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pH-Responsive Polymers for Delivery of Nucleic Acid Therapeutics
Published in Severian Dumitriu, Valentin Popa, Polymeric Biomaterials, 2020
Subsequently the investigators functionalized the siRNA nanoparticles with a bombesin peptide analog, which presents a targeting ligand to the bombesin receptor. This receptor is overexpressed on the cell surface of various cancer cells. The targeted siRNA nanoparticles resulted in specific gene silencing efficiency in CHO and U87 cells in vitro. Systemic administration of a therapeutic anti-HIF-1R siRNA with the bombesin-loaded carrier resulted in significant tumor growth inhibition in nude mice bearing human glioma U87 xenografts (Wang et al. 2009b).
Radiolabeled Agents for Molecular Imaging and/or Therapy
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Dimitrios Psimadas, Eirini A. Fragogeorgi
Bombesin (BN) is a small neuropeptide of 14 amino acids originally isolated from frog skin. One of its mammalian counterparts is the 27-amino acid gastrin-releasing peptide (GRP). Both peptides show similar biological behavior in humans. GRP and bombesin can bind to GRP receptors (GRPR), which are G-protein coupled receptors (GPCRs) and are present on cells of many human cancer types, such as prostate, breast, and pancreatic cancer and small-cell lung carcinoma, making radiolabeled BN analogs attractive candidates for targeting GRPR (Fani and Maecke 2012). The half-life of natural BN is about 2–3 min and, therefore, more resistant analogs have been developed as molecular imaging tracers. The binding site of BN consists of eight amino acid residues, and in the literature peptides that incorporate these eight peptides are usually termed BN. Radiolabeled BN analogs are usually based on the eight amino acid sequence peptide analogs that have modified amino acid residues in order to improve their stability and allow conjugation of chelators for radiolabeling.
Radionuclide-based Diagnosis and Therapy of Prostate Cancer
Published in Michael Ljungberg, Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
Sven-Erik Strand, Mohamed Altai, Joanna Strand, David Ulmert
The high-density expression of gastrin-releasing peptide receptors (GRPRs) in several human cancer forms, as PCa, compared to their low expression in surrounding healthy tissues, provided an opportunity to develop several theranostic agents targeting this tumour marker. Bombesin, a 14 amino acids peptide, was initially isolated from the skin of the European frog Bombina bombina in the early 1970s. Among several identified bombesin agonists, [Leu13]BN was found to have the highest affinity towards GRPR, and high homology to its endogenous ligand gastrin-releasing peptide (GRP). Agonists trigger internalization into the cell upon binding to GRPR. When labelled with residualizing labels efficient internalization, enables prominent accumulation of radioactivity in the tumour. High-affinity antagonists on the other hand have low internalization, but were still found to have superior tumour-targeting and pharmacokinetic properties compared to agonists [73]. The GRPR antagonist [111In]-RM1, showed superior in vivo targeting properties, that is, 3-fold higher tumour uptake, compared to the potent GRPR agonist [111In]- AMBA81 [74]. C-terminus modification of RM1, has led to the development of the more potent GRPR antagonist (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt). Efforts to optimize targeting properties of this antagonist by conjugating it to different macrocyclic chelators as well as radiolabelling with several clinically relevant radionuclides resulted in developing 68Ga-DOTA-Sarabesin3 [75], which exhibited encouraging results in men [76]. By replacement of the C-terminal Leu13-Met14-NH2dipeptide of SB3 bySta13-Leu14-NH2, the novel GRPR antagonist NeoBOMB1 was generated [77]. NeoBOMB1, was labelled with 68Ga (for PET), 111In (for SPECT), and 177Lu (for therapy). 68Ga-Neo-BOMB1, 111In-NeoBOMB1, and 177Lu-NeoBOMB1 efficiently localized in PCa cell line PC-3. Successful visualization of PCa lesions in men was possible using 68Ga-NeoBOMB1 and PET/CT imaging [77]. The statine-based high affinity GRPR antagonist RM26 (also known as JMV594) formed the basis for various tracers that are under development for imaging and therapy in PCa [78]. RM26 was radiolabelled with cobalt isotopes and evaluated in PCa tumour-bearing mice. The cobalt-radiolabelled NOTA-PEG2-RM26 demonstrated favourable biodistribution, which translated into high-contrast preclinical PET/CT (using 55Co) and SPECT/CT (using 57Co) images of PC-3 xenografts [79]. Recently a study was designed to analyse the safety, biodistribution, and radiation dosimetry of 68Ga-RM26 in healthy human volunteers [80]. Moreover, a direct comparison between GRPR antagonist 68Ga-RM26 and agonist 68Ga-BBN was evaluated. This study demonstrated the safety and significant efficiency of 68Ga-RM26. The antagonist 68Ga-RM26 was shown to be better than the GRPR agonist as an imaging marker to evaluate GRPR expression in PCa.
Engineering of 177Lu-labeled gold encapsulated into dendrimeric nanomaterials for the treatment of lung cancer
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Zheng Wang, Minhua Ye, Dehua Ma, Jianfei Shen, Fang Fang
Bombesin and GRP-similar peptides have been implicated as growth factors in various kinds of carcinoma over the last two decades. Most of the lung cancer tissues overexpress the gastrin-releasing peptide receptors [41–44]. Several bombesin derivatives with solid potential for GRPR have explored in clinical investigations for specific receptors treatment and imaging. Radionuclide imaging of lung cancers has been successfully performed using radio-bombesin analogues in clinical trials [45–47]. Therefore, HEL-299 human lung cells have been utilized as tumour models to assess novel bombesin probes [48]. A membrane-bound protein with a great affinity for binding and delivering folate into cells, folate receptor-α (FR-α) is a folate receptor. Enhanced control of cell metabolism, folate is also involved in DNA synthesis and repair and cellular respiration. Antifolates are often used in cancer treatment because cancer cells, which quickly increase, have higher folate requirements to retain DNA engineering. All lung cancer subtypes and overexpress FRs. FRs are significantly expressed in HEL-299 cells, according to current polymerase chain reaction (PCR) investigations [49–52].
Functional biomimetic nanoparticles for drug delivery and theranostic applications in cancer treatment
Published in Science and Technology of Advanced Materials, 2018
Lei Li, Junqing Wang, Hangru Kong, Yun Zeng, Gang Liu
In addition to the drug delivery, pH-sensitive liposomes could also act as a delivery system for tumor identification. De Barros et al. prepared the long-circulating, pH-sensitive liposomes to encapsulate the radiolabeled bombesin derivative 99mTc-BBN(7–14), which is a tetradecapeptide that binds specifically to gastrin-releasing peptide receptors in humans [77]. Several forms of cancer, including lung, prostate, breast, and colon usually over-express receptors for bombesin-like peptides. The formulation showed high stability in vitro and the results of biodistribution study with Ehrlich tumor-bearing mice showed that the pH-sensitive liposomes could be taken by the tumor cells, exhibiting efficient delivery of the radiolabeled bombesin analog and providing a new possibility to improve images quality of tumors.