An experimental model to study the effects of a senna extract on the blood constituent labeling and biodistribution of a radiopharmaceutical in rats

ABSTRACT Cassia angustifolia Vahl (senna) is a natural product that contains sennosides, which are active components that affect the intestinal tract and induce diarrhea. Authors have shown that senna produces DNA (deoxyribonucleic acid) lesions in Escherichia coli cultures and can act as an antifungal agent. Natural drugs can alter the labeling of blood constituents with technetium-99m (^99mTc) and can affect the biodistribution of radiopharmaceuticals. In this work, we have evaluated the influence of a senna extract on the radiolabeling of blood constituents and on the biodistribution of the radiopharmaceutical sodium pertechnetate (Na^99mTcO₄) in Wistar rats. Twelve animals were treated with senna extract for 7 days. Blood samples were withdrawn from the animals and the radiolabeling procedure was carried out. The senna extract did not modify the radiolabeling of the blood constituents. A biodistributional assay was performed by administering Na^99mTcO₄ and determining its activity in different organs and in blood. The senna extract altered the biodistribution of Na^99mTcO₄ in the thyroid, liver, pancreas, lungs and blood. These results are associated with properties of the chemical substances present in the aqueous senna extract. Although these assays were performed in animals, our findings suggest that caution should be exercised when nuclear medicine examinations using Na^99mTcO₄ are conducted in patients who are using senna extract.     

Lanthanide-based nanocrystals as dual-modal probes for SPECT and X-ray CT imaging

Applications of lanthanide-based nanoparticles for bioimaging have attracted increasing attention. Herein, small size PEG-EuOF:¹⁵³Sm nanocrystals (∼5 nm) (PEG = poly(ethylene glycol)bis(carboxymethyl)ether) combined with the radioactive and X-ray absorption properties were synthesized. The distribution of the PEG-EuOF nanocrystals in living animals was studied by ex vivo radioassay, inductively coupled plasma-atomic emission spectrum (ICP-AES) analysis and in vivo SPECT imaging, which indicated that the small size PEG-EuOF:¹⁵³Sm had long blood retention time (blood half-life (t_1/2) reach to 4.65 h) and were eliminated significantly through biliary/gastrointestinal pathway in vivo. Meanwhile, benefiting from the high attenuation ability of Eu, the small size PEG-EuOF was successfully applied for lymph node CT imaging, extending the bio-applications of these small nanocrystals. The results of cytotoxicity and in vivo toxicity also showed that the PEG-EuOF nanocrystals have relatively low toxicity, which suggest their safety for in vivo imaging. The studies provide preliminary validation for the use of PEG-EuOF nanocrystals for in vivo bioimaging applications.     

Feasibility of islet magnetic resonance imaging using ferumoxytol in intraportal islet transplantation

There is a clinical need for an alternative labeling agent for magnetic resonance imaging (MRI) in islet transplantation. We aimed to evaluate the feasibility of islet MRI using ferumoxytol, which is the only clinically-available ultrasmall superparamagnetic iron oxide. We compared islet function and viability of control islets and islets labeled with ferumoxytol and/or a heparin-protamine complex (HPF). Efficacy of ferumoxytol labeling was assessed in both ex vivo and in vivo models. Labeling for 48 h with HPF, but not up to 800 μg/mL ferumoxytol, deranged ex vivo islet viability and function. The T2¹ relaxation time was optimal when islets were labeled with 800 μg/mL of ferumoxytol for 48 h. Prussian blue stain, iron content assay, transmission electron microscopy (TEM) supported internalization of ferumoxytol particles. However, the labeling intensity in the ex vivo MRI of islets labeled with ferumoxytol was much weaker than that of islets labeled with ferucarbotran. In syngeneic intraportal islet transplantation, there was a correlation between the total area of visualized islets and the transplanted islet mass. In conclusion, islet MRI using ferumoxytol was feasible in terms of in vitro and in vivo efficacy and safety. However, the weak labeling efficacy is still a hurdle for the clinical application.     

Near-infrared fluorescence imaging using organic dye nanoparticles

Near-infrared (NIR) fluorescence imaging in the 700–1000 nm wavelength range has been very attractive for early detection of cancers. Conventional NIR dyes often suffer from limitation of low brightness due to self-quenching, insufficient photo- and bioenvironmental stability, and small Stokes shift. Herein, we present a strategy of using small-molecule organic dye nanoparticles (ONPs) to encapsulate NIR dyes to enable efficient fluorescence resonance energy transfer to obtain NIR probes with remarkably enhanced performance for in vitro and in vivo imaging. In our design, host ONPs are used as not only carriers to trap and stabilize NIR dyes, but also light-harvesting agent to transfer energy to NIR dyes to enhance their brightness. In comparison with pure NIR dyes, our organic dye nanoparticles possess almost 50-fold increased brightness, large Stokes shifts (∼250 nm) and dramatically enhanced photostability. With surface modification, these NIR-emissive organic nanoparticles have water-dispersity and size- and fluorescence- stability over pH values from 2 to 10 for almost 60 days. With these superior advantages, these NIR-emissive organic nanoparticles can be used for highly efficient folic-acid aided specific targeting in vivo and ex vivo cellular imaging. Finally, during in vivo imaging, the nanoparticles show negligible toxicity. Overall, the results clearly display a potential application of using the NIR-emissive organic nanoparticles for in vitro and in vivo imaging.     

Long-term biodistribution in vivo and toxicity of radioactive/magnetic hydroxyapatite nanorods

Although nanoscale hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂; HA] has been widely investigated as a carrier in the delivery of drugs, genes, or siRNA, the in vivo toxicity of nanoscale HA is not clear and the long-term dynamic distribution in vivo has not hitherto been visualized. In this work, gadolinium-doped HA nanorods (HA:Gd) with an r₁ value of 5.49 s⁻¹ (mm)⁻¹ have been prepared by a hydrothermal method. Samarium-153 (¹⁵³Sm) was then effectively post-labeled onto the HA:Gd (¹⁵³Sm-HA:Gd) with a labeling rate of ∼100% and a radio-labeling stability in vitro of ∼100% over 48 h. The product could serve as a new dual-modality probe for SPECT and MR imaging in vivo. By means of SPECT and MRI, the HA:Gd nanorods were found to be quickly taken up by the mononuclear phagocyte system, especially the liver and spleen. The nanorods in the liver and lung tended to be eliminated within 24 h, but nanorods in the spleen behaved differently and proved difficult to excrete. In vitro studies by cell transmission electron microscopy (TEM) and methyl thiazolyl tetrazolium (MTT) assay showed good biocompatibility of the HA:Gd nanorods with HeLa cells, even at a high concentration. The indicators of body weight, histology, and serology demonstrated that the HA:Gd nanorods exhibited excellent biocompatibility in vivo for at least 61 days. Therefore, ¹⁵³Sm-HA:Gd nanorods with excellent relaxivity, γ-emission, and biosafety offer clear advantages and potential for bioapplications.     

Drug‐induced cardiomyopathy: Characterization of a rat model by [18F]FDG/PET and [99mTc]MIBI/SPECT

BackgroundDrug‐induced cardiomyopathy is a significant medical problem. Clinical diagnosis of myocardial injury is based on initial electrocardiogram, levels of circulating biomarkers, and perfusion imaging with single photon emission computed tomography (SPECT). Positron emission tomography (PET) is an alternative imaging modality that provides better resolution and sensitivity than SPECT, improves diagnostic accuracy, and allows therapeutic monitoring. The objective of this study was to assess the detection of drug‐induced cardiomyopathy by PET using 2‐deoxy‐2‐[¹⁸F]fluoro‐D‐glucose (FDG) and compare it with the conventional SPECT technique with [^99mTc]‐Sestamibi (MIBI).MethodsCardiomyopathy was induced in Sprague Dawley rats using high‐dose isoproterenol. Nuclear [¹⁸F]FDG/PET and [^99mTc]MIBI/SPECT were performed before and after isoproterenol administration. [¹⁸F]FDG (0.1 mCi, 200‐400 µL) and [^99mTc]MIBI (2 mCi, 200‐600 µL) were administered via the tail vein and imaging was performed 1 hour postinjection. Isoproterenol‐induced injury was confirmed by the plasma level of cardiac troponin and triphenyltetrazolium chloride (TTC) staining.ResultsIsoproterenol administration resulted in an increase in circulating cardiac troponin I and showed histologic damage in the myocardium. Visually, preisoproterenol and postisoproterenol images showed alterations in cardiac accumulation of [¹⁸F]FDG, but not of [^99mTc]MIBI. Image analysis revealed that myocardial uptake of [¹⁸F]FDG reduced by 60% after isoproterenol treatment, whereas that of [^99mTc]MIBI decreased by 45%.ConclusionWe conclude that [¹⁸F]FDG is a more sensitive radiotracer than [^99mTc]MIBI for imaging of drug‐induced cardiomyopathy. We theorize that isoproterenol‐induced cardiomyopathy impacts cellular metabolism more than perfusion, which results in more substantial changes in [¹⁸F]FDG uptake than in [^99mTc]MIBI accumulation in cardiac tissue.     

Gadolinium-chelate nanoparticle entrapped human mesenchymal stem cell via photochemical internalization for cancer diagnosis

To improve the gadolinium (Gd) internalization efficiency in stem cells, gadolinium-chelate nanoparticles were prepared from a pullulan derivative (pullulan-deoxycholic acid (DOCA)-diethylene triamine pentaacetic (DTPA)-Gd conjugate; PDDG) and then the PDDG was entrapped into human mesenchymal stem cells (hMSCs) by the photochemical-internalization (PCI) method for cancer diagnosis via the cancer homing property of hMSCs. The internalization efficiency of Gd in hMSCs was significantly increased to 98 ± 4 pg Gd/cell from 32 ± 2 pg Gd/cell via the PCI method. Moreover, the Gd-entrapped hMSCs revealed a low exocytosis ratio of gadolinium-chelate nanoparticles during cell division in vitro and a high cellular labeling efficiency for at least 21 days in vivo. The cancer-targeting and diagnosis effect of the Gd-entrapped hMSCs were confirmed in a small CT26 tumor-bearing mice model. The stem cells detected an early tumor (∼3 mm³) within 2 h using 4.7-T MR and optical imaging. The results demonstrated that the PCI-mediated internalization of Gd-incorporated nanoparticles into hMSCs is a promising protocol for efficient cell labeling and tracking.     

Dragon fruit-like biocage as an iron trapping nanoplatform for high efficiency targeted cancer multimodality imaging

Natural biopolymer based multifunctional nanomaterials are perfect candidates for multimodality imaging and therapeutic applications. Conventional methods of building multimodal imaging probe require either cross-linking manners to increase its in vivo stability or attach a target module to realize targeted imaging. In this study, the intrinsic photoacoustic signals and the native strong chelating properties with metal ions of melanin nanoparticle (MNP), and transferrin receptor 1 (TfR1) targeting ability of apoferritin (APF) was employed to construct an efficient nanoplatform (AMF) without tedious assembling process. Smart APF shell significantly increased metal ions loading (molar ratio of 1:800, APF/Fe³⁺) and therefore improved magnetic resonance imaging (MRI) sensitivity. Moreover, synergistic use of Fe³⁺ and APF contributed to high photoacounstic imaging (PAI) sensitivity. AMF showed excellent bio-stability and presented good in vivo multimodality imaging (PET/MRI/PAI) properties (good tumor uptake, high specificity and high tumor contrast) in HT29 tumor because of its targeting property combined with the enhanced permeability and retention (EPR) effect, making it promising in theranostics and translational nanomedicine.     

Nanoparticle toxicity assessment using an in vitro 3-D kidney organoid culture model

Nanocarriers and nanoparticles remain an intense pharmaceutical and medical imaging technology interest. Their entry into clinical use is hampered by the lack of reliable in vitro models that accurately predict in vivo toxicity. This study evaluates a 3-D kidney organoid proximal tubule culture to assess in vitro toxicity of the hydroxylated generation-5 PAMAM dendrimer (G5-OH) compared to previously published preclinical in vivo rodent nephrotoxicity data. 3-D kidney proximal tubule cultures were created using isolated murine proximal tubule fractions suspended in a biomedical grade hyaluronic acid-based hydrogel. Toxicity in these cultures to neutral G5-OH dendrimer nanoparticles and gold nanoparticles in vitro was assessed using clinical biomarker generation. Neutral PAMAM nanoparticle dendrimers elicit in vivo-relevant kidney biomarkers and cell viability in a 3-D kidney organoid culture that closely reflect toxicity markers reported in vivo in rodent nephrotoxicity models exposed to this same nanoparticle.     

Graphene oxide-BaGdF5 nanocomposites for multi-modal imaging and photothermal therapy

By using a solvothermal method in the presence of polyethylene glycol (PEG), BaGdF₅ nanoparticles are firmly attached on the surface of graphene oxide (GO) nanosheets to form the GO/BaGdF₅/PEG nanocomposites. The resulting GO/BaGdF₅/PEG shows low cytotoxicity, positive magnetic resonance (MR) contrast effect and better X-ray attenuation property than Iohexol, which enables effective dual-modality MR and X-ray computed tomography (CT) imaging of the tumor model in vivo. The enhanced near-infrared absorbance, good photothermal stability and efficient tumor passive targeting of GO/BaGdF₅/PEG result in the highly efficient photothermal ablation of tumor in vivo after intravenous injection of GO/BaGdF₅/PEG and the following 808-nm laser irradiation (0.5 W/cm²). The histological and biochemical analysis data reveal no perceptible toxicity of GO/BaGdF₅/PEG in mice after treatment. These results indicate potential application of GO/BaGdF₅/PEG in dual-modality MR/CT imaging and photothermal therapy of cancers.     

Lesion based diagnostic performance of dual phase <Superscript>99m</Superscript>Tc-MIBI SPECT/CT imaging and ultrasonography in patients with secondary hyperparathyroidism

Background

We aimed to evaluate the diagnostic performance of ^99mTc-MIBI SPECT/CT and ultrasonography in patients with secondary hyperparathyroidism (SHPT), and explored the factors that affect the diagnostic performance.

Methods

^99mTc-MIBI SPECT/CT and ultrasonography were performed in 50 patients with SHPT within 1 month before they underwent surgery. Imaging results were confirmed by the pathology. Pearson correlation analysis was used to determine the correlation of PTH level with clinical data. The optimal cutoff value for predicting positive ^99mTc-MIBI results was evaluated by ROC analysis in lesions diameter.

Results

Forty-nine patients had a positive ^99mTc-MIBI imaging results and 39 patients had positive ultrasonography results. The sensitivities of ^99mTc-MIBI and ultrasonography were 98.00% and 78.00%, respectively. A total of 199 lesions were resected in 50 patients. Among them, 183 lesions were proved to be parathyroid hyperplasia. On per-lesion basis analysis, the sensitivity and specificity of ^99mTc-MIBI and ultrasonography were 59.34% and 75.00% vs 46.24% and 80.00%, respectively. The Pearson correlation analysis showed that the serum AKP and PTH level had a significant linear association (r?=?0.699, P?<?0.001). The lesion diameter was a statistically significant predictive factor in predicting positive ^99mTc-MIBI SPECT/CT. The optimal cutoff value for predicting positive ^99mTc-MIBI results evaluated by ROC analysis in lesions diameter was 8.05 mm.

Conclusion

Dual phase ^99mTc-MIBI SPECT/CT imaging had a higher sensitivity in patients with SHPT than ultrasonography. Therefore, using ^99mTc-MIBI positioning the lesion could be an effective method pre-surgical in patients with SHPT.

     

Ultra-small BaGdF5-based upconversion nanoparticles as drug carriers and multimodal imaging probes

A new type of drug-delivery system (DDS) was constructed, in which the anti-cancer drug doxorubicin (DOX) was conjugated to the ultra-small sized (sub-10 nm) BaGdF₅:Yb³⁺/Tm³⁺ based upconversion nanoparticles (UCNPs). This multifunctional DDS simultaneously possesses drug delivery and optical/magnetic/X-ray computed tomography imaging capabilities. The DOX can be selectively released by cleavage of hydrazone bonds in acidic environment, which shows a pH-triggered drug release behavior. The MTT assay shows these DOX-conjugated UCNPs exhibit obvious cytotoxic effect on HeLa cells. Moreover, to improve the upconversion luminescence intensity, core–shell structured UCNPs were constructed. The in vitro upconversion luminescence images of these UCNPs uptaken by HeLa cells show bright emission with high contrast. In addition, these UCNPs were further explored for T₁-weighted magnetic resonance (MR) and X-ray computed tomography (CT) imaging in vitro. Long-term in vivo toxicity studies indicated that mice intravenously injected with 10 mg/kg of UCNPs survived for 40 days without any apparent adverse effects to their health. The results indicate that this multifunctional drug-delivery system with optimized size, excellent optical/MR/CT trimodal imaging capabilities, and pH-triggered drug release property is expected to be a promising platform for simultaneous cancer therapy and bioimaging.     

Tumor targeting HPMA-porphyrin-99mTc copolymer molecular imaging agent

Porphyrins typically show preferential uptake and retention by tumor tissues via receptor-mediated endocytosis of low-density lipoproteins. To investigate the relative importance of active and passive targeting strategies, the synthesis, characterization, in vitro uptake, and in vivo biodistribution of specific targeting porphyrin HPMA [HPMA: N-(2-hydroxypropyl)methacrylamide] copolymer tracer poly(HPMA)-porphyrin-DTPA-^99mTc (DTPA: diethylenetriaminepentaacetic acid), nonspecific targeting HPMA copolymer tracer poly(HPMA)-DTPA-^99mTc, and nontargeting tracer DTPA-^99mTc are described in this study. The results showed that the cellular accumulation of poly(HPMA)-porphyrin-DTPA-^99mTc complex was found to be time-dependent. The uptake of poly(HPMA)-porphyrin-DTPA-^99mTc was significantly higher than that of poly(HPMA)-DTPA-^99mTc, indicating that uptake of the poly(HPMA)-porphyrin-DTPA-^99mTc was active binding. The uptake of poly(HPMA)-DTPA-^99mTc was significantly higher than that of DTPA-^99mTc, suggesting that uptake of the poly(HPMA)-DTPA-^99mTc was passive binding. Twenty-four hour necropsy data in the hepatocellular carcinoma tumor model showed significantly higher (p < 0.001) tumor localization for poly(HPMA)-porphyrin-DTPA-^99mTc (5.18 ± 0.50% ID/g [percentage injected dose per gram tissue]) compared with poly(HPMA)-DTPA-^99mTc (2.69 ± 0.15% ID/g) and DTPA-^99mTc (0.83 ± 0.03% ID/g). Moreover, higher T/B for poly(HPMA)-porphyrin-DTPA-^99mTc indicated reduced extravasation of the targeted polymeric conjugates in normal tissues. Thus, the poly(HPMA)-porphyrin-DTPA-^99mTc is a potential macromolecular tumor targeting molecular agent.     

The relationship between the diameter of chemically-functionalized multi-walled carbon nanotubes and their organ biodistribution profiles in vivo

Carbon nanotubes (CNTs) exhibit unique properties which have led to their applications in the biomedical field as novel delivery systems for diagnosis and therapy purposes. We have previously reported that the degree of functionalization of CNTs is a key factor determining their biological behaviour. The present study broadens the spectrum by investigating the impact of the diameter of CNTs using two series of multi-walled CNTs (MWNTs) with distinct differences in their diameters. Both MWNTs were doubly functionalized by 1,3-dipolar cycloaddition and amidation reactions, allowing the appended functional groups to be further conjugated with radionuclide chelating moieties and antibodies or antibody fragments. All constructs possessed comparable degree of functionalization and were characterized by thermogravimetric analysis, transmission electron microscopy, gel electrophoresis and surface plasmon resonance. The MWNT conjugates were radio-labelled with indium-111, which thereby enabled in vivo single photon emission computed tomography/computed tomography (SPECT/CT) imaging and organ biodistribution study using γ-scintigraphy. The narrow MWNTs (average diameter: 9.2 nm) demonstrated enhanced tissue affinity including non-reticular endothelial tissues compared to the wider MWNTs (average diameter: 39.5 nm). The results indicate that the higher aspect ratio of narrow MWNTs may be beneficial for their future biological applications due to higher tissue accumulation.     

An “imaging-biopsy” strategy for colorectal tumor reconfirmation by multipurpose paramagnetic quantum dots

Glucose transporter1 (Glut1) plays important roles in treatment of colorectal cancer (CRC) involving early-stage diagnosis, subtype, TNM stage, and therapeutic schedule. Currently, in situ marking and tracking of the tumor biomarkers via clinical imaging remains great challenges in early stage CRC diagnosis. In this study, we have developed a unique cell-targeted, paramagnetic-fluorescent double-signal molecular nanoprobe for CRC in vivo magnetic resonance imaging (MRI) diagnosis and subsequent biopsy. The unique molecular nanoprobe is composed of a fluorescent quantum dot (QD) core; a coating layer of paramagnetic DTPA-Gd coupled BSA (GdDTPA∙BSA), and a surface targeting moiety of anti-Glut1 polyclonal antibody. The engineered GdDTPA∙BSA@QDs-PcAb is 35 nm in diameter and colloidally stable under both basic and acidic conditions. It exhibits strong fluorescent intensities and high relaxivity (r₁ and r₂: 16.561 and 27.702 s⁻¹ per mM of Gd³⁺). Distribution and expression of Glut1 of CRC cells are investigated by in vitro cellular confocal fluorescent imaging and MR scanning upon treating with the ^GdDTPA∙BSA@QDs-PcAb nanoprobes. In vivo MRI shows real-time imaging of CRC tumor on nude mice after intravenously injection of the ^GdDTPA∙BSA@QDs-PcAb nanoprobes. Ex vivo biopsy is subsequently conducted for expression of Glut1 on tumor tissues. These nanoprobes are found biocompatible in vitro and in vivo. ^GdDTPA∙BSA@QDs-PcAb targeted nanoprobe is shown to be a promising agent for CRC cancer in vivo MRI diagnosis and ex vivo biopsy analysis. The “imaging-biopsy” is a viable strategy for tumor reconfirmation with improved diagnostic accuracy and biopsy in personalized treatment.     

PET imaging of a collagen matrix reveals its effective injection and targeted retention in a mouse model of myocardial infarction

Injectable biomaterials have shown promise for cardiac regeneration therapy. However, little is known regarding their retention and distribution upon application in vivo. Matrix imaging would be useful for evaluating these important properties. Herein, hexadecyl-4-[¹⁸F]fluorobenzoate (¹⁸F-HFB) and Qdot labeling was used to evaluate collagen matrix delivery in a mouse model of myocardial infarction (MI). At 1wk post-MI, mice received myocardial injections of ¹⁸F-HFB- or Qdot-labeled matrix to assess its early retention and distribution (at 10 min and 2 h) by positron emission tomography (PET), or fluorescence imaging, respectively. PET imaging showed that the bolus of matrix at 10 min redistributed evenly within the ischemic territory by 2 h. Ex vivo biodistribution revealed myocardial matrix retention of ∼65%, which correlated with PET results, but may be an underestimate since ¹⁸F-HFB matrix labeling efficiency was ∼82%. For covalently linked Qdots, labeling efficiency was ∼96%. Ex vivo Qdot quantification showed that ∼84% of the injected matrix was retained in the myocardium. Serial non-invasive PET imaging and validation by fluorescence imaging confirmed the effectiveness of the collagen matrix to be retained and redistributed within the infarcted myocardium. This study identifies matrix-targeted imaging as a promising modality for assessing the biodistribution of injectable biomaterials for application in the heart.     

Gas-generating polymeric microspheres for long-term and continuous in vivo ultrasound imaging

Ultrasound (US) imaging is one of the most common biomedical imaging methods, due to the easy assessment and noninvasive way. For more precise and accurate US imaging, many contrast agents have been developed in a form of microbubbles composed of inner gas and shell materials. However, microbubbles showed undesirable short half-life under acoustic field during US imaging and insufficient in vivo stability in blood flow due to diffusion or bubble destruction. Therefore, the improvement of the half-life and stability of microbubbles under in vivo condition is highly needed for long-term in vivo US imaging. Herein, we developed rationally designed gas-generating polymeric microsphere (GGPM) that can produce microbubbles without encapsulation of gas for long-term and continuous US imaging. The poly(cholesteryl γ-butyrolactone-b-propylene oxide), poly(CB-PO), with carbonate side chains was synthesized as gas-generating polymer by ring-opening polymerization of cholestryl γ-butyrolactone (CB) and propylene oxide (PO). As optimal structure for intense US signal generation, porous GGPMs (p-GGPMs) with the average size about 3-5 μm were prepared with poly(CB-PO) by double emulsion method. These p-GGPMs generated continuous US signals over 70 min, while the signals from Sonovue^®, a commercial US contrast agent were completely attenuated within 15 min. This long-term signal duration of p-GGPM was also reproduced when they were subcutaneously injected under the skin of mouse. Moreover, as advanced in vivo application, the fine US imaging of heart in rat was enabled by intravenous injection of p-GGPM. Therefore, these overall results showed the great potential of p-GGPM as gas-generating US contrast agent for in vivo biomedical imaging and diagnosis.     

Passive and active hepatoma tumor targeting of new N-(2-hydroxypropyl)methacrylamide copolymer conjugates: synthesis,characterization, and evaluation in vitro and in vivo

Human hepatocellular carcinoma (HCC) is one of the major causes of death worldwide. To investigate the relative importance of active and passive targeting strategies, the synthesis, characterization, in vitro uptake, and in vivo biodistribution of specific sulfapyridine HPMA (HPMA: N-(2-hydroxypropyl methacrylamide)) copolymer (sulfapyridine: SPD) conjugates, nonspecific HPMA copolymer conjugates, and DTPA are described in this study. The poly(HPMA)-SPD-DTPA (DTPA: diethylenetriaminepentaacetic acid), poly(HPMA)-DTPA, and DTPA conjugates were radiolabeled with the radionuclide ^99mTc and tested for uptake by cultured H22 cells. The cellular accumulation of poly(HPMA)-SPD-DTPA-^99mTc complex was found to be time-dependent. The poly(HPMA)-SPD-DTPA-^99mTc tracer exhibited rapid uptake kinetics in cell culture with a t _1/2 of ～5?min. The uptake of poly(HPMA)-SPD-DTPA-^99mTc was significantly higher than that of poly(HPMA)-DTPA-^99mTc, indicating that the uptake of the poly(HPMA)-SPD-DTPA-^99mT was active binding. The uptake of poly(HPMA)-DTPA-^99mTc was significantly higher than that of DTPA-^99mTc, suggesting that the uptake of the poly(HPMA)-DTPA-^99mT was passive binding. Twenty-four hour necropsy data in the hepatocellular carcinoma tumor model showed significantly higher (p?<?0.001) tumor localization for poly(HPMA)-SPD-DTPA-^99mTc (4.98?±?0.48%ID/g [percentage injected dose per gram tissue]) compared with poly(HPMA)-DTPA-^99mTc (2.69?±?0.15% ID/g) and DTPA-^99mTc (0.83?±?0.03%ID/g). Moreover, higher T/B for poly(HPMA)-SPD-DTPA-^99mTc indicated reduced extravazation of the targeted polymeric conjugates in normal tissues. Specific molecular targeting and nonspecific vascular permeability are both significant in the relative tumor localization of poly(HPMA)-SPD-DTPA-^99mTc. Extravascular leak in nonspecific organs appears to be a major factor in reducing the T/B for the sulfapyridine molecules. Thus, the poly(HPMA)-SPD-DTPA is expected to be used as the potential macromolecular targeting carrier for hepatoma carcinoma in mice.     

NIR photothermal therapy using polyaniline nanoparticles

Developing a biocompatible and efficient photothermal coupling agent with appropriate size is a prerequisite for the development of near-infrared (NIR) light-induced photothermal therapy (PTT). In the present study, polyaniline nanoparticles (PANPs) with a size of 48.5 ± 1.5 nm were fabricated and exhibited excellent dispersibility in water by a hydrothermal method and further surface functionalization by capping with F127. The developed F127-modified PANPs (F-PANPs) had a high molar extinction coefficient of 8.95 × 10⁸ m⁻¹ cm⁻¹, and high NIR photothermal conversion efficiency of 48.5%. Furthermore, combined with NIR irradiation at 808 nm and injection of F-PANP samples, in vivo photothermal ablation of tumor with excellent treatment efficacy was achieved. In vitro transmission electron microscopy (TEM) images of cells, methyl thiazolyl tetrazolium (MTT) assay, histology, and hematology studies revealed that the F-PANPs exhibit low toxicity to living systems. Therefore, F-PANPs could be used as PTT agents for ablating cancer, and the concept of developing polyaniline-based nanoparticles can serve as a platform technology for the next generation of in vivo PTT agents.