9 research outputs found
Novel Self-Forming Nanosized DDS Particles for BNCT: Utilizing A Hydrophobic Boron Cluster and Its Molecular Glue Effect
BNCT is a non-invasive cancer therapy that allows for cancer cell death without harming adjacent cells. However, the application is limited, owing to the challenges of working with clinically approved boron (B) compounds and drug delivery systems (DDS). To address the issues, we developed self-forming nanoparticles consisting of a biodegradable polymer, namely, "AB-type Lactosome (AB-Lac)" loaded with B compounds. Three carborane isomers (o-, m-, and p-carborane) and three related alkylated derivatives, i.e., 1,2-dimethy-o-carborane (diC1-Carb), 1,2-dihexyl-o-carborane (diC6-Carb), and 1,2-didodecyl-o-carborane (diC12-Carb), were separately loaded. diC6-Carb was highly loaded with AB-Lac particles, and their stability indicated the "molecular glue" effect. The efficiency of in vitro B uptake of diC6-Carb for BNCT was confirmed at non-cytotoxic concentration in several cancer cell lines. In vivo/ex vivo biodistribution studies indicated that the AB-Lac particles were remarkably accumulated within 72 h post-injection in the tumor lesions of mice bearing syngeneic breast cancer (4T1) cells, but the maximum accumulation was reached at 12 h. In ex vivo B biodistribution, the ratios of tumor/normal tissue (T/N) and tumor/blood (T/Bl) of the diC6-Carb-loaded particles remained stably high up to 72 h. Therefore, we propose the diC6-Carb-loaded AB-Lac particles as a promising candidate medicine for BNCT
The Function of β2-glycoprotein I in Angiogenesis and Its in Vivo Distribution in Tumor Xenografts
Intact β2-glycoprotein I (iβ2GPI) is a glycoprotein that regulates coagulation and fibrinolysis. Nicked β2GPI (nβ2GPI) possesses an angiogenic property at a relatively low concentration, and an antiangiogenic property at a high concentration. Here we investigated the functions of βi 2GPI and nβ2GPI in vascular endothelial growth factor (VEGF)-A-induced endothelial cell proliferation and tube formation. We used noninvasive PET imaging to analyze the in vivo distribution of intravenously injected β2GPI variants in tumor lesions in mice. iβ2GPI was incubated with plasmin to obtain nβ2GPI, and its N-terminal sequence was analyzed. nβ2GPI had at least one other cleavage site upstream of the β2GPIʼs domain V, whereas the former plasmin-cleavage site locates between K317 and T318. Both of intact and nicked β2GPI significantly inhibited the VEGF-A-induced cell proliferation and the tube formation of human umbilical vein endothelial cells (HUVECs). PET imaging visualized considerably distributed intensities of all tested β2GPI variants in tumor lesions of pancreatic tumor cell-xenografts. These results indicate that β2GPI may be physiologically and pathophysiologically important in the regulation of not only coagulation and fibrinolysis, but also angiogenesis
A Novel 89Zr-labeled DDS Device Utilizing Human IgG Variant (scFv): “Lactosome” Nanoparticle-Based Theranostics for PET Imaging and Targeted Therapy
“Theranostics,” a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel 89Zr-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, “Lactosome” nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the “89Zr-labeled CPP and TPP-loaded Lactosome particles” and future directions based on important milestones and recent developments in this platform
In vivo tracking transplanted cardiomyocytes derived from human induced pluripotent stem cells using nuclear medicine imaging
Introduction: Transplantation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a promising treatment for heart failure. Information on long-term cell engraftment after transplantation is clinically important. However, clinically applicable evaluation methods have not yet been established.
Methods: In this study, to noninvasively assess transplanted cell engraftment, human SLC5A5, which encodes a sodium/iodide symporter (NIS) that transports radioactive tracers such as 125I, 18F-tetrafluoroborate (TFB), and 99mTc-pertechnetate (99mTcO4−), was transduced into human induced pluripotent stem cells (iPSCs), and nuclear medicine imaging was used to track engrafted human iPSC-CMs.
Results: To evaluate the pluripotency of NIS-expressing human iPSCs, they were subcutaneously transplanted into immunodeficient rats. Teratomas were detected by 99mTcO4− single photon emission computed tomography (SPECT/CT) imaging. NIS expression and the uptake ability of 125I were maintained in purified human iPSC-CMs. NIS-expressing human iPSC-CMs transplanted into immunodeficient rats could be detected over time using 99mTcO4− SPECT/CT imaging. Unexpectedly, NIS expression affected cell proliferation of human iPSCs and iPSC-derived cells.
Discussion: Such functionally designed iPSC-CMs have potential clinical applications as a noninvasive method of grafted cell evaluation, but further studies are needed to determine the effects of NIS transduction on cellular characteristics and functions
The Function of β2-glycoprotein I in Angiogenesis and Its in Vivo Distribution in Tumor Xenografts
In vivo tracking transplanted cardiomyocytes derived from human induced pluripotent stem cells using nuclear medicine imaging
Positron Emission Tomography to Elucidate Pharmacokinetic Differences of Regioisomeric Retinoid X Receptor Agonists
RXR
partial agonist NEt-4IB (<b>2a</b>, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic
acid: EC<sub>50</sub> = 169 nM, <i>E</i><sub>max</sub> =
55%) showed a blood concentration higher than its <i>E</i><sub>max</sub> after single oral administration at 30 mg/kg to mice,
and repeated oral administration at 10 mg/kg/day to KK-A<sup>y</sup> mice afforded antitype 2 diabetes activity without the side effects
caused by RXR full agonists. However, RXR full agonist NEt-3IB (<b>1a</b>), in which the isobutoxy and isopropyl groups of <b>2a</b> are interchanged, gave a much lower blood concentration
than <b>2a</b>. Here we used positron emission tomography (PET)
with tracers [<sup>11</sup>C]<b>1a</b>, [<sup>11</sup>C]<b>2a</b> and fluorinated derivatives [<sup>18</sup>F]<b>1b</b>, [<sup>18</sup>F]<b>2b</b>, which have longer half-lives,
to examine the reason why <b>1a</b> and <b>2a</b> exhibited
significantly different blood concentrations. As a result, the reason
for the high blood concentration of <b>2a</b> after oral administration
was found to be linked to higher intestinal absorbability together
with lower biliary excretion, compared with <b>1a</b>
Synthesis of <sup>11</sup>C‑Labeled RXR Partial Agonist 1‑[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic Acid (CBt-PMN) by Direct [<sup>11</sup>C]Carbon Dioxide Fixation via Organolithiation of Trialkyltin Precursor and PET Imaging Thereof
The
retinoid X receptor (RXR) partial agonist 1-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic
acid (<b>1</b>; CBt-PMN, <i>E</i><sub>max</sub> =
75%, EC<sub>50</sub> = 143 nM) is a candidate for treatment of central
nervous system (CNS) diseases such as Alzheimer’s and Parkinson’s
diseases based on reports that RXR-full agonist 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic
acid (bexarotene) shows therapeutic effects on these disease in rodent
models. Here, we synthesized carbon-11-labeled ([<sup>11</sup>C]<b>1</b>) as a tracer for positron emission tomography (PET) and
used it in a PET imaging study to examine the brain uptake and biodistribution
of <b>1</b>. We found that <sup>11</sup>CO<sub>2</sub> fixation
after tin–lithium exchange at −20 °C afforded [<sup>11</sup>C]<b>1</b>. This methodology may also be useful for
synthesizing <sup>11</sup>CO<sub>2</sub>H-PET tracer derivatives of
other compounds bearing π-rich heterocyclic rings. A PET/CT
imaging study of [<sup>11</sup>C]<b>1</b> in mice indicated <b>1</b> is distributed to the brain and is thus a candidate for
treatment of CNS diseases