload. Chelator-free labeling of bMSNs with 89Zr (t1/2 = 72. 8 h) was used to track their in vivo pharmacokinetics and CD105 targeting ability via positron emission tomography (PET) imaging.

Methods Multi-generational bMSNs with tunable pore diameters, were synthesized using a biphase stratification approach and characterized systematically. In vitro degradation and dual drug loading and release studies were carried out in simulated body fluid (SBF) for 21 days and assessed using standard techniques. bMSNs were intrinsically chelated with oxophilic radionuclide 89Zr, followed by conjugation with polyethylene glycol (PEG) and TRC105 antibody to form (89)bMSN-PEG-TRC05 for in vivo PET imaging in 4T1 metastatic murine breast tumor model. Extensive in vitro, in vivo and ex vivo experiments were carried out to evaluate the stability, pharmacokinetics and tumor vasculature targeting of the as prepared radiotracers.

Results Degradation of nanocarriers into biocompatible and non-toxic byproducts presents a favorable prospect for their clinical translation. We engineered dendritic biodegradable silica nanoparticles (bMSNs) with spoke-like radiating bimodal mesoporous channels. The hierarchically structured large pore size (5.4 nm and 12 nm) of bMSNs resulted in rapid and complete degradation in SBF within 21 days, while the solid silica (dSN;no pores) and mesoporous silica (MSN; pore size~ 2-3 nm) nanoparticle controls showed marginal fragmentation. The mesostructure further allowed greater co-encapsulation of small-molecule drug (Sunitinib (SUN); 295.95 mg loaded per g bMSN) and large biomolecular proteins (Bovine Serum Albumin (BSA); 589.28 mg loaded per g bMSN). Gradual pH-dependent release of the cargo was observed; the trend matching closely with the biodegradation pattern of bMSNs. Excellent 89Zr labeling yield (~ 98 % within 2 h at 75 °C) and radiostability (> 95% upto 72 h) were observed. CD105 specificity of (89Zr)bMSN-PEG-TRC05 was confirmed in vivo with PET images showing significantly enhanced tumor uptake (4.5±0.6, 11.2±2.1, 11.5±1.3 and 11.2±0.9 %ID/g at 0.5, 6, 24 and 48 h post injection), compared to non-targeting and blocking controls. The specificity was further confirmed with extensive ex vivo biodistribution and histological examination.

Conclusions We report the first systematic in vivo study of intrinsically 89Zr labeled biodegradable silica nanoparticles (bMSNs), targeted for CD105 marker specificity in murine metastatic breast cancer model. The simple, versatile and easily tunable approach shows great potential for bench-to-bedside transition of personalized nanomedicine. By simple modifications, the nanoparticles can be tailored to (i) label a wide plethora of clinically relevant diagnostic and even therapeutic radioisotopes without the need for tiresome specific chelator chemistries, (ii) carry small-molecule and large biomolecular drugs concurrently for combination therapy, (iii) specifically target any tumor type by simply modifying the targeting ligand, and, (iv) auto-destruct and excrete from the body within a reasonable time period.

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Journal of Nuclear Medicine
Vol. 57, Issue supplement 2
May 1, 2016
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Engineering of intrinsically zirconium-89 radiolabeled self-destructing mesoporous silica nanostructures for in vivo tumor vasculature targeting
Shreya Goel, Feng Chen, Sixiang Shi, Hector Valdovinos, Todd Barnhart, Weibo Cai
Journal of Nuclear Medicine May 2016, 57 (supplement 2) 1151;

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Engineering of intrinsically zirconium-89 radiolabeled self-destructing mesoporous silica nanostructures for in vivo tumor vasculature targeting
Shreya Goel, Feng Chen, Sixiang Shi, Hector Valdovinos, Todd Barnhart, Weibo Cai
Journal of Nuclear Medicine May 2016, 57 (supplement 2) 1151;
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