A viral envelope as a vehicle for tracer, drug, and gene delivery: initial biodistribution study using PET imaging.

Viral envelopes can be used as an effective vehicle to deliver imaging tracers as well as therapeutic drugs and genes. However, the current methods for in vivo tracking of viral envelopes are limited. This purpose of this study is to investigate dynamically the in vivo biodistribution of viral envelopes using positron emission tomography (PET) imaging. The hemagglutinating virus of Japan envelope (HVJ-E) was labeled with radioactive fluorine (F-18) for tracking with PET imaging. Due to the low molecular weight of F-18, the encapsulation process by HVJ-E was optimized using the cationic agent poly-L-lysine (PLL, MW 66.7 kDa) and Feridex, a magnetic resonance imaging tracer. After labeling, HVJ-Es were injected intravenously into the normal rat and followed for 2 h using high resolution PET imaging. Region of interest analysis showed a significant increase in average liver accumulation based on radioactivity as compared to all control subjects. Average brain uptake showed a significant increase in radioactivity as compared to control subjects receiving F-18-PLL complexes or F-18 alone. Control subjects showed F-18 uptake primarily in the bones. These results demonstrate a molecular imaging technique that can be used to monitor drug and gene delivery and evaluate potential targeting mechanisms.

A Viral Envelope as a Vehicle for Tracer, Drug, and Gene Delivery: Initial Biodistribution Study Using PET Imaging.

Viral envelopes can be used as an effective vehicle to deliver imaging tracers as well as therapeutic drugs and genes. However, the current methods for in vivo tracking of viral envelopes are limited. This purpose of this study is to investigate dynamically the in vivo biodistribution of viral envelopes using positron emission tomography (PET) imaging. The hemagglutinating virus of Japan envelope (HVJ-E) was labeled with radioactive fluorine (F-18) for tracking with PET imaging. Due to the low molecular weight of F-18, the encapsulation process by HVJ-E was optimized using the cationic agent poly-L-lysine (PLL, MW 66.7 kDa) and Feridex, a magnetic resonance imaging tracer. After labeling, HVJ-Es were injected intravenously into the normal rat and followed for 2 h using high resolution PET imaging. Region of interest analysis showed a significant increase in average liver accumulation based on radioactivity as compared to all control subjects. Average brain uptake showed a significant increase in radioactivity as compared to control subjects receiving F-18-PLL complexes or F-18 alone. Control subjects showed F-18 uptake primarily in the bones. These results demonstrate a molecular imaging technique that can be used to monitor drug and gene delivery and evaluate potential targeting mechanisms.

Carbon-11-thymidine and FDG to measure therapy response.

UNLABELLED: This study was performed to determine if PET imaging with 11C-thymidine could measure tumor response to chemotherapy early after the initiation of treatment. Imaging of deoxyriboneucleic acid biosynthesis, quantitated with 11C-thymidine, was compared with measurements of tumor energetics, obtained by imaging with 18F-fluorodeoxyglucose (FDG). METHODS: We imaged four patients with small cell lung cancer and two with high-grade sarcoma both before and approximately 1 wk after the start of chemotherapy. Thymidine and FDG studies were done on the same day. Tumor uptake was quantified by standardized uptake values (SUVs) for both tracers by the metabolic rate of FDG and thymidine flux constant (K(TdR)) using regions of interest placed on the most active part of the tumor. RESULTS: In the four patients with clinical response to treatment, both thymidine and FDG uptake markedly declined 1 wk after therapy. Thymidine measurements of SUV and K(TdR) declined by 64% +/- 15% and 84% +/- 33%, respectively. FDG SUV and the metabolic rate of FDG declined by 51% +/- 9% and 63% +/- 23%, respectively. In the patient with metastatic small cell lung cancer who had disease progression, the thymidine SUV decreased by only 8% (FDG not done). In a patient with abdominal sarcoma and progressive disease, thymidine SUV was essentially unchanged (declined by 3%), whereas FDG SUV increased by 69%. CONCLUSION: Images show a decline in both cellular energetics and proliferative rate after successful chemotherapy. In the two patients with progressive disease, thymidine uptake was unchanged 1 wk after therapy. In our limited series, K(TdR) measurements showed a complete shutdown in tumor proliferation in patients in whom FDG showed a more limited decrease in glucose metabolism.

Glucose metabolism in human malignant gliomas measured quantitatively with PET, 1-[C-11]glucose and FDG: analysis of the FDG lumped constant.

UNLABELLED: Calculation of the glucose metabolic rate (MRGlc) in brain with PET and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) requires knowing the rate of uptake of FDG relative to glucose from plasma into metabolite pools in the tissue. The proportionality factor for this is the FDG lumped constant (LC[FDG]), the ratio of the volumes of distribution of FDG and glucose multiplied by the hexokinase phosphorylation ratio for the two hexoses, Km(Glc) x Vm(FDG)/Km(FDG) x Vm(Glc) x MRGlc equals the FDG metabolic rate (MRFDG) divided by the LC(FDG), i.e., MRGlc = MRFDG/LC(FDG) and LC(FDG) = MRFDG/MRGlc. This investigation tested the hypothesis that LC(FDG) is significantly higher in gliomas than it is in brain uninvolved with tumor. METHODS: We imaged 40 patients with malignant gliomas with 1-[11C]glucose followed by FDG. The metabolic rates MRGlc and MRFDG were estimated for glioma and contralateral brain regions of interest by an optimization program based on three-compartment, four-rate constant models for the two hexoses. RESULTS: The LC(FDG), estimated as MRFDG/MRGlc, in gliomas was 1.40 +/- 0.46 (mean +/- s.d.; range = 0.72-3.10), whereas in non-tumor-bearing contralateral brain, it was 0.86 +/- 0.14 (range = 0.61-1.21) (p < 0.001, glioma versus contralateral brain). CONCLUSION: These data strongly suggest that the glioma LC(FDG) exceeds that of contralateral brain, that quantitation of the glioma MRGlc with FDG requires knowing the LC(FDG) specific for the glioma and that the LC(FDG) of normal brain is higher than previously reported estimates of about 0.50. 2-Fluoro-2-deoxy-D-glucose/PET studies in which glioma glucose metabolism is calculated by the autoradiographic approach with normal brain rate constants and LC(FDG) will overestimate glioma MRGlc, to the extent that the glioma LC(FDG) exceeds the normal brain LC(FDG). "Hot spots" visualized in FDG/PET studies of gliomas represent regions where MRGlc, LC(FDG) or their product is higher in glioma than it is in uninvolved brain tissue.

High-speed automated discrete blood sampling for positron emission tomography.

A computer controlled blood sampling system was designed specifically for rapid blood sampling for quantitative PET studies and uses solenoids that pinch silastic tubing, a roller pump and an inexpensive fraction collector. The controlling computer is an Apple II plus. The maximum sampling rate is one sample per 2 sec. Typical sample size is 0.90 +/- 0.02 g s.d. The loss of blood per sample is 2.6 ml. Tubing dead space is 1.2 ml. The response to a step change in activity between samples is 91% of the expected activity during high-speed sampling and 99% in the slower sampling mode. The major advantage of this device over flow-through detectors is that the blood is available for further processing to measure plasma or metabolite activities. This device has become a useful tool for quantitative PET studies, resulting in reliable sampling, lower radiation dose to personnel and fewer personnel necessary to conduct a study.