TY - JOUR
T1 - Ultrasmall, elementary and highly translational nanoparticle X-ray contrast media from amphiphilic iodinated statistical copolymers
AU - Su, Lu
AU - Dalby, Kellie S.
AU - Luehmann, Hannah
AU - Elkassih, Sussana A.
AU - Cho, Sangho
AU - He, Xun
AU - Detering, Lisa
AU - Lin, Yen Nan
AU - Kang, Nari
AU - Moore, Dennis A.
AU - Laforest, Richard
AU - Sun, Guorong
AU - Liu, Yongjian
AU - Wooley, Karen L.
N1 - Funding Information:
Given the facts that ICP-2 showed a good balance between high solution iodine concentration and low viscosity, long term thermodynamic stability, and unimodal distribution with narrow dispersity in MQ water, DOTA-ICP (Table 1) was synthesized by using DOTA-CTA and following the RAFT copolymerization protocol of ICP-2 (Scheme 1B and Supporting Information Fig. S12). The 64Cu radiolabeling result with specific activity of 0.037 MBq/μg polymer supported the successful introduction of DOTA that served as chelator for 64Cu towards PET/CT dual-modality imaging. Interestingly, although the THF-SEC of DOTA-ICP (Fig. S12A) indicated its Mn, THF-SEC should be smaller than ICP-2, the measured value (67.0 kDa) was ca. 48% larger than the Mn, THF-SEC of ICP-2 (45.2 kDa), which was significantly different from the DMF-SEC (Table S1) and the DMF-DLS (Fig. 3) characterizations. The DOTA-ICP showed similar DSC profile (Fig. S12B) as ICP-2, suggesting an effective “delocalization” of TIBEAs that was further validated through its high water solubility of >600 mg polymer/mL H2O. As depicted in Fig. 3, the Rh, water of DOTA-ICP-fabricated NPs was close to the NPs from ICP-2. It is noteworthy that the Rhs of DOTA-ICP in THF and chloroform (CHCl3) were different from other ICPs, which indicated the formation of nanoscopic assemblies in these two organic solvents. This observation also solved the Mn, THF-SEC variation issue (vide supra) as the obtained in-line refractive index increment (dn/dc) value in THF was not solely from DOTA-ICP single chains. The X-ray attenuation of the DOTA-ICP NPs was evaluated by acquiring images of a series of DOTA-ICP solutions with increased concentrations and subsequently converting them to Hounsfield Units (HU) for quantitative analysis. A linear correlation between DOTA-ICP concentration and the calculated CT attenuation was observed (Supporting Information Fig. S13), demonstrating that ICPs can function as contrast agents for quantitative CT studies.
Funding Information:
We gratefully acknowledge financial support from the National Science Foundation (DMR-1905818 and REU Grant CHE-1062840, USA) and the Robert A. Welch Foundation through the W. T. Doherty-Welch Chair in Chemistry (A-0001, USA). The Laboratory for Synthetic-Biologic Interactions (LSBI) at Texas A&M University (College Station, TX, USA) is also acknowledged. We thank Prof. Chong Cheng and Dr. Yukun Li (University at Buffalo, The State University of New York, Buffalo, NY, USA) for assisting with DMF-SEC characterizations, Prof. Ilja Voets and Lafayette de Windt (Eindhoven University of Technology, Eindhoven, The Netherlands) for discussion of SLS/DLS results.
Publisher Copyright:
© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences
PY - 2023/4
Y1 - 2023/4
N2 - To expand the single-dose duration over which noninvasive clinical and preclinical cancer imaging can be conducted with high sensitivity, and well-defined spatial and temporal resolutions, a facile strategy to prepare ultrasmall nanoparticulate X-ray contrast media (nano-XRCM) as dual-modality imaging agents for positron emission tomography (PET) and computed tomography (CT) has been established. Synthesized from controlled copolymerization of triiodobenzoyl ethyl acrylate and oligo(ethylene oxide) acrylate monomers, the amphiphilic statistical iodocopolymers (ICPs) could directly dissolve in water to afford thermodynamically stable solutions with high aqueous iodine concentrations (>140 mg iodine/mL water) and comparable viscosities to conventional small molecule XRCM. The formation of ultrasmall iodinated nanoparticles with hydrodynamic diameters of ca. 10 nm in water was confirmed by dynamic and static light scattering techniques. In a breast cancer mouse model, in vivo biodistribution studies revealed that the 64Cu-chelator-functionalized iodinated nano-XRCM exhibited extended blood residency and higher tumor accumulation compared to typical small molecule imaging agents. PET/CT imaging of tumor over 3 days showed good correlation between PET and CT signals, while CT imaging allowed continuous observation of tumor retention even after 10 days post-injection, enabling longitudinal monitoring of tumor retention for imaging or potentially therapeutic effect after a single administration of nano-XRCM.
AB - To expand the single-dose duration over which noninvasive clinical and preclinical cancer imaging can be conducted with high sensitivity, and well-defined spatial and temporal resolutions, a facile strategy to prepare ultrasmall nanoparticulate X-ray contrast media (nano-XRCM) as dual-modality imaging agents for positron emission tomography (PET) and computed tomography (CT) has been established. Synthesized from controlled copolymerization of triiodobenzoyl ethyl acrylate and oligo(ethylene oxide) acrylate monomers, the amphiphilic statistical iodocopolymers (ICPs) could directly dissolve in water to afford thermodynamically stable solutions with high aqueous iodine concentrations (>140 mg iodine/mL water) and comparable viscosities to conventional small molecule XRCM. The formation of ultrasmall iodinated nanoparticles with hydrodynamic diameters of ca. 10 nm in water was confirmed by dynamic and static light scattering techniques. In a breast cancer mouse model, in vivo biodistribution studies revealed that the 64Cu-chelator-functionalized iodinated nano-XRCM exhibited extended blood residency and higher tumor accumulation compared to typical small molecule imaging agents. PET/CT imaging of tumor over 3 days showed good correlation between PET and CT signals, while CT imaging allowed continuous observation of tumor retention even after 10 days post-injection, enabling longitudinal monitoring of tumor retention for imaging or potentially therapeutic effect after a single administration of nano-XRCM.
KW - Amphiphilic statistical iodocopolymer
KW - CT
KW - Longitudinal tumor monitoring
KW - PET/CT
KW - Ultrasmall nanoassembly
KW - X-ray contrast media
UR - http://www.scopus.com/inward/record.url?scp=85139294971&partnerID=8YFLogxK
U2 - 10.1016/j.apsb.2022.09.009
DO - 10.1016/j.apsb.2022.09.009
M3 - Article
C2 - 37139426
AN - SCOPUS:85139294971
SN - 2211-3835
VL - 13
SP - 1660
EP - 1670
JO - Acta Pharmaceutica Sinica B
JF - Acta Pharmaceutica Sinica B
IS - 4
ER -