Effective targeting of magnetic radioactive 90Y-microspheres to tumor cells by an externally applied magnetic field. Preliminary in vitro and in vivo results.

Magnetic biodegradable poly(lactic acid) microspheres that incorporate both magnetite and the beta-emitter 90Y were prepared. By applying a directional external magnetic field gradient in excess of 0.02 Tesla/cm across a 96-well plate containing neuroblastoma cells incubated with the 90Y magnetite loaded microspheres, the radiation dose to the cells could be enhanced or reduced relative to the dose from a uniform loading of the well with 90Y-DTPA. Using the MTT assay, cell survival was measured for the magnetic field directed from above (cell sparing) and from below (cell targeting) the well plate, resulting in 65 +/- 8% or 18 +/- 5% survival respectively. This method was then applied to an in vivo murine tumor model. The biodistribution of intraperitoneally injected magnetic radioactive microspheres, after 24 h in mice, showed that 73 +/- 32% of the radioactivity was found on the subcutaneous tumor that had a rare earth magnet fixed above it. In contrast, the tumor radioactivity with no attached magnet was 6 +/- 4%. Magnetically targeted radiopolymers such as 90Y-microspheres show great promise for regional or intracavitary radiotherapy.

Magnetically directed poly(lactic acid) 90Y-microspheres: novel agents for targeted intracavitary radiotherapy.

High energy beta-emitting radioisotopes like Yttrium-90 have a radiotoxic range of about one centimeter. For cancer treatment they must be brought near the tumor cells and kept there for as long as they are radioactive. We developed as carriers for the ionic form of 90Y a matrix-type polymeric drug delivery system, poly(lactic acid) (PLA) microspheres. This radiopharmaceutical could be selectively delivered to the target site after incorporating 10% Fe3O4 (magnetite) which made the magnetic microspheres (MMS) responsive to an external magnetic field. Furthermore, MMS are biodegradable and slowly hydrolyze into physiologic lactic acid after the radioactivity is completely decayed. Previously prepared 10-40 microns MMS were radiochemically loaded to high specific activity with 90Y at a pH of 5.7. Stability studies showed that approximately 95% of added 90Y is retained within the PLA matrix after 28 days (> 10 half-lives) at 37 degrees C in serum, and electron microscopy showed that the microspheres retained their characteristic morphologic appearance for the same time period. Cytotoxicity studies with SK-N-SH neuroblastoma cells growing in monolayer showed that the radiocytotoxicity of the microspheres could be directed magnetically to either kill or spare specific cell populations, thus making them of great interest for targeted intracavitary tumor therapy. We are currently optimizing this system for use in the treatment of neoplastic meningitis.

Radiobiologic studies of low-dose-rate 90Y-lymphoma therapy.

BACKGROUND: Radioimmunotherapy and other forms of biologically targeted radiopharmaceutic treatment appear to show unexpected efficacy in many patients with lymphoma, neuroblastoma, and several other types of nonepithelial malignancies. The radiobiologic mechanisms responsible for this high clinical radioresponsiveness are unclear, but must involve some sort of cytotoxic enhancement or sensitization to protracted courses of low-dose-rate radiation exposure. MATERIALS AND METHODS: A series of in vitro experiments was performed with malignant lymphoma cell lines exposed under various conditions to high-dose-rate external beam radiotherapy or low-dose-rate 90Y radiation. Data were collected on cell cycle effects, DNA fragmentation, and modulation of cytotoxicity by caffeine and treatment sequence alterations. RESULTS: The data showed that some malignant lymphoma lines are highly sensitive to low-dose-rate radiation and that a portion of the cytotoxicity appears to be mediated by the induction of radiation-associated apoptosis (programmed cell death). Cell cycle effects of low-dose-rate radiation (such as G2M block) appear to be relatively minor in this experimental system. Agents that modulate apoptosis (such as the calcium-releasing agent caffeine) significantly enhance cell kill and DNA fragmentation after 90Y treatment. CONCLUSIONS: These results suggest that radiation-associated apoptosis may be important in the radiobiology of targeted radiopharmaceutical therapy.

Resources and strategies: how parents cope with the care of a disabled child.

This review has considered the ways parents cope with the chronic strain and daily stressors associated with caring for and bringing up a disabled child. The review has been structured around key concepts from the process model of stress and coping. Coping resources--both personal and socio-ecological--have been described, and the notion of vulnerability when resources are not available has been considered. It is only recently that research has turned to look at the coping strategies parents use. The review drew on research using a variety of methodologies to demonstrate the range of strategies used by parents. The relationship between coping strategies and adjustment was explored, although certain methodological difficulties impede firm conclusions being drawn. Finally, the review examined whether the process model of stress and coping could be usefully operationalised to inform intervention practices with families caring for a disabled child.

Easing the strain: assessing the impact of a Family Fund grant on mothers caring for a severely disabled child.

Measures of perceptions of care-related stress and maternal adjustment were used to assess the extent to which receiving help from the Family Fund eases the stress of caring for a disabled child. A sample of 162 mothers completed a questionnaire before and after receiving help from the Family Fund. The findings suggest that the Family Fund has a significant impact on mothers' perceptions of the stresses of caring for their child, as well as improving mother's wellbeing and adjustment. However, receiving help from the Family Fund did not improve mothers' perceptions of the severity of the child's disability or the extent to which the disability had adversely affected their personal lives.

Cell cycle alterations, apoptosis, and response to low-dose-rate radioimmunotherapy in lymphoma cells.

PURPOSE: In an attempt to elucidate some aspects of the radiobiological basis of radioimmunotherapy, we have evaluated the in vitro cellular response patterns for malignant lymphoma cell lines exposed to high- and low-dose-rate radiation administered within the physiological context of antibody cell-surface binding. METHODS AND MATERIALS: We used two different malignant lymphoma cell lines, a Thy1.2+ murine T-lymphoma line called EL-4 and a CD20+ human B-lymphoma line called Raji. Cells were grown in suspension cultures and exposed to high-dose-rate gamma radiation from an external 137Cs source or low-dose-rate beta radiation from DTPA-solubilized 90Y in solution. In some experiments, cells were pre-incubated with an excess of nonradioactive antibody in order to assess the effects of immunoglobulin surface binding during radiation exposure. Irradiated cells were evaluated for viability, cell-cycle changes, patterns of post-radiation morphologic changes, and biochemical hallmarks of radiation-associated necrosis and programmed cell death. RESULTS: The EL-4 line was sensitive to both high-dose-rate and low-dose-rate irradiation, while the Raji showed efficient cell kill only after high-dose-rate irradiation. Studies of radiation-induced cell cycle changes demonstrated that both cell lines were efficiently blocked at the G2/M interface by high-dose-rate irradiation, with the Raji cells appearing somewhat more susceptible than the EL-4 cells to low-dose-rate radiation-induced G2/M block. Electron microscopy and DNA gel electrophoresis studies showed that a significant proportion of the EL-4 cells appeared to be dying by radiation-induced programmed cell death (apoptosis) while the Raji cells appeared to be dying primarily by classical radiation-induced cellular necrosis. CONCLUSION: We propose that the unusual clinical responsiveness of some high and low grade lymphomas to modest doses of low-dose-rate radioimmunotherapy may be explained in part by the induction of apoptosis. The unusual dose-response characteristics observed in some experimental models of radiation-induced apoptosis may require a reappraisal of standard linear quadratic and alpha/beta algorithms used to predict target tissue cytoreduction after radioimmunotherapy.