BackgroundThe transgenic adenocarcinoma of the mouse prostate (TRAMP) is a widely used genetically engineered spontaneous prostate cancer model. However, both the degree of malignancy and time of cancer onset vary. While most mice display slowly progressing cancer, a subgroup develops fast‐growing poorly differentiated (PD) tumors, making the model challenging to use. We investigated the feasibility of using ultrasound (US) imaging to screen for PD tumors and compared the performances of US and magnetic resonance imaging (MRI) in providing reliable measurements of disease burden.MethodsTRAMP mice (n = 74) were screened for PD tumors with US imaging and findings verified with MRI, or in two cases with gross pathology. PD tumor volume was estimated with US and MR imaging and the methods compared (n = 11). For non‐PD mice, prostate volume was used as a marker for disease burden and estimated with US imaging, MRI, and histology (n = 11). The agreement between the measurements obtained by the various methods and the intraobserver variability (IOV) was assessed using Bland‐Altman analysis.ResultsUS screening showed 81% sensitivity, 91% specificity, 72% positive predictive value, and 91% negative predictive value. The smallest tumor detected by US screening was 14 mm3 and had a maximum diameter of 2.6 mm. MRI had the lowest IOV for both PD tumor and prostate volume estimation. US IOV was almost as low as MRI for PD tumor volumes but was considerably higher for prostate volumes.ConclusionsUS imaging was found to be a good screening method for detecting PD tumors and estimating tumor volume in the TRAMP model. MRI had better repeatability than US, especially when estimating prostate volumes.
Ultrasound (US) in combination with microbubbles (MB) has had promising results in improving delivery of chemotherapeutic agents. However, most studies are done in immunodeficient mice with xenografted tumors. We used two phenotypes of the spontaneous transgenic adenocarcinoma of the mouse prostate (TRAMP) model to evaluate if US + MB could enhance the therapeutic efficacy of cabazitaxel (Cab). Cab was either injected intravenously as free drug or encapsulated into nanoparticles. In both cases, Cab transiently reduced tumor and prostate volume in the TRAMP model. No additional therapeutic efficacy was observed combining Cab with US + MB, except for one tumor. Additionally, histology grading and immunostaining of Ki67 did not reveal differences between treatment groups. Mass spectrometry revealed that nanoparticle encapsulation of Cab increased the circulation time and enhanced the accumulation in liver and spleen compared with free Cab. The therapeutic results in this spontaneous, clinically relevant tumor model differ from the improved therapeutic response observed in xenografts combining US + MB and chemotherapy.
Ultrasound-mediated delivery of a novel nanoparticle-microbubble platform. A major obstacle in delivery of nanoparticles (NPs) to tumor cells is the low uptake and heterogeneous distribution of the NPs in tumor tissue. Ultrasound (US) may improve the delivery of encapsulated drug in various ways depending on the frequency and intensity applied, by inducing heating, radiation force or cavitation. We have developed a novel multimodal, multifunctional drug delivery system consisting of microbubbles stabilized by polymeric NPs to be used in US-mediated delivery of NPs. Miniemulsion polymerization was used to prepare NPs of the biocompatible and biodegradable polymer poly(butyl-2-cyanoacrylate) (PBCA). The NPs were coated with PEG to improve the circulation time and biodistribution. Microbubbles stabilized by these NPs were prepared by mixing the NP dispersion with proteins and air using an ultra-turrax. The aim of the present work was to study the cellular uptake of the NP in vitro and the microdistribution of the NP in tumor tissue in vivo. Human prostate cancer cells were incubated with fluorescently labeled (Nile red and DiR) NPs and the cellular uptake measured by flow cytometry and confocal laser scanning microscopy (CLSM). Prostate cancer xenografts were grown subcutaneously on the leg of athymic mice, and NP alone or NPs stabilizing microbubbles were injected intravenously. The particles circulated for 5 min or 24 hr, before the tumors were exposed to US, thus the effect of US both on extravasation and penetration through the extracellular matrix could be studied. The tumors were exposed to a focused US beam at low (300 kHz or 1 MHz) or high (5 MHz) frequency, applying various intensities. The blood vessels were visualized by injection of FITC- tomato lectin 5 min before euthanizing the mice. The distribution of NPs was studied by CLSM, imaging frozen tumor sections along a radial track from the periphery of the tumor sections. The biodistribution of NPs comparing the uptake in normal and tumor tissue, was studied by whole animal optical imaging. The cellular uptake of the NPs in vitro depended on the length and type of PEG used. In vivo, ultrasound enhanced the uptake and improved the distribution of the NPs in the extracellular matrix. In untreated tumors only small amounts of NPs were observed and they were located close to the blood vessels. In the US-exposed tumors, the uptake was enhanced and the NP had penetrated further away from the blood vessels compared with unexposed tumors. US administered 5 min after NP-injection was more efficient than US given after 24 h. This demonstrates that the effect of US on extravasation is more important than the effect on penetration of NPs through the extracellular matrix. A prerequisite for successful cancer therapy is that the cytotoxic drugs reach all the cancer cells. The present results demonstrate that US improves the delivery of NPs, and mainly by increasing the permeability of the capillary wall. Citation Format: Catharina De Lange Davies, Siv Eggen, Stein-Martin Fagerland, Mercy Afadzi, Audun Dybvik Bøhn, Håkon Furu, Rune Hansen, Bjørn Angelsen, Per Stenstad, Yrr Mørch. Ultrasound-mediated delivery of a novel nanoparticle-microbubble platform. [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 5618. doi:10.1158/1538-7445.AM2013-5618
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