Multilayer Microcapsules with Shell-Chelated ⁸⁹Zr for PET Imaging and Controlled Delivery

Abstract

Radionuclide-functionalized drug delivery vehicles capable of being imaged via positron emission tomography (PET) are of increasing interest in the biomedical field as they can reveal the in vivo behavior of encapsulated therapeutics with high sensitivity. However, the majority of current PET-guided theranostic agents suffer from poor retention of radiometal over time, low drug loading capacities, and time-limited PET imaging capability. To overcome these challenges, we have developed hollow microcapsules with a thin (<100 nm) multilayer shell as advanced theranostic delivery systems for multiday PET tracking in vivo. The 3 μm capsules were fabricated via the aqueous multilayer assembly of a natural antioxidant, tannic acid (TA), and a poly(N-vinylpyrrolidone) (PVPON) copolymer containing monomer units functionalized with deferoxamine (DFO) to chelate the 89 Zr radionuclide, which has a half-life of 3.3 days. We have found using radiochromatography that (TA/PVPON-DFO) 6 capsules retained on average 17% more 89 Zr than their (TA/PVPON) 6 counterparts, which suggests that the covalent attachment of the DFO to PVPON provides stable 89 Zr chelation. In vivo PET imaging studies performed in mice demonstrated that excellent stability and imaging contrast were still present 7 days postinjection. Animal biodistribution analyses showed that capsules primarily accumulated in the spleen, liver, and lungs with negligible accumulation in the femur, with the latter confirming the stable binding of the radiotracer to the capsule walls. The application of therapeutic ultrasound (US) (60 s of 20 kHz US at 120 W cm −2 ) to Zr-functionalized capsules could release the hydrophilic anticancer drug doxorubicin from the capsules in the therapeutic amounts. Polymeric capsules with the capability of extended in vivo PET-based tracking and US-induced drug release provide an advanced platform for development of precisiontargeted therapeutic carriers and could aid in the development of more effective drug delivery systems.

Polyelectrolyte Multilayered Capsules as Biomedical Tools

“…This type of capsule presents an improved circulation in the blood stream in relation to free doxorubicin, providing a 16-fold increase for the doxorubicin targeting in breast cancer cells. Dual triggering was also used by Kozlovskaya et al [291] with multilayers of tannic acid and poly(N-vinylpyrrolidone) containing doxorubicin and chelated on their surface with 89 Zr. This type of system offers very good properties for in vivo imaging via positron emission tomography (PET) and doxorubicin targeting tumors cell through ther- The results by Kalinechenko et al [36] evidenced that (PAH-PSS) n capsules provide a sustained release of the encapsulated doxorubicin at pH 7.4, with the decrease in the pH resulting in a burst release, probably mediated by the erosion of the capsules.…”

“…Table 5 summarizes some examples of LbL systems designed for theranostic purposes. tannic acid and poly(Nvinylpyrrolidone) doxorubicin (post-loaded by direct incubation) 89 Zr (PET imaging) anticancer Kozlovskaya et al [291] tannic acid and bovine serum albumin 225 Ac (pre-loading by radiolabeling) 89 Zr (PET imaging) anticancer Muslimov et al [292] poly-L-arginine and dextran sulfate doxorubicin (pre-loaded in CaCO 3 templates) fluorescent probes and magnetic nanoparticles (fluorescent tomography and optoacoustic signal) anticancer Novoselova et al [294] The above discussion evidences the power of LbL capsules as theranostic agents in externally triggered chemotherapy, presenting a high encapsulation efficiency and biocompatibility, and tunable drug release.…”

Integrating Antioxidant Functionality into Polymer Materials: Fundamentals, Strategies, and Applications

“…Furthermore, the hollow polymer microcapsules were unrecognizable to macrophages, in contrast to their rigid counterparts with an intact core . More recently, ultrasound stimulus was applied to provide on-demand, controlled release of DOX from PVP/TA capsules (Figure j) . In addition, intracellular protein delivery have been pursued using hollow protein/TA microcapsules .…”

Biopolymer-Based Multilayer Capsules and Beads Made via Templating: Advantages, Hurdles and Perspectives

“…Recently, biopolymercoated CaCO 3 particles were applied as local radionuclide therapy agents for melanoma treatment (Figure 13). Human serum albumin/TA-coated sub-micron CaCO 3 particles were radiolabelled with actinium-225 to increase the efficacy of α-radionuclide therapy in mice bearing B16-F10 tumours [253], as well as zirconium-89 within the shell of PEMCs and coated-CaCO 3 templates for the positron emission tomographic imaging of vehicles in vivo [253,254]. Figure 13(1) demonstrates a schematic for the radiotherapy treatment and subsequent tumour growth inhibition, while Figure 13(2) gives representative PET images of mice treated with 89 Zr-labelled LbL particles, demonstrating the retained high resolution after 14 days [253].…”

“…Nanomaterials 2021, 11, x FOR PEER REVIEW 22 of 36 mice bearing B16-F10 tumours [253], as well as zirconium-89 within the shell of PEMCs and coated-CaCO3 templates for the positron emission tomographic imaging of vehicles in vivo [253,254]. Figure 13(1) demonstrates a schematic for the radiotherapy treatment and subsequent tumour growth inhibition, while Figure 13(2) gives representative PET images of mice treated with 89 Zr-labelled LbL particles, demonstrating the retained high resolution after 14 days [253].…”