Background and objective

Photodynamic therapy (PDT)-induced disruption of the blood-brain barrier (BBB) has been investigated as a technique for the delivery of therapeutic agents to selective regions of the brain. The purpose of this study was to determine the effects of PDT on the migration of systemically administered exogenous macrophages (Ma) loaded with iron oxide nanoparticles in non-tumor bearing rats.

Materials and methods

A control group consisting of three Sprague-Dawley rats was injected with iron oxide-loaded rat alveolar Ma via jugular vein catheter while two animals were subjected to intracranial injection of iron oxide-loaded Ma. PDT-treated animals were injected with photosensitizer (AlPcS2a ; 1 mg/kg i.p.) followed by light irradiation (wavelength = 670 nm; light dose = 2.5 J) 48 hours later. Light irradiation was performed through the skull. Prior to light irradiation, iron oxide-loaded Ma were administered to each animal. Animals in all groups were imaged in a 7 Tesla (T) magnetic resonance (MR) imager to determine the extent of PDT-induced edema and to evaluate for the presence of iron oxide nanoparticles. Animals were sacrificed 7 days post-Ma administration and their brains analyzed for the presence of iron oxide using Perls staining.

Results

Significant uptake of iron oxide nanoparticles by rat alveolar Ma was observed thus providing the rationale for their use as delivery vectors. Histopathological analyses failed to find evidence of iron oxide in normal rat brain. Accumulations of iron oxide-loaded Ma were observed in both MR images and histological sections of non-tumor bearing rat brain following PDT-induced disruption of the BBB.

Conclusions

MR imaging was shown to be useful for localizing iron-oxide loaded Ma in rat brains. Exogenous Ma are incapable of traversing the normal BBB and therefore, the use of Ma as delivery vehicles into the brain requires selective disruption of the BBB.

Cells infiltrating into normal brain from malignant brain tumors are protected by the blood brain barrier (BBB) which prevents the delivery and limits the effects of anti-tumor agents. We have evaluated the ability of photochemical internalization (PCI) to limit the effects of an agent known to broadly open the BBB to a target region of the brain. The PCI-based relocation and activation of macromolecules into the cell cytosol has the advantage of minimal side effects since the effect is localized to the area exposed to light, allowing the access of chemotherapeutic agents only to these regions. Non tumor bearing inbred Fisher rats were treated with photosesitizer, and a nontoxic intraperitoneal dose of Clostridium perfringens epsilon prototoxin (ETXp) followed by light exposure. Post-contrast T1 MRI scans were used to monitor the degree BBB disruption. F98 tumor cells were implanted into the brains of other animals that were subsequently treated 24 h later with ETXp-PCI BBB opening followed by the i.p. administration of bleomycin (BLM). PCI delivery of ETXp at low fluence levels demonstrated significant MRI enhancement. No effect on the BBB was observed if photosesitizer and light was given in the absence ETXp. The survival of animals implanted with F98 tumor cells was significantly extended following ETXp-PCI BBB opening and BLM therapy compared to controls. PCI delivered ETXp was effective in opening the BBB in a limited region of the brain. ETXp-PCI mediated BBB opening clearly increased the efficacy of BLM therapy.

Purpose

Respiratory motion prediction using an artificial neural network (ANN) was integrated with pseudocontinuous arterial spin labeling (pCASL) MRI to allow free-breathing perfusion measurements in the kidney. In this study, we evaluated the performance of the ANN to accurately predict the location of the kidneys during image acquisition.

Methods

A pencil-beam navigator was integrated with a pCASL sequence to measure lung/diaphragm motion during ANN training and the pCASL transit delay. The ANN algorithm ran concurrently in the background to predict organ location during the 0.7-s 15-slice acquisition based on the navigator data. The predictions were supplied to the pulse sequence to prospectively adjust the axial slice acquisition to match the predicted organ location. Additional navigators were acquired immediately after the multislice acquisition to assess the performance and accuracy of the ANN. The technique was tested in eight healthy volunteers.

Results

The root-mean-square error (RMSE) and mean absolute error (MAE) for the eight volunteers were 1.91 ± 0.17 mm and 1.43 ± 0.17 mm, respectively, for the ANN. The RMSE increased with transit delay. The MAE typically increased from the first to last prediction in the image acquisition. The overshoot was 23.58% ± 3.05% using the target prediction accuracy of ± 1 mm.

Conclusion

Respiratory motion prediction with prospective motion correction was successfully demonstrated for free-breathing perfusion MRI of the kidney. The method serves as an alternative to multiple breathholds and requires minimal effort from the patient.