Introduction: Articular cartilage needs sulfated-glycosaminoglycans (sGAGs) to withstand high pressures while mechanically loaded. Chondrocyte sGAG synthesis is regulated by exposure to compressive forces. Moderate physical exercise is known to improve cartilage sGAG content and might protect against osteoarthritis (OA). This study investigated whether rat knee joints with sGAG depleted articular cartilage through papain injections might benefit from moderate exercise, or whether this increases the susceptibility for cartilage degeneration.
Breast cancer (BC) consists of multiple subtypes defined by various molecular characteristics, for instance, estrogen receptor (ER) expression. Methods for visualizing BC include mammography, MR imaging, ultrasound, and nuclear medicine-based methods such as 99m Tcsestamibi and 18 F-FDG PET, unfortunately all lacking specificity. Peptide receptor scintigraphy and peptide receptor radionuclide therapy are successfully applied for imaging and therapy of somatostatin receptor-expressing neuroendocrine tumors using somatostatin receptor radioligands. On the basis of a similar rationale, radioligands targeting the gastrin-releasing peptide receptor (GRP-R) might offer a specific method for imaging and therapy of BC. The aim of this study was to explore the application of GRP-R radioligands for imaging and therapy of BC by introducing valid preclinical in vitro and in vivo models. Methods: GRP-R expression of 50 clinical BC specimens and the correlation with ER expression was studied by in vitro autoradiography with the GRP-R agonist 111 In-AMBA. GRP-R expression was also analyzed in 9 BC cell lines applying 111 In-AMBA internalization assays and quantitative reverse transcriptase polymerase chain reaction. In vitro cytotoxicity of 177 Lu-AMBA was determined on the GRP-Rexpressing BC cell line T47D. SPECT/CT imaging and biodistribution were studied in mice with subcutaneous and orthotopic ER-positive T47D and MCF7 xenografts after injection of the GRP-R antagonist 111 In-JMV4168. Results: Most of the human BC specimens (96%) and BC cell lines (6/9) were found to express GRP-R. GRP-R tumor expression was positively (P 5 0.026, χ 2 (4) 5 12,911) correlated with ER expression in the human BC specimens. Treatment of T47D cells with 10 −7 M/50 MBq of 177 Lu-AMBA resulted in 80% reduction of cells in vitro. Furthermore, subcutaneous and orthotopic tumors from both BC cell lines were successfully visualized in vivo by SPECT/CT using 111 In-JMV4168; T47D tumors exhibited a higher uptake than MCF7 xenografts. Conclusion: Targeting GRP-R-expressing BC tumors using GRP-R radioligands is promising for nuclear imaging and therapy, especially in ER-positive BC patients.
All DOTA-conjugated peptides showed high receptor binding and internalization properties and appear suitable for further characterization, as described in other articles of this issue.
Liposomal chemotherapy offers several advantages over conventional therapies, including high intratumoral drug delivery, reduced side effects, prolonged circulation time, and the possibility to dose higher. The efficient delivery of liposomal chemotherapeutics relies, however, on the enhanced permeability and retention (EPR) effect, which refers to the ability of macromolecules to extravasate leaky tumor vessels and accumulate in the tumor tissue. Using a panel of human xenograft tumors, we evaluated the influence of the EPR effect on liposomal distribution in vivo by injection of pegylated liposomes radiolabeled with 111 In. Liposomal accumulation in tumors and organs was followed over time by SPECT/CT imaging. We observed that fast-growing xenografts, which may be less representative of tumor development in patients, showed higher liposomal accumulation than slow-growing xenografts. Additionally, several other parameters known to influence the EPR effect were evaluated, such as blood and lymphatic vessel density, intratumoral hypoxia, and the presence of infiltrating macrophages. The investigation of various parameters showed a few correlations. Although hypoxia, proliferation, and macrophage presence were associated with tumor growth, no hard conclusions or predictions could be made regarding the EPR effect or liposomal uptake. However, liposomal uptake was significantly correlated with tumor growth, with fast-growing tumors showing a higher uptake, although no biological determinants could be elucidated to explain this correlation. Al most all nanocarriers, including liposomes (1), and many other anticancer drugs rely on the enhanced permeability and retention (EPR) effect for accumulation in tumor tissue. The EPR effect is defined as the process of extravasation of large molecules from leaky tumor vasculature, leading to accumulation in tumor tissue (2). The EPR effect is dependent on many biological parameters, with the development of the abnormal tumor vasculature playing a major role, although other parameters such as the composition of the surrounding stroma, absence of functional lymphatics, and presence of tumor infiltrating macrophages also play an important role (3). Abnormally upregulated growth factors affect the vasculature of the tumor (4) and lead to large endothelial junctions at the luminal surface, resulting in a leaky vasculature (5). In addition, vessels lack smooth muscle cell layers and supporting cells (6), and the fast recruitment of blood vessels results in tumor neovasculature that is not hierarchically organized, causing a heterogeneous spatial distribution (4,7,8). Finally, tumors overexpress many permeability-enhancing factors, which contribute to an enhanced EPR effect (9). These observations suggest that most tumors may be susceptible to nanoparticle treatment, but thus far such particles show only a limited effect in vivo due to various barriers such as the mononuclear phagocyte system, extracellular matrix, low pH, low oxygenation, and high interstitial fluid pressure (10-12)....
Inhibition of mTOR is commonly considered a valid target in cancer treatment, but this assertion does not address effects on the immune microenvironment that may be detrimental to cancer treatment. Here we show how administration of the mTOR inhibitor RAD001 (everolimus) results in the occurrence of distant metastasis in a rat model of pancreatic cancer. RAD001 was administered twice weekly for 4.
BackgroundTargeted alpha therapy has been postulated to have great potential for the treatment of small clusters of tumour cells as well as small metastases. 213Bismuth, an α-emitter with a half-life of 46 min, has shown to be effective in preclinical as well as in clinical applications. In this study, we evaluated whether 213Bi-[DOTA0, Tyr3]-octreotate (213Bi-DOTATATE), a 213Bi-labelled somatostatin analogue with high affinity for somatostatin receptor subtype 2 (SSTR2), is suitable for the treatment of larger neuroendocrine tumours overexpressing SSTR2 in comparison to its effectiveness for smaller tumours. We performed a preclinical targeted radionuclide therapy study with 213Bi-DOTATATE in animals bearing tumours of different sizes (50 and 200 mm3) using two tumour models: H69 (human small cell lung carcinoma) and CA20948 (rat pancreatic tumour).MethodsPharmacokinetics was determined for calculation of dosimetry in organs and tumours. H69- or CA20948-xenografted mice with tumour volumes of approximately 120 mm3 were euthanized at 10, 30, 60 and 120 min post injection of a single dose of 213Bi-DOTATATE (1.5–4.8 MBq). To investigate the therapeutic efficacy of 213Bi-DOTATATE, xenografted H69 and CA20948 tumour-bearing mice with tumour sizes of 50 and 200 mm3 were administered daily with a therapeutic dose of 213Bi-DOTATATE (0.3 nmol, 2–4 MBq) for three consecutive days. The animals were followed for 90 days after treatment. At day 90, mice were injected with 25 MBq 99mTc-DMSA and imaged by SPECT/CT to investigate possible renal dysfunction due to 213Bi-DOTATATE treatment.ResultsHigher tumour uptakes were found in CA20948 tumour-bearing animals compared to those in H69 tumour-bearing mice with the highest tumour uptake of 19.6 ± 6.6 %IA/g in CA20948 tumour-bearing animals, while for H69 tumour-bearing mice, the highest tumour uptake was found to be 9.8 ± 2.4 %IA/g. Nevertheless, as the anti-tumour effect was more pronounced in H69 tumour-bearing mice, the survival rate was higher. Furthermore, in the small tumour groups, no regrowth of tumour was found in two H69 tumour-bearing mice and in one of the CA20948 tumour-bearing mice. No renal dysfunction was observed in 213Bi-DOTATATE-treated mice after the doses were applied.Conclusions213Bi-DOTATATE demonstrated a great therapeutic effect in both small and larger tumour lesions. Higher probability for stable disease was found in animals with small tumours. 213Bi-DOTATATE was effective in different neuroendocrine (H69 and CA20948) tumour models with overexpression of SSTR2 in mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0162-2) contains supplementary material, which is available to authorized users.
High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with b-particle-emitting radiolabeled somatostatin analogs will lead to renal failure several months after treatment, urging the coinfusion of the cationic amino acids lysine and arginine to reduce the renal radiation dose. In rat PRRT studies, renal protection by the coadministration of lysine was confirmed by histologic examination of kidney specimens indicating nephrotoxicity. In the current study, we investigated dedicated small-animal SPECT/CT renal imaging in rats to monitor renal function in vivo during follow-up of PRRT, with and without lysine. Methods: The following 3 groups of rats were imaged using a multipinhole SPECT/CT camera: controls (group 1) and rats at more than 90 d after therapy with 460 MBq (15 mg) of 177 Lu-DOTA-Tyr 3 -octreotate without (group 2) or with (group 3) a 400-mg/kg lysine coinjection as kidney protection (n $ 6 per group). At 90 and 140 d after therapy, static kidney scintigraphy was performed at 2 h after injection of 25 MBq of 99m Tc-dimercaptosuccinic acid ( 99m Tc-DMSA). In addition, dynamic dual-isotope renography was performed using 50 MBq of 111 In-diethylenetriaminepentaacetic acid ( 111 In-DTPA) and 50 MBq of 99m Tc-mercaptoacetyltriglycine ( 99m Tc-MAG3) at 100-120 d after therapy. Results: 111 In-DTPA and 99m Tc-MAG3 studies revealed a time-activity pattern comparable to those in patients, with a peak at 2-6 min followed by a decline of renal radioactivity. Reduced 111 In-DTPA, 99m Tc-MAG3, and 99m Tc-DMSA uptake indicated renal damage in group 2, whereas group 3 showed only a decrease of 99m Tc-MAG3 peak activity. These results indicating nephrotoxicity in group 2 and renal protection in group 3 correlated with levels of urinary protein and serum creatinine and urea and were confirmed by renal histology. Conclusion: Quantitative dynamic dual-isotope imaging using both 111 In-DTPA and 99m Tc-MAG3 and static 99m Tc-DMSA imaging in rats is feasible using small-animal SPECT, enabling longitudinal monitoring of renal function. 99m Tc-MAG3 renography, especially, appears to be a more sensitive marker of tubular function after PRRT than serum chemistry or 99m Tc-DMSA scintigraphy.
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