In vivo monitoring of tissue pharmacokinetics of liposome/drug using MRI: illustration of targeted delivery.

The purpose of this study was to determine if MnSO(4)/doxorubicin (DOX) loaded liposomes could be used for in vivo monitoring of liposome concentration distribution and drug release using MRI. In vitro results show that T(1) shortening correlates with MnSO(4) concentration. Using a temperature-sensitive liposome formulation, it was found that MnSO(4) release significantly shortened T(1). This feature, therefore, suggests that content release can also be measured with these MnSO(4)-loaded liposomes. The feasibility of monitoring this drug delivery and release-imaging agent was shown in a murine tumor model. Upon tumor heating, nonthermally sensitive liposomes selectively but heterogeneously accumulated in the tumor region. The thermally sensitive liposomes showed a clear pattern of accumulation at the periphery of the tumor, concordant with the release temperature of this formulation (39-40 degrees C). This liposome contrast agent has potential for use with hyperthermia by providing individualized monitoring of tissue drug concentration distribution during or after treatment. This would allow for: 1) modification of treatment variables to improve the uniformity of drug delivery, and 2) provide a means to select patients most likely to benefit from this liposomal drug treatment. Additionally, the drug-loading method used for this liposome is applicable to a wide range of drugs, thereby broadening its applicability. The method is also applicable to other liposomal formulations with triggered release mechanisms.     

经聚乙烯亚胺钝化的荧光碳点负载阿霉素抑制非小细胞肺癌细胞增殖、迁移侵袭的治疗研究

目的研究利用经聚乙烯亚胺（PEI）钝化的荧光碳点（CD）装载阿霉素（DOX）进行药物递送，旨在增加DOX对非小细胞肺癌的治疗作用，减少DOX的心肌毒性。 方法通过一步微波加热法将甘油和PEI的混合物制备成CD-PEI，并通过静电效应将DOX装载至CD-PEI。采用CCK8实验检测CD-PEI-DOX对非小细胞肺癌细胞A549的增殖能力的影响；Transwell实验评估CD-PEI-DOX对A549细胞迁移侵袭能力的影响；最后通过体内动物实验评估CD-PEI-DOX的心肌毒性以及对非小细胞肺癌皮下肿瘤生长的抑制效果。 结果体外细胞实验证实，对比单纯的DOX处理组，CD-PEI-DOX对非小细胞肺癌A549细胞增殖、迁移侵袭能力的抑制作用更为显著。体内实验证实，CD-PEI-DOX纳米复合物治疗组小鼠心肌细胞结构完整，并且能有效抑制小鼠皮下肺癌肿瘤的生长。 结论经PEI钝化的荧光碳点负载阿霉素能显著提高DOX对非小细胞肺癌的治疗效果，并减少DOX对心脏的毒性作用。运用CD-PEI纳米颗粒改善化疗药物递送的治疗方案取得了初步证实，这可为肺癌化学治疗提供新思路，具有广大的临床应用前景。     

Targeting EGFR-overexpressing tumor cells using Cetuximab-immunomicelles loaded with doxorubicin and superparamagnetic iron oxide

Epidermal growth factor receptor (EGFR), a cellular transmembrane receptor, plays a key role in cell proliferation and is linked to a poor prognosis in various human cancers. In this study, we constructed Cetuximab-immunomicelles in which the anti-EGFR monoclonal antibody was linked to poly(ethylene glycol)-block-poly(?-caprolactone) (PEG–PCL) nanomicelles that were loaded with doxorubicin (DOX) and superparamagnetic iron oxide (SPIO). The specific interactions between EGFR-overexpressing tumor cells (A431) and immunomicelles were observed using confocal laser scanning microscopy (CLSM) and flow cytometry. Furthermore, the capacity of transporting SPIO into tumor cells using these immunomicelles was evaluated with a 1.5 T clinical magnetic resonance imaging (MRI) scanner. It was found that the acquired MRI T2 signal intensity of A431 cells that were treated with the SPIO-loaded and antibody-functionalized micelles decreased significantly. Using the thiazolyl blue tetrazolium bromide (MTT) assay, we also demonstrated that the immunomicelles inhibited cell proliferation more effectively than their nontargeting counterparts. Our results suggest that Cetuximab-immunomicelles are a useful delivery vehicle for DOX and SPIO to EGFR-overexpressing tumor cells in vitro and that Cetuximab-immunomicelles can serve as a MRI-visible and targeted drug delivery agent for better tumor imaging and therapy.     

多西他赛磷脂／胆盐复合胶束的制备及性质研究

目的：制备多西他赛磷脂／胆盐复合胶束（ DOX MMs）并进行处方筛选及初步性质研究。方法以共沉淀法制备多西他赛磷脂胆盐复合胶束,利用高效液相色谱法考察不同条件（磷脂比例、辅料总浓度、pH值、离子强度）对多西他赛在复合胶束中溶解度的影响。通过激光粒度仪测定胶束的粒径分布和电位,透射电子显微镜测定胶束的表面形态,稀释实验考察胶束的稳定性。结果 DOX MMs优化处方中磷脂／总辅料比例为0．4;辅料总浓度为2．5％;水化介质为纯水。载药胶束平均粒径为18．56 nm,Zeta电位为－24．3 mV,胶束为类圆多边形,分布均匀。胶束具有较好的稀释稳定性。结论 DOX MMs的制备工艺简单,能有效提高多西他赛的溶解度,稳定性好,有望成为多西他赛的新型药物传递系统。     

A practical SPECT technique for quantitation of drug delivery to human tumors and organ absorbed radiation dose

A practical quantitative single photon emission computed tomographic (SPECT) technique based on an empirical threshold analysis permits accurate measurements in humans of drug delivery and absorbed radiation dose. The limits of the method have been explored using a wide range of phantom volumes, concentrations, and target-to-nontarget ratios. A threshold of 43% was found to give the best results using volumes of 30 to 3,800 cc. An excellent correlation (r = .99 with a standard error of estimate [SEE] of 41 cc) was found between SPECT measured volumes and actual phantom volumes. A similarly high correlation (r = .98, SEE = 260 counts/voxel) was found in 77 measurements of concentrations between 0.01 and 3.6 microCi/cc. There was a direct relationship between the target-to-nontarget ratio of phantoms and the accuracy of volume measurements. The technique has been validated by an excellent in vivo/in vitro correlation of uptake in human tumors. The tumor cumulative concentration and tumor-to-blood ratio were used for assessment of drug delivery. In vivo quantitative measurements of the pharmacokinetics of technetium-99m (99mTc) glucoheptonate, cobalt-57 (57Co) bleomycin and platinum-195m (195mPt) cisplatin in human tumors in vivo indicates that, in contrast with tumor models in animals, there is a marked variability in drug delivery even in tumors with the same histology. Future development of labeled drugs should make it possible to use quantitative SPECT for predicting tumor response to therapy and for tailoring chemotherapy for the individual patient under treatment. SPECT quantitation of organ concentration was used for Medical Internal Radiation Dose committee (MIRD) calculations of organ absorbed radiation dose from 99mTc-labeled RBCs. Excellent in vivo/in vitro correlations were obtained between SPECT measured concentrations of blood radioactivity in the heart and in vitro measurements of blood samples. The possibilities and limitations of this technique are discussed and its use for in vivo measurement in humans of absorbed radiation dose from radiopharmaceuticals is suggested.     

Lactate, choline, and creatine levels measured by vitro 1H-MRS as prognostic parameters in patients with non-small-cell lung cancer

PURPOSE: To determine the biochemical characteristics of lung cancer tissue using in vitro (1)H-MRS, and investigate the correlation between survival probabilities and lactate (Lac), creatine (Cr), and choline (Cho) concentrations measured by in vitro (1)H-MRS. MATERIALS AND METHODS: A total of 21 patients with lung cancer were included in this retrospective study. (1)H-MRS spectra measurements were performed at 6.35T using a JNM-EX270, high-resolution FT-NMR spectrometer. RESULTS: When normal lung tissue was compared with lung cancer tissue, significant differences were noted most consistently in the levels of Lac and Cho, with lung cancer tissue showing higher values than normal lung tissue. Lac concentrations of lung cancer tissue were significantly higher in patients with recurrence compared to patients without recurrence (0.285 +/- 0.096 mumol/g). The mean overall survival of patients in the low-Lac group was 50.28 +/- 6.47 months, which is significantly higher compared to the high-Lac group, which had a mean survival time of only 30.49 +/- 5.41 months. CONCLUSION: Kaplan-Meier analysis of the data showed that the overall and disease-free survival probabilities were significantly higher in patients with low tumor Lac values than in those with high tumor Lac concentrations.     

Novel system for determining contrast agent concentration in mouse blood in vivo.

A method for measuring contrast agent concentration in blood was developed using a switchable RF tail coil to obtain MR signal from the mouse tail vein. The switchable RF coil was used to obtain quantitative high-resolution T1 maps of the tail in combination with a second coil used to obtain images from regions of interest in a mouse tumor model. The effect of flow rates on the T1 measurements was validated using a flow-phantom. Reliable estimates of blood T1 were obtained for flow rates up to 0.5 cm/sec in SCID mice. There was no significant difference between the in vivo tail coil measurements and in vitro blood sample relaxation rates of blood. The ability to measure the concentration of contrast agents in mouse blood in vivo is useful for several applications, such as obtaining quantitative values of tumor vascular volume and permeability, determining the effectiveness of drug delivery to tumors, or for detecting lymphatic drain.     

Contribution of paramagnetic trace elements to the spin-lattice relaxation time in the liver

The relaxation times of water protons in rat liver tissue were measured with a NMR spectrometer at 20 MHz. The paramagnetic trace elements Cu, Fe, and Mn were determined by neutron activation analysis. No shortening of T1 could be observed when liver Cu or Fe concentration was increased in the microgram range. T1 was strongly correlated with the liver Mn concentration of untreated animals and animals whose liver Mn concentration was artificially increased or decreased by intravenous injection of manganous acetate or a metal chelating agent with high affinity for hepatobiliary excretion. Deviations from this Mn-T1 correlation were found in the initial phase of liver cirrhosis induced by thioacetamide (elongated T1, normal Mn concentration) and after stimulation of liver growth by phenobarbital (normal T1, decreased Mn concentration). An increased or decreased enhancement factor for Mn may have contributed to the observed deviations during phenobarbital and thioacetamide treatment.     

Direct CSF injection of MnCl(2) for dynamic manganese-enhanced MRI.

MnCl(2) was injected intrathecally through the cisterna magna in rats, allowing infusion of divalent manganese ions (Mn(++)) into the CSF space and thence into the brain, without breaking the blood-brain barrier (BBB). Mn(++) uptake and washout dynamics in the brain were measured by serial T(1)-weighted MRI and EPI T(1) and T(2) mapping for up to 3 weeks after injection. Observations within the first 6 hr after injection demonstrated anterograde and bilateral distribution of the Mn(++) within the CSF space, from the olfactory bulb and frontal cortex to the brain stem. Enhancement increased in most brain areas up to 4 days after injection, and then slowly decreased. Relaxation maps at each time point demonstrated higher concentrations of Mn in basal ganglia. Residual concentrations were still observable after 3 weeks in all brain regions. With the use of MnCl(2) calibration phantoms, the maximum Mn concentration in the brain was estimated to be approximately 27 +/- 16 microM, corresponding to changes in relaxation rates of 0.49 +/- 0.30 s(-1) for R(1) and 3.9 +/- 2.4 s(-1) for R(2). For comparison, an intrathecal GdDTPA injection was performed. This injection showed different distribution dynamics: it remained chiefly within the CSF spaces, and was largely washed out after 1 day. This method shows promise as a means of supplying Mn(++) uniformly to the whole brain for a variety of chronic functional activation studies.     

In vivo studies of Gd-DTPA-monoclonal antibody and gd-porphyrins: potential magnetic resonance imaging contrast agents for melanoma

New tumor-specific contrast agents for clinical imaging and therapy for cancer are required. To this end Gd-H (Gd-hematoporphyrin), Gd-TCP (Gd-tetra-carboranylmethoxyphenyl-porphyrin), Gd-DTPA-WM53, and Gd-DTPA-9.2.27 were synthesized and administered by systemic injection to nude mice with human melanoma (MM-138) xenografts. The biodistribution T1 relaxation times and magnetic resonance (MR) image signal enhancement of the contrast agents are presented for the first time and compared for each group of five mice. A change (20%) in T1 relaxation times of water in human melanoma tumor xenografts was revealed 24 hours after injection of the labeled immunoconjugate Gd-DTPA-9.2.27. The percent of injected antibody or gadolinium that localized to the tumor was measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES) to be approximately 35%. A higher concentration of gadolinium was achieved compared with nonspecific compounds, indicating selective delivery of Gd-DTPA-9.2.27 to the melanoma xenografts. Porphyrin-based contrast agents (Gd-H and Gd-TCP) also showed significant uptake in melanomas. The uptake of Gd-TCP by the tumor was sufficient to deliver boron atoms into the tumor, making possible dual use for both MR imaging (MRI) and boron neutron capture therapy (BNCT). The linear relationship found between the paramagnetic contribution to the relaxation rates and contrast agent concentration allows quantitative studies of paramagnetic contrast agent uptake.     

Effects of the type of embolization particles on carboplatin concentration in liver tumors after transcatheter arterial chemoembolization in a rabbit model of liver cancer

PURPOSE: To study the effect of particle type used during transarterial hepatic chemoembolization (TACE) on carboplatin concentration after TACE in an animal model of liver cancer (VX2) and to determine the concentration of carboplatin within tumor, liver, and plasma. MATERIALS AND METHODS: The VX2 tumors were grown in the livers of 23 rabbits. Carboplatin (5 mg/kg) was selected because of its known potency against VX2 tumor. Group 1 was treated with TACE with tris-acryl gelatin microspheres (100-300 microm), group 2 was treated with TACE with polyvinyl alcohol (PVA; 150-250 microm), group 3 (control) was treated with intraarterial saline solution, and group 4 (pharmacokinetic) was treated with intraarterial carboplatin. Animals were killed after 48 hours, and concentrations of carboplatin were measured by atomic absorption spectroscopy from samples of blood and liver (central and peripheral zones of tumor and nontumorous liver tissue). RESULTS: In group 1 (tris-acryl gelatin microspheres) and group 2 (PVA), the mean carboplatin concentrations were 117 microg/g and 31.8 microg/g, respectively, within the central zone of the tumor and 38.5 mug/g versus 7.9 microg/g, respectively, in the peripheral zone. No carboplatin was detected in nontumorous liver tissue and plasma concentrations were low in both treated groups (<0.079 microg/mL). CONCLUSIONS: Carboplatin concentration was significantly greater (by a factor of two to four) within the central zone of the tumor compared with the peripheral zone in both treated groups. The overall tumor carboplatin concentrations were significantly greater in the tris-acryl gelatin microsphere group than in the PVA group (P < .001), which could translate into greater potency and tumor kill. Administration of tris-acryl gelatin microspheres may be clinically advantageous during TACE, as it contributed to greater delivery of chemotherapy to tumor in the present study.     

Evaluation of unnatural cyclic amino acids as boron delivery agents for treatment of melanomas and gliomas

Unnatural cyclic amino acids (UNAAs) are a new class of boron delivery agents that are in a pre-clinical stage of evaluation. In the present study, the biodistribution of racemic forms of the cis- and trans-isomers of the boronated UNAA 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) and 1-amino-3-boronocycloheptanecarboxylic acid (ABCHC) were evaluted in B16 melanoma bearing mice and this was compared to l-p-boronophenylalanine (BPA). Boron concentrations were determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES) at 2.5 h following intraperitoneal (i.p.) injection of the test agents at a concentration equivalent to 24 mg/B/kg. While all compounds attained comparable tumor boron concentrations, the tumor/blood (T/Bl) boron concentration ratios were far superior for both cis-ABCPC and cis-ABCHC compared to BPA (T/Bl=16.4, and 15.1 vs. 5.4). Secondary ion mass spectrometry (SIMS) imaging revealed that the cis-ABCPC delivered boron to the nuclei, as well as the cytoplasm of B16 cells. Next, a biodistribution study of cis-ABCPC and BPA was carried out in F98 glioma bearing rats following i.p. administration. Both compounds attained comparable tumor boron concentrations but the tumor/brain (T/Br) boron ratio was superior for cis-ABCPC compared to BPA (6 vs. 3.3). Since UNAAs are water soluble and cannot be metabolized by tumor cells, they could be potentially more effective boron delivery agents than BPA. Our data suggest that further studies are warranted to evaluate these compounds prior to the initiation of clinical studies.     

Tumor acidity and near-infrared light responsive drug delivery MoS2-based nanoparticles for chemo-photothermal therapy

The rational design of tumor microenvironment (TME)- multifunctional stimuli-responsive nanocomposites is appealing for effective cancer treatment. However, multidrug resistance remains an obstacle to construct responsive oncotherapy. Herein, a novel MoS₂/PDA-TPP nanocomposite loaded with chemotherapy drug of doxorubicin (DOX) is designed for TME dual-response and synergistically enhanced anti-tumor therapy based on the tumor-specific mitochondria accumulation ability and photothermal (PTT) therapy. In detail, the designed MoS₂/PDA-TPP nanoplatform can act as a pH-responsive dissociation to endow fast release of DOX under an acidic TME and simultaneously improve the efficiency of PTT. Moreover, the mechanism shows that MoS₂/PDA-TPP trigger mitochondrial-dependent apoptosis by producing reactive oxygen species (ROS) and reducing mitochondrial membrane potential (MMP). Most importantly, during PTT procedure, hyperthermia up to 50 °C can effectively induce tumor cell death without causing severe inflammation to adjacent tissues. Tumor targeting double stimulation response of nanocomposites is a novel idea to overcome drug resistance, which will provide a more effective strategy for solving practical problems.     

Improved neuronal tract tracing using manganese enhanced magnetic resonance imaging with fast T(1) mapping.

There has been growing interest in using manganese-enhanced MRI (MEMRI) to detect neuronal activation, neural architecture, and neuronal connections. Usually Mn(2+) produces a very wide range of T(1) change. In particular, in neuronal tract tracing experiments the site of Mn(2+) injection can have very short T(1) while distant regions have small T(1) reductions, primarily due to dilution of Mn(2+). Most MEMRI studies use T(1)-weighted sequences, which can only give optimal contrast for a narrow range of T(1) changes. To improve sensitivity to the full extent of Mn(2+) concentrations and to optimize detection of low concentrations of Mn(2+), a fast T(1) mapping sequence based on the Look and Locker technique was implemented. Phantom studies demonstrated less than 6.5% error in T(1) compared to more conventional T(1) measurements. Using center-out segmented EPI, whole-brain 3D T(1) maps with 200-microm isotropic resolution were obtained in 2 h from rat brain. Mn(2+) transport from the rat olfactory bulb through appropriate brain structures could be detected to the amygdala in individual animals. The method reliably detected less than 7% reductions in T(1). With this quantitative imaging it should be possible to study more extensive pathways using MEMRI and decrease the dose of Mn(2+) used.     

Evidence for a contribution of paramagnetic ions to water proton spin-lattice relaxation in normal and malignant mouse tissues.

Paramagnetic ions complexed to proteins may lose, retain, or enhance solvent paramagnetic relaxation (SPR) relative to free solution. We measured T1 and T2 of three mouse cancers, their normal counterparts, and six additional tissues. Long T1 of cancers was not caused by necrosis or by different contents of water, fat, or blood. Dissociable (TCA-extractable) and nondissociable (ashed) Mn, Cu, and Fe were measured by AA. Cancers had less Mn, Cu, and Fe than did normal counterparts. All 12 tissues had inverse correlations between T1 and dissociable Mn and Cu. For Mn alone to account for reduced T1, the extent to which SPR of the Mn-protein complexes would be enhanced is by factors of 0.6 to 13, below the maximum observed in Mn-enzymes. Different amounts of paramagnetic ion-protein complexes may account for part of the differences in T1 of water protons in different tissues, and the longer T1 of cancer cell water may be caused in part by reduced amounts of such complexes.     

Retrospective measurement of different size parameters of non-radiated rectal cancer on MR images and pathology slides and their comparison

There are no non-invasive methods to assess the real tumor size in rectal cancer prior to surgery, especially following radio/chemotherapy. Magnetic resonance imaging is gaining increasing acceptance as the primary modality at many centers for evaluation of pelvic malignancies including rectal cancers. The aim of this study was to evaluate if the tumor size as assessed by stereological or metric means on MRI correlates to the corresponding pathologic findings. To our knowledge, no such previous work has been reported in the literature. From the Cancer Register Center, 18 patients in the age range of 39–90 years with rectal cancer who had complete preoperative MR with subsequent giant section pathological examinations of the resected bowel were included. The tumor size was measured on MR and histopathologic specimen using both a stereologic and a metric mode. The measured parameters included the maximum transverse area occupied by the tumor, thickness, width, and the length of tumor and the volume of the tumor measured in two different fashions by the product of area and length (al) or the product of thickness, width, and length (twl). The depth of tumor infiltration (T) and presence of local lymph node metastases (N) were also separately evaluated on the histopathologic specimen. There were 1, 4, 12, and 1 patients with tumor stages T1, T2, T3, and T4, respectively. The mean thickness, width, length, area, and volumes, al and twl, were 1.62, 2.8, and 4.78 cm, and 4.72 cm², 26.29 cm³, and 20.07 cm³, respectively. Regression curves were drawn for above-mentioned parameters. They showed some correlation with square correlation coefficient measuring between 0.38 and 0.82. The best correlation was seen for area (0.75) and volume measured by the product of area and length of the tumor (0.82). With the formula proposed from this material, we assume that rectal tumors can be measured on MR images using a metric model, especially area and the volume (the product of area and length), and then extrapolated to what we would expect from pathology, hence providing us with a tool where we could measure tumor response after neoadjuvant therapy.     

Evaluation of biodistribution and anti-tumor effect of a dimeric RGD peptide–paclitaxel conjugate in mice with breast cancer

PURPOSE: Targeting drugs to receptors involved in tumor angiogenesis has been demonstrated as a novel and promising approach to improve cancer treatment. In this study, we evaluated the anti-tumor efficacy of a dimeric RGD peptide-paclitaxel conjugate (RGD2-PTX) in an orthotopic MDA-MB-435 breast cancer model. METHODS: To assess the effect of conjugation and the presence of drug moiety on the MDA-MB-435 tumor and normal tissue uptake, the biodistribution of (3)H-RGD2-PTX was compared with that of (3)H-PTX. The treatment effect of RGD2-PTX and RGD2+PTX was measured by tumor size, (18)F-FDG/PET, (18)F-FLT/PET, and postmortem histopathology. RESULTS: By comparing the biodistribution of (3)H-RGD2-PTX and (3)H-PTX, we found that (3)H-RGD2-PTX had higher initial tumor exposure dose and prolonged tumor retention than (3)H-PTX. Metronomic low-dose treatment of breast cancer indicated that RGD2-PTX is significantly more effective than PTX+RGD2 combination and solvent control. Although in vivo (18)F-FLT/PET imaging and ex vivo Ki67 staining indicated little effect of the PTX-based drug on cell proliferation, (18)F-FDG/PET imaging showed significantly reduced tumor metabolism in the RGD2-PTX-treated mice versus those treated with RGD2+PTX and solvent control. Terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining also showed that RGD2-PTX treatment also had significantly higher cell apoptosis ratio than the other two groups. Moreover, the microvessel density was significantly reduced after RGD2-PTX treatment as determined by CD31 staining. CONCLUSION: Our results demonstrate that integrin-targeted delivery of paclitaxel allows preferential cytotoxicity to integrin-expressing tumor cells and tumor vasculature. The targeted delivery strategies developed in this study may also be applied to other chemotherapeutics for selective tumor killing.     

Sequential change of MR signal intensity of the brain after manganese administration in rabbits. Correlation with manganese concentration and histopathologic findings.

RATIONALE AND OBJECTIVES: High signal intensity in the basal ganglia on T1-weighted MR imaging has been reported in chronic manganese (Mn) poisoning. However, the exact meaning of the high signal intensity remains unclear: does it result from Mn itself, secondary pathologic changes of the brain tissue, or both? The goal of this study was to evaluate the sequential change of MR signal intensity and to correlate the MR intensity of the globus pallidus and the hypothalamus with the Mn concentration in the blood and the brain tissue, and with the histopathologic findings. METHODS: Ten milligrams per kilogram of Mn was administered once a week for 4 weeks to 14 rabbits. The rabbits in the control group (n = 2) were killed without Mn administration; those in group I (n = 4) were killed 1 day after the completion of Mn administration, those in group II (n = 4) were killed at 4 weeks, and those in group III (n = 6) were killed at 8 weeks. Sequential MR imaging, blood and tissue concentration measurement, and pathologic examination were performed. Sequential changes of the percent contrasts, contrast-to-noise ratios, and T1 relaxation times were analyzed with blood and tissue concentrations and histopathologic findings. RESULTS: The signal intensity of the basal ganglia on T1-weighted imaging was highest 1 day after cessation of Mn administration and sequentially washed out. The contrast, contrast-to-noise ratio, and T1 relaxation time showed significant correlations with blood concentration. Only the T1 relaxation time of the globus pallidus showed a significant correlation with tissue concentration. Histopathologic examination disclosed mild abnormalities in the globus pallidus, thalamus, and hypothalamus. CONCLUSIONS: The high signal intensity on T1-weighted MR imaging presumably indicates mainly the exposure marker of Mn, although mild pathologic findings were observed.     

Magnetic resonance imaging of implanted melanomas before and after chemotherapy. Relation to 31P magnetic resonance spectroscopy and tumor histology

The early effects of in vivo platinum-rhodamine (PtR) chemotherapy on tumor high-energy phosphorous metabolism was investigated using phosphorus-31 (31P) magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and histologic examination in a subcutaneously implanted hamster melanoma model. PtR was chosen because of its potential antimitochondrial and antineoplastic properties. All melanomas were clearly observed on both T1- and T2-weighted images (T1WI and T2WI), with viable tumor regions generally characterized by low to intermediate intensity on T1WI and high intensity on T2WI. Necrotic regions were more variable in appearance, depending on the amount of cystic fluid and hemorrhage. No changes were detected on either T1WI or T2WI within 90 minutes of a tumoristatic dose of PtR (40 mg/kg) by visual examination, but slight differences were seen on calculations of relative signal intensities. However, this same dose of PtR caused a 50% drop in tumor ATP and phosphocreatine content (relative to Pi) measured by 31P MRS within 90 minutes of drug injection. Magnetic resonance spectroscopy appears to offer a sensitive means of detecting the earliest biochemical effects of chemotherapeutic agents that are known to affect tumor bioenergetics.