Bombesin Encapsulated in Long-Circulating pH-Sensitive Liposomes as a Radiotracer for Breast Tumor Identification

Abstract

Bombesin (BBN) is a tetradecapeptide that binds specifically to gastrin-releasing peptide receptors in humans. These receptors are over-expressed in several forms of cancer; radiolabeled BBN could therefore be used to detect such cancers. However, the degradation of peptides is a critical issue in the development of tumor tracers. Liposomes can be used to overcome this problem and improve the uptake of tracers by tumors. Therefore, the purpose of this study was to prepare and characterize long-circulating and pH-sensitive liposomes (SpHL) containing 99m Tc-HYNIC-Ala-Bombesin 7-14 ( 99m Tc-BBN 7-14 ). In addition, the ability of this system to identify human breast cancer tissue was evaluated using biodistribution studies and scintigraphic images. Long-circulating and pH-sensitive liposomes (SpHL) were prepared and freeze-dried in the presence of cryoprotectants (glucose, mannitol, and trehalose). They were subsequently reconstituted with a solution of 99m Tc-HYNIC-Ala-Bombesin 7-14 ( 99m Tc-BBN 7-14 ). The liposomes were evaluated for size, encapsulation percentage, radiotracer leakage, and storage stability. In addition, in vivo studies were performed in breast tumor-bearing nude mice. Liposomes in the presence of glucose (SpHLG), exhibited a mean diameter of 164.5 ± 6.5 nm and exhibited a 99m Tc-BBN 7-14 encapsulation percentage of 30%. In addition, they remained highly stable for up to 120 days of storage. SpHLG99m Tc-BBN 7-14 showed longer blood circulation than free 99m Tc-BBN 7-14 did. The tumor-to-muscle and tumor-to-blood ratios for SpHLG-99m Tc-BBN 7-14 were high at 4 h post-injection (9.31%ID/g and 7.93%ID/g, respectively). Furthermore, scintigraphic images revealed a strong signal in the tumor area, indicating tumor specificity of SpHLG-99m Tc-BBN 7-14 . In summary, SpHLG-99m Tc-BBN 7-14 presented characteristics suitable for a diagnostic agent, and is a potential tool for tumor identification.

Paclitaxel-loaded folate-coated long circulating and pH-sensitive liposomes as a potential drug delivery system: A biodistribution study

“…Nanoparticles are extensively phagocytosed by macrophages present in the liver and spleen organs [25,26,46,47]. As predicted, the biodistribution studies showed high uptake in liver and spleen for 99m Tc-SpHL-DTPA-PTX and 99m Tc-SpHL-folate-DTPA-PTX.…”

Technetium-99 m radiolabeled paclitaxel as an imaging probe for breast cancer in vivo

“…This finding might be explained by the extensive phagocytosis typically experienced by nanoparticles after intravenous injection [40–42]. The substantial uptake in kidneys (Fig.…”

“…99m Tc-PTX showed time-dependent accumulation and tumor-to-muscle ratios superior than 1.5. This fact could be explained by the long blood circulation time, leading to more passages through the tumor region, favoring 99m Tc-PTX extravasation and therefore, tumor accumulation [37–42]. …”

Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment

“…Various radiolabeled ( 111 In, 64 Cu, 99M Tc, 68 Ga, 18 F) BnR-agonists(primarily for GRPR) image[118–122] or allow targeted-delivery of cytotoxic-radioisotopes( 177 Lu) to bind to breast-cancer-cells both in vitro [118,120–122] and in vivo to image breast-cancers xenografts in nude-mice[120–123]. In a comparative study in vivo of xenografts of breast-cancers in nude-mice, a 68 Ga-labeled-BnR-agonist showed greater tumor-uptake than a commonly used PET-imaging agent, 18 FDG.…”

“…99m Tc-labeled-liposomes conjugated to a BnR-agonist demonstrate high-uptake and strong scintigraphy images of breast-cancers xenografts in nude-mice[101,123]. Heterodiameric-PET-probes combining the RGD sequence, which binds to α(v)β(3)-integrins[119] and a BnR-agonist to various radioisotopes( 18 F, 64 Cu, 68 Ga) demonstrates high-uptake and the ability to image breast-cancer-cells in xenografts in nude-mice.…”