• Archives of Pharmacal Research
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• 제28권5호
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• pp.626-635
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• 2005

Liposome as a carrier of topotecan (TPT), a promising anticancer drug, has been reported in attempt to improve the stability and antitumor activity of TPT. However, the biodistr ibution pattern of TPT liposome in vivo and PEG-modified liposome containing TPT have not been studied systemically. In this paper, the in vitro stability and in vivo biodistribution behavior of several liposomes containing TPT with different lipid compositions and PEG-modification were studied. Compared with the 'fluid' liposome (S-Lip) composed of soybean phosphatidylcholine (SPC), the 'solid' liposome (H-Lip) composed of hydrogenated soybean phosphatidylcholine HSPC decreased the leaking efficiency of TPT from liposome and enhanced the stability of liposome in fetal bovine serum (FBS) or human blood plasma (HBP). The results of biodistribution studies in S$_{180}$ tumor-bearing mice showed that liposomal encapsulation increased the concentrations of total TPT and the ratio of lactone form in plasma. Compared with free TPT, S-Lip and H-Lip resulted in 5- and 19- fold increase in the area under the curve (AUC$_{0\rightarrow\propto}$), respectively. PEG- modified H-Lip (H-PEG) showed 3.7-fold increase in AUC$_{0\rightarrow\propto}$ compared with H-Lip, but there was no significant increase in t$_{1/2}$ and AUC$_{0\rightarrow\propto}$ for PEG-modified S-Lip (S-PEG) compared with S-Lip. Moreover, the liposomal encapsulation changed the biodistribution behavior, and H-Lip and H-PEG dramatically increased the accumulation of TPT in tumor, and the relative tumor uptake ratios were 3.4 and 4.3 compared with free drug, respectively. There was also a marked increase in the distribution of TPT in lung when the drug was encapsulated into H-Lip and H-PEG. Moreover, H-PEG decreased the accumulation of TPT in bore marrow compared with unmodified H-Lip. All these results indicated that the membrane fluidity of liposome has an important effect on in vitro stability and in vivo biodistribution pattern of liposomes containing TPT, and PEG-modified 'solid' liposome may be an efficient carrier of TPT.

• Investigative Magnetic Resonance Imaging
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• 제23권1호
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• pp.34-37
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• 2019

Gadolinium contrast agents (CAs) are integral components of clinical magnetic resonance imaging (MRI). However, safety concerns have arisen regarding the use of gadolinium CAs, due to their association with nephrogenic systemic fibrosis (NSF). Furthermore, recently the long-term retention of $Gd^{3+}-based$ CAs in brains patients with normal renal function raised another possible safety issue. The safety concerns of $Gd^{3+}-based$ CAs have been based on the ligand structure of $Gd^{3+}-based$ CAs, and findings that $Gd^{3+}-based$ CAs with linear ligand structures showed much higher incidences of NSF and brain retention of CAs than $Gd^{3+}-based$ CAs with macrocyclic ligand structure. In the current study, we report the in vivo biodistribution profile of a new highly stable multifunctional $Gd^{3+}-based$ CA, with macrocyclic ligand structure (HNP-2006). MR imaging using HNP-2006 demonstrated a significant contrast enhancement in many different organs. Furthermore, the contrast enhanced tumor imaging using HNP-2006 confirmed that this new macrocyclic CA can be used for detecting tumor in the central nervous system. Therefore, this new multifunctional HNP-2006 with macrocyclic ligand structure shows great promise for whole-body clinical application.

• International Journal of Stem Cells
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• 제16권4호
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• pp.415-424
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• 2023

Therapeutic efficacy of mesenchymal stem cells (MSCs) is determined by biodistribution and engraftment in vivo. Compared to intravenous infusion, biodistribution of locally transplanted MSCs are partially understood. Here, we performed a pharmacokinetics (PK) study of MSCs after local transplantation. We grafted human MSCs into the brains of immune-compromised nude mice. Then we extracted genomic DNA from brains, lungs, and livers after transplantation over a month. Using quantitative polymerase chain reaction with human Alu-specific primers, we analyzed biodistribution of the transplanted cells. To evaluate the role of residual immune response in the brain, MSCs expressing a cytosine deaminase (MSCs/CD) were used to ablate resident immune cells at the injection site. The majority of the Alu signals mostly remained at the injection site and decreased over a week, finally becoming undetectable after one month. Negligible signals were transiently detected in the lung and liver during the first week. Suppression of Iba1-positive microglia in the vicinity of the injection site using MSCs/CD prolonged the presence of the Alu signals. After local transplantation in xenograft animal models, human MSCs remain predominantly near the injection site for limited time without disseminating to other organs. Transplantation of human MSCs can locally elicit an immune response in immune compromised animals, and suppressing resident immune cells can prolong the presence of transplanted cells. Our study provides valuable insights into the in vivo fate of locally transplanted stem cells and a local delivery is effective to achieve desired dosages for neurological diseases.

• 방사선산업학회지
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• 제12권4호
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• pp.355-363
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• 2018

A novel $N_3S_1$ chelate, Pro-Lys-Cys (PKC) to cyclic RGD to radiolabel with $^{99m}Tc$ was conjugated in an effort to decrease the high intestinal accumulation observed for $^{99m}Tc$-labeled PGC-RGD. The target specificity of the resulting PKC-RGD was similar to that of PGC-RGD as determined by a cell binding assay and a competition binding assay. The $^{99m}Tc$ radiolabeling of PKC-RGD resulted in radiochemical yields of 98% under mild conditions at high specific activities. Biodistribution data in normal mice clearly showed a significant decrease in intestinal uptake at 2 h postinjection for the $^{99m}Tc-PKC-c$ (RGDyK) compared to the $^{99m}Tc-GC-c$ (RGDyK) (from $19.65%ID{\cdot}g^{-1}$ to $7.31%ID{\cdot}g^{-1}$ for the GI tract). The $^{99m}Tc-PKC-c$ (RGDyK) biodistribution was also shown by a higher retention of radioactivity in the whole body, but with kidney accumulation over 8-fold higher than observed with $^{99m}Tc-PGC-c$ (RGDyK) at 2 h ($12.62%ID{\cdot}g^{-1}$ for PKC-RGD and $1.54%ID{\cdot}g^{-1}$ for PGC-RGD, respectively). These results show that the biodistribution may be altered especially concerning lipophilicity resulting in renal rather than hepatobiliary excretion. This comparative study made it possible to explore the effects of lipophilicity on the biodistribution of $^{99m}Tc$-labeled c (RGDyK) through the use of different tripeptide $N_3S_1$ chelators. Therefore, $^{99m}Tc-PKC-c$ (RGDyK) may be an attractive alternative for the in vivo imaging of integrin receptors.

• Advances in nano research
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• 제10권5호
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• pp.461-470
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• 2021

Infection is one of the major mortality causes throughout the globe. Nuclear medicine plays an important role in diagnosis of deep infections such as osteomyelitis, arthritis infection, heart valve and heart prosthesis infections. Techniques such as labeled leukocytes are sensitive and selective for tracking the inflammations but they are not suitable for differentiating infection from inflammation. Anionic linear-globular dendrimer-G₂ was synthesized then conjugation to gemifloxacin antibiotic. The structures were identified by FT-IR, ¹H-NMR, C-NMR, LC-MS and DLS. The toxicity of gemifloxacin and dendrimer-gemifloxacin complex was compared by MTT test. Dendrimer-G₂-gemifloxacin was labeled by Technetium-99m and its in-vitro stability and radiochemical purity were investigated. In-vivo biodistribution and SPECT imaging were studied in a rabbit model. Identify and verify the structure of the each object was confirmed by FT-IR, ¹H-NMR, C-NMR and LC-MS, also, the size and charge of this compound were 128 nm and -3/68 mv respectively. MTT test showed less toxicity of the dendrimer-G₂-gemifloxacin than free gemifluxacin (P < 0.001). Radiochemical yield was > %98. Human serum stability was 84% up to 24 h. Biodistribution study at 50 min, 24 and 48 h showed that the complex is significantly absorbed by the intestine and accumulation in the lungs and affects them, finally excreted through the kidneys, biodistribution results are consistent with results from full image means of SPECT/CT technique.

• Macromolecular Research
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• 제11권1호
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• pp.19-24
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• 2003

Polymeric gene delivery system attracts profound attention as it shows less toxicity, versatility, and reasonable gene expression efficiency. Terplex system, a synthetic biopolymeric gene delivery system consisting of stearyl poly-L-lysine (stearyl-PLL) and low density lipoprotein (LDL) was evaluated for its body distribution of gene expression of exogenously administered pDNA after tail-vein injection in mice. Kidney and spleen are two major organs with highest gene expression, whereas liver and heart showed marginal gene expression among the organs examined. Hemolytic effect of the terplex system was evaluated using human red blood cells, where terplex system did not cause significant hemolysis at the concentrations above the experimental ranges, although unmodified PLL or stearyl-PLL without LDL did. Serum stability of terplex system against enzymatic degradation was also significantly enhanced, presumably due to the steric stabilization from the polymers. Based on these findings and along with its high in vitro transfection efficiency, terplex system could serve as a safe and efficient polymeric gene delivery system with many applications for the in vivo gene therapy.

• Journal of Microbiology and Biotechnology
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• 제25권6호
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• pp.863-871
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• 2015

Bifidobacterium longum subsp. longum BBMN68, isolated from centenarians in Guangxi, China, has been proved to be a promising probiotic strain for its health benefits. In this study, the biodistribution of this strain in the rat gut was first investigated using the quantitative realtime PCR assay and propidium monoazide. Strain-specific primers were originally designed based on the BBMN68 genome sequence. Healthy rats were orally inoculated with either a single dose of BBMN68 (10¹⁰ colony-forming units/kg), or with one dose per day for 7 days and bacterial concentrations were analyzed in detail from the intestinal contents and feces of four different gut locations, including stomach, small intestine, colon, and rectum. Results indicated that strain BBMN68 could overcome the rigors of passage through the upper gastrointestinal tract and transiently accumulate in the colon, even though survival in the stomach and small intestine was not high. A good level of BBMN8 could stay in vivo for 72 h following a 7-day oral administration, and a daily administration is suggested for a considerable and continuous population of BBMN68 to be maintained in the host intestine.

• Archives of Pharmacal Research
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• 제26권6호
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• pp.493-498
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• 2003

In this study we have investigated the pharmacokinetics and tissue distribution of GX-12, a multiple plasmid DNA vaccine for the treatment of HIV-1 infection. Plasmid DNA was rapidly degraded in blood with a half-life of 1.34 min and was no longer detectable at 90 min after intravenous injection in mice. After intramuscular injection, plasmid DNA concentration in the injection site rapidly declined to less than 1 ％ of the initial concentration by 90 min post-injection. However, sub-picogram levels (per mg tissue) were occasionally detected for several days after injection. The relative proportions of the individual plasm ids of GX-12 remained relatively constant at the injection site until 90 min post-injection. The concentration of plasmid DNA in tissues other than the injection site peaked at 90 min post-injection and decreased to undetectable levels at 8 h post-injection. The rapid in vivo degradation of GX-12 and absence of persistence in non-target tissues suggest that the risk of potential gene-related toxicities by GX-12 administration, such as expression in non-target tissues, insertional mutagenesis and germline transmission, is minimal.

• Journal of Pharmaceutical Investigation
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• 제39권5호
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• pp.359-366
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• 2009

In this study, paclitaxel-loaded lipid nanosuspension (PxLN) was prepared and the in vivo profiles after intravenous administration in rats were investigated. We compared the manufacturing processes depending on the temperature: PxLN-H for a hot homogenization process and PxLN-C for solidification of lipid-drug mixtures by liquid nitrogen. Both formulations showed submicron size distribution and the similar drug loading efficiency of about 70%. In vitro release of PxLNs and Taxol$^{(R)}$ performed by a dialysis diffusion method showed similar pattern for PxLN-H and Taxol$^{(R)}$, but the reduced release profile for PxLN-C. PxLN or Taxol$^{(R)}$ was intravenously administered to the rats at a dose of 5 mg/kg as paclitaxel. The drug in blood samples were assayed by the HPLC/MS/MS method. The AUC$_t$ of PxLN-H was 3.4-fold greater than that of Taxol$^{(R)}$. PxLN-H gave higher biodistribution in all tissues than did Taxol$^{(R)}$. In addition, it maintained the higher drug concentration for 12 h. This lipid nanosuspension might be a promising candidate for an alternative formulation for the parenteral delivery of poorly water-soluble paclitaxel.

• 대한방사성의약품학회지
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• 제5권1호
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• pp.11-17
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• 2019

Recently, antibody-like scaffold proteins have received a great deal of interest in diagnosis and therapy applications because of their intrinsic features that are often required for tumor imaging and therapy. Intrinsic issues that are associated with therapeutic application of antibody-like scaffold proteins, particularly in cancer treatment, include an efficient and straightforward radiolabeling for understanding in vivo biodistribution and excretion route, and monitoring therapeutic responses. Herein, we report an efficient and straightforward method for radiolabeling of antibody-like scaffold proteins with the $[^{99m}Tc(OH_2)_3(CO)_3]^+$ ($^{99m}Tc$-tricarbonyl) by using a site-specific direct labeling method via hexahistidine-tag, which is a widely used for general purification of recombinant proteins with His-affinity chromatography. Repebody is a new class of antibody-like scaffold protein that consists of highly diverse leucine-rich repeat (LRR) modules. Although all possible biomedical applications with repebody are ongoing, it's in vivo biodistribution and excretion pathway has not yet been explored. In this study, hexahistidine ($His_6$)-tag bearing repebody (rEgH9) was labeled with [$^{99m}Tc$]-tricarbonyl. Repebody protein was radiolabeled with high radiolabeling efficiency (>90%) and radiolabeled compound was more than 99% pure after purification. These results clearly demonstrate that the present radiolabeling method will be useful molecular imaging study.