Magnetic resonance imaging of local and remote vascular remodelling after experimental stroke.

The pattern of vascular remodelling in relation to recovery after stroke remains largely unclear. We used steady-state contrast-enhanced magnetic resonance imaging to assess the development of cerebral blood volume and microvascular density in perilesional and exofocal areas from (sub)acutely to chronically after transient stroke in rats. Microvascular density was verified histologically after infusion with Evans Blue dye. At day 1, microvascular cerebral blood volume and microvascular density were reduced in and around the ischemic lesion (intralesional borderzone: microvascular cerebral blood volume = 72 ± 8%; microvascular density = 76 ± 8%) (P < 0.05), while total cerebral blood volume remained relatively unchanged. Perilesional microvascular cerebral blood volume and microvascular density subsequently normalized (day 7) and remained relatively stable (day 70). In remote ipsilateral areas in the thalamus and substantia nigra - not part of the ischemic lesion - microvascular density gradually increased between days 1 and 70 (thalamic ventral posterior nucleus: microvascular density = 119 ± 9%; substantia nigra: microvascular density = 122 ± 8% (P < 0.05)), which was confirmed histologically. Our data indicate that initial microvascular collapse, with maintained collateral flow in larger vessels, is followed by dynamic revascularization in perilesional tissue. Furthermore, progressive neovascularization in non-ischemic connected areas may offset secondary neuronal degeneration and/or contribute to non-neuronal tissue remodelling. The complex spatiotemporal pattern of vascular remodelling, involving regions outside the lesion territory, may be a critical endogenous process to promote post-stroke brain reorganization.FSW – Publicaties zonder aanstelling Universiteit Leide

Multimodal imaging of holmium-loaded microsphere for internal Radiation therapy

In this dissertation, the qualitative and quantitative multimodal imaging possibilities of holmium-166 loaded poly(L-lactic acid) microspheres (166Ho-PLLA MS) are explored and exploited to improve biodistribution assessment and dose calculations for planning, image-guidance and evaluation of hepatic arterial radioembolization of liver malignancies. This relatively novel radiotherapy treatment modality represents a promising treatment option for patients with unresectable liver malignancies. In hepatic arterial radioembolization, radioactive microspheres are administered directly into the hepatic artery using a catheter. Targeting of tumors is accomplished by exploiting the predominance of the arterial blood supply to liver tumors, while normal parenchyma largely depends on portal blood supply. Ideally, this results in a high tumor-to-liver ratio, leading to an increased radiation dose to the tumor tissue while minimizing exposure to healthy liver parenchyma. An essential element of successful radioembolization of hepatic malignancies is preprocedural biodistribution assessment. The large variation in vascularity of tumor and liver tissue observed between patients necessitates extensive treatment planning to assure a favorable dose distribution in each individual patient. Due to their multimodal imaging properties, 166Ho-PLLA MS are believed to be an improvement as compared to the already clinically applied yttrium-90 microspheres, which lack high quality medical imaging possibilities. To fully exploit 166Ho-PLLA MS’ imaging opportunities and enable accurate biodistribution assessment and dose calculations, the qualitative and quantitative multimodal imaging possibilities of 166Ho-PLLA MS were investigated, focusing on magnetic resonance imaging (MRI), X ray computed tomography (CT) and Single Photon Emission Computed Tomography (SPECT). In vitro experiments demonstrated that SPECT has the highest sensitivity and lowest detection limit for 166Ho-PLLA MS, followed by MRI and CT, respectively. The development of highly-loaded holmium microspheres, with increased holmium content from 17% to 45% w/w, strongly increased the specific activity for therapeutic purposes and more than doubled the multimodal diagnostic properties for SPECT, MRI and CT. MicroCT imaging was demonstrated to enable high resolution 3D biodistribution assessment of 166Ho-PLLA MS in liver tissue after hepatic arterial radioembolization of a Vx2 tumor-bearing rabbit liver both qualitatively and quantitatively. Single microspheres were detectable using microCT. Microspheres mainly lodged in the periphery of the tumor, revealing a highly skewed cluster volume distribution towards small volumes. Macroscopically, MRI was demonstrated to enable selective depiction of Ho-PLLA MS with positive contrast in liver tissue in the presence of macroscopic magnetic field distortions, using a method called susceptibility gradient mapping. For MR-based quantitative assessment of the distribution of Ho-PLLA MS in liver tissue using T2* relaxometry, sampling of free induction decay (FID) was shown to be superior to sampling of the spin echo (SE), due to diffusion sensitivity of the SE signal decay time course. By means of MR experiments and Monte Carlo simulations FID signal behavior of a diffusive medium containing Ho-PLLA MS was shown to exhibit monoexponential signal decay. Both the static dephasing theory and the theory of strong field behavior accurately predicted transverse relaxivity, allowing MR-based quantification of the local concentration of HoMS. Furthermore, a method which increases the upper detection limit of the Ho-PLLA MS concentration by estimating the S0 value of the signal decay curve to be used in the quantitative fitting procedure was proposed. Finally, the feasibility to utilize quantitative MR data for dosimetric calculations of 166Ho-PLLA MS was demonstrated in an anthropomorphic gel phantom, indicating the potential of MR-based dosimetry for planning, guidance and evaluation of transcatheter radioembolization of hepatic malignancies

Superparamagnetic Iron Oxide Nanoparticles Encapsulated in Biodegradable Thermosensitive Polymeric Micelles: Toward a Targeted Nanomedicine Suitable for Image-Guided Drug Delivery

Superparamagnetic iron oxide nanoparticles (SPIONs) have been receiving great attention lately due to their various biomedical applications, such as in MR imaging and image guided drug delivery. However, their systemic administration still remains a challenge. In this study, the ability of biodegradable thermosensitive polymeric micelles to stably encapsulate hydrophobic oleic-acid-coated SPIONs (diameter 5-10 nm) was investigated, to result in a system fulfilling the requirements for systemic administration. The micelles were composed of amphiphilic, thermosensitive, and biodegradable block copolymers of poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide dilactate] (mPEGb-p(HPMAm-Lac(2))) The encapsulation was performed by addition of one volume of SPIONs in THF to nine volumes of a cold aqueous mPEG-b-p(HPMAm-Lac(2)) Solution (0 degrees C; below the cloud point of the polymer), followed by rapid heating of the resulting mixture to 50 degrees C, to induce micelle formation ("rapid heating" procedure). Dynamic light scattering (DLS) measurements revealed that similar to 200 nm particles (PDI = 0.2) were formed, while transmission electron microscopy (TEM) analysis demonstrated that clusters of SPIONs were present in the core of the micelles. A maximum loading of 40% was obtained, while magnetic resonance imaging (MRI) scanning of the samples demonstrated that the SPION-loaded micelles had high r(2) and r(2)* relaxivities. Furthermore, the r(2)* values were found to be at least 2-fold higher than the r(2) values, confirming the clustering of the SPIONs in the micellar core. The particles showed excellent stability under physiological conditions for 7 days, even in the presence of fetal bovine serum. This, together with their ease of preparation and their size of similar to 200 nm, makes these systems highly suitable for image-guided drug delivery

Microspheres with Ultrahigh Holmium Content for Radioablation of Malignancies

The aim of this study was to develop microspheres with an ultra high holmium content which can be neutron activated for radioablation of malignancies. These microspheres are proposed to be delivered selectively through either intratumoral injections into solid tumors or administered via an intravascularly placed catheter. Microspheres were prepared by solvent evaporation, using holmium acetylacetonate (HoAcAc) crystals as the sole ingredient. Microspheres were characterized using light and scanning electron microscopy, coulter counter, titrimetry, infrared and Raman spectroscopy, differential scanning calorimetry, X-ray powder diffraction, magnetic resonance imaging (MRI), and X-ray computed tomography (CT). Microspheres, thus prepared displayed a smooth surface. The holmium content of the HoAcAc microspheres (44% (w/w)) was higher than the holmium content of the starting material, HoAcAc crystals (33% (w/w)). This was attributed to the loss of acetylacetonate from the HoAcAc complex, during rearrangement of acetylacetonate around the holmium ion. The increase of the holmium content allows for the detection of (sub)microgram amounts of microspheres using MRI and CT. HoAcAc microspheres with an ultra-high holmium content were prepared. These microspheres are suitable for radioablation of tumors by intratumoral injections or treatment of liver tumors through transcatheter administration

Intratumoral administration of Holmium-166 Acetylacetonate Microspheres: Antitumor efficacy and feasibility of multimodality imaging in renal cancer

The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of holmium-166 microspheres (166HoAcAcMS). This new technique locally ablates renal tumors through high-energy beta particles, while the gamma rays allow for nuclear imaging and the paramagnetism of holmium allows for MRI.Radiation, Radionuclides and ReactorsApplied Science