Background: Minibeam radiation therapy is an experimental radiation therapy utilizing an array of parallel submillimeter planar X-ray beams. In preclinical studies, minibeam radiation therapy has been shown to eradicate tumors and cause significantly less damage to normal tissue compared to equivalent radiation doses delivered by conventional broadbeam radiation therapy, where radiation dose is uniformly distributed. Methods: Expanding on prior studies that suggested minibeam radiation therapy increased perfusion in tumors, we compared a single fraction of minibeam radiation therapy (peak dose:valley dose of 28 Gy:2.1 Gy and 100 Gy:7.5 Gy) and broadbeam radiation therapy (7 Gy) in their ability to enhance tumor delivery of PEGylated liposomal doxorubicin and alter the tumor microenvironment in a murine tumor model. Plasma and tumor pharmacokinetic studies of PEGylated liposomal doxorubicin and tumor microenvironment profiling were performed in a genetically engineered mouse model of claudin-low triple-negative breast cancer (T11). Results: Minibeam radiation therapy (28 Gy) and broadbeam radiation therapy (7 Gy) increased PEGylated liposomal doxorubicin tumor delivery by 7.1-fold and 2.7-fold, respectively, compared to PEGylated liposomal doxorubicin alone, without altering the plasma disposition. The enhanced tumor delivery of PEGylated liposomal doxorubicin by minibeam radiation therapy is consistent after repeated dosing, is associated with changes in tumor macrophages but not collagen or angiogenesis, and nontoxic to local tissues. Our study indicated that the minibeam radiation therapy’s ability to enhance the drug delivery decreases from 28 to 100 Gy peak dose. Discussion: Our studies suggest that low-dose minibeam radiation therapy is a safe and effective method to significantly enhance the tumor delivery of nanoparticle agents.

The study aims to assess site assessment of the performance of 18F-PBR-111 as a neuroinflammation marker in the cuprizone mouse model of multiple sclerosis (MS). 18F-PBR-111 PET imaging has not been well evaluated in multiple sclerosis applications both in preclinical and clinical research. This study will help establish the potential utility of 18F-PBR-111 PET in preclinical MS research and future animal and future human applications.18F-PBR-111 PET/CT was conducted at 3.5 weeks (n = 7) and 5.0 weeks (n = 7) after cuprizone treatment or sham control (n = 3) in the mouse model. A subgroup of mice underwent autoradiography with cryosectioned brain tissue. T2 weighted MRI was performed to obtain the brain structural data of each mouse. 18F-PBR-111 uptake was assessed in multiple brain regions with PET and autoradiography images. The correlation between autoradiography and immunofluorescence staining of neuroinflammation (F4/80 and CD11b) was measured. Compared to control mice, significant 18F-PBR-111 uptake in the corpus callosum (p < 0.001), striatum (caudate and internal capsule, p < 0.001), and hippocampus (p < 0.05) was identified with PET images at both 3.5 weeks and 5.0 weeks, and validated with autoradiography. No significant uptake differences were detected between 3.5 weeks and 5.0 weeks assessing these regions as a whole, although there was a trend of increased uptake at 5.0 weeks compared to 3.5 weeks in the CC. High 18F-PBR-111 uptake regions correlated with microglial/ macrophage locations by immunofluorescence staining with F4/80 and CD11b antibodies. 18F-PBR-111 uptake in anatomic locations correlated with activated microglia at histology in the cuprizone mouse model of MS suggests that 18F-PBR-111 has potential for in vivo evaluation of therapy response and potential for use in MS patients and animal studies.

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Introduction: Solid tumors consist of both malignant cells and non-malignant stromal cells. Stromal cells typically include vascular, mesenchymal, and pro-inflammatory cells. Macrophages are the most abundant pro-inflammatory cell type in solid tumors and are termed TAMs. TAMs are derived from monocytes (mononuclear phagocyte system, MPS) and are associated with tumor progression, angiogenesis, and metastasis. The MPS are responsible for the clearance and distribution of nanoparticle (NP) anticaner agents such as PLD. However, the role of MPS in the tumor delivery of NP have not been evaluated. In this study, we evaluated the relationship between TAM-related tumor microenvironment factors, tumor delivery, and efficacy of PLD and NL-doxo in GEMMs of BC. Methods: Basal-like (C3(1)T-antigen) and claudin-low (T11/TP53-/-) GEMMs of human BC subtypes were evaluated. PLD or NL-doxo was administered at 6 mg/kg IV x 1 via a tail vein. For each GEMM, mice (n=3) were sacrificed prior to dose, and from 5 min to 96 h post dose. Plasma encapsulated and released doxo and sum total doxo conc in tumor was measured by HPLC. Area under the plasma and tumor conc versus time curves (AUC) were calculated. TAM infiltration was visualized and measured via immunohistochemistry (IHC) for F4/80. Endothelial cells in tumors were detected by CD31 IHC. Density of TAMs and endothelial cells in tumors were measured by the Aperio analysis algorithms. In efficacy study, PLD or NL-doxo at 6 mg/kg was administered every week for 6 weeks (n=20 per model). Tumor growth and overall survival were monitored. Results: Mean ± SD of plasma AUC of PLD encapsulated doxo in T11 and C3tag were1,449 ± 57 and 1,610 ± 111 (μg·h/ml), respectively. Mean ± SD of tumor sum total AUC of PLD in T11 and C3tag were 210 ± 26 and 480 ± 71 (μg·h/ml), respectively. Mean ± SD of tumor AUC of NL-doxo in T11 and C3tag were 61 ± 12 and 57 ± 10 (μg·h/ml), respectively. Mean ± SD baseline % positive cells of TAM in T11 and C3tag were 113 ± 45 and 110 ± 50, respectively. Mean ± SD baseline microvessel density in T11 and C3tag were 8.8 ± 2.5 and 6.1 ± 1.8 (number of vessels x10ˆ5 per unit area), respectively. C3tag demonstrated greater antitumor response to PLD compared to T11. Conclusions: There was a substantial difference in tumor exposure of PLD, but not NL-doxo, in the two GEMMs. These findings suggest that TM factors in BC may affect the delivery of NP agents, but not small molecules (SM). However, the similar TAM and microvessel baseline density in GEMMs suggest alternative tumor factors specifically affecting the delivery of NP agents. Further studies are warranted to elucidate the mechanisms underlying the delivery of NP agents in these and other tumors which may explain different tumor phenotypes and therapeutic outcomes related to treatment with NP and SM agents. Citation Format: Gina Song, David B. Darr, Charlene M. Santos, Taylor F. White, Jamie L. Jordan, Mimi Kim, Bentley R. Midkiff, Nana N. Feinberg, Ryan Miller, Arlin B. Rogers, Andrew C. Dudley, Charles M. Perou, William C. Zamboni. Relationship between tumor-associated macrophages (TAMs), tumor delivery, and efficacy of PEGylated liposomal doxorubicin (PLD) and non-liposomal doxorubicin (NL-doxo) in genetically engineered mouse models (GEMMs) of breast cancer (BC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3354. doi:10.1158/1538-7445.AM2013-3354