Search Results (42)

Background/Objectives: Gastrin-releasing peptide receptor is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of reported GRPR-targeted radioligands limits their clinical applications. Our group previously reported one ⁶⁸Ga-labeled GRPR antagonist, [⁶⁸Ga]Ga-TacsBOMB5 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,NMe-Gly¹¹,Leu¹³ψThz¹⁴]Bombesin(6–14)), and two agonists, [⁶⁸Ga]Ga-LW01110 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(6–14)) and [⁶⁸Ga]Ga-LW01142 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,His⁷,Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(6–14)) showing minimal pancreas uptake. Thus, in this study, we prepared their ¹⁷⁷Lu-labeled analogs, evaluated their therapeutic potentials, and compared them with the clinically evaluated [¹⁷⁷Lu]Lu-AMBA. Methods: GRPR binding affinities were determined by in vitro competition binding assay using PC-3 prostate cancer cells. Longitudinal SPECT/CT imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Dosimetry data were calculated from the biodistribution results. Results: The K_i(GRPR) values of Lu-TacsBOMB5, Lu-LW01110, Lu-LW01142, and Lu-AMBA were 12.6 ± 1.02, 3.07 ± 0.15, 2.37 ± 0.28, and 0.33 ± 0.16 nM, respectively. SPECT/CT images and biodistribution results demonstrated good tumor accumulation of [¹⁷⁷Lu]Lu-TacsBOMB5, [¹⁷⁷Lu]Lu-LW01110, and [¹⁷⁷Lu]Lu-LW01142 at early time points with rapid clearance over time. The pancreas uptake of all three [Thz¹⁴]Bombesin(6–14)-derived ligands was significantly lower than that of [¹⁷⁷Lu]Lu-AMBA at all time points. The calculated absorbed doses of [¹⁷⁷Lu]Lu-TacsBOMB5, [¹⁷⁷Lu]Lu-LW01110, and [¹⁷⁷Lu]Lu-LW01142 in PC-3 tumor xenografts were 87.1, 312, and 312 mGy/MBq, respectively, higher than that of [¹⁷⁷Lu]Lu-AMBA (79.1 mGy/MBq), but lower than that of the previously reported [¹⁷⁷Lu]Lu-RM2 (429 mGy/MBq). Conclusions: Our data suggest that [¹⁷⁷Lu]Lu-TacsBOMB5 and [¹⁷⁷Lu]Lu-LW01142 reduce radiation exposure to the pancreas. However, further optimizations are needed for both radioligands to prolong their tumor retention and enhance treatment efficacy. Full article

The identification of exogenous ligands from natural products is an alternative strategy to explore the unrevealed physiological functions of orphan G-protein-coupled receptors (GPCRs). In this study, we have successfully identified and pharmacologically characterized licoisoflavone A (LIA) as a novel selective antagonist of BRS-3, an orphan GPCR. Functional studies showed that pretreatment with LIA ameliorated hydrogen peroxide (H₂O₂)-induced cardiomyocyte injury. Furthermore, LIA pretreatment significantly restored the activities of malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT), as well as lactate dehydrogenase (LDH) levels, in H9c2 cells following H₂O₂ exposure. The protective effect of LIA was also evident in primary cardiomyocytes from rats and mice against H₂O₂-induced cell injury but was absent in primary cardiomyocytes derived from bombesin receptor subtype-3 knockout (Brs3^−/y) mice, strongly confirming the mechanism of LIA’s action through BRS-3 antagonism. Proteomics studies further revealed that LIA exerted its protective effects via activating the integrin/ILK/AKT and ERK/MAPK signaling pathways. Complementary findings from Bantag-1, a well-recognized antagonist of BRS-3, in human embryonic kidney 293 mBRS-3 (HEK293-mBRS-3) stable cells and B16 cell lines, which demonstrated resistance to H₂O₂-induced damage, further supported the pivotal role of BRS-3 in oxidative stress-induced cell injury. Our study contributes to expanding our understanding of the potential pharmacological functions of BRS-3, unveiling previously unknown pharmacological functionality of this orphan receptor. Full article

Bombesin receptor subtype-3 (BRS-3) is a type 1 G-protein-coupled receptor (GPCR). BRS-3 is an orphan GPCR that is structurally related to neuromedin B and gastrin-releasing peptide receptors. When activated, BRS-3 causes phosphatidylinositol turnover in lung cancer cells. BRS-3 stimulates tyrosine the phosphorylation of the epidermal growth-factor receptor (ErbB1); however, it is unknown whether it transactivates ErbB2/HER2. Adding the nonpeptide BRS-3 allosteric agonist MK-5046 or the peptide agonist BA1 to the lung cancer cell line NCI-H727 or to BRS-3-transfected NCI-H1299 lung cancer cells increased the tyrosine phosphorylation of HER2/ERK2. This increase was antagonized by the BRS-3 peptide antagonist Bantag-1 and the small-molecule BRS-3 antagonist ML-18. The increase in HER2/ERK phosphorylation caused by MK-5046 was inhibited by the ROS inhibitors N-acetylcysteine and Tiron (superoxide scavengers). Adding MK-5046 to lung cancer cells increased reactive oxygen species, which was inhibited by NAC or Tiron. MK-5046 and BA1 increased non-small lung cancer cell (NSCLC) colony formation, whereas Bantag-1/ML-18 inhibited proliferation. These results indicate that in lung cancer cells, the activation of BRS-3 regulates HER2 transactivation in an ROS-dependent manner, which can mediate tumor growth. These results raise the possibility that the use of HER2-inhibiting compounds alone or in combination with other agents could represent a novel approach to the treatment of these tumors. Full article

Background/Objectives: Overexpressed in various solid tumors, the gastrin-releasing peptide receptor (GRPR) is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of the current clinically evaluated GRPR-targeted radiopharmaceuticals limits their applications. In this study, we replaced the Pro¹⁴ residue in our previously reported GRPR-targeted LW02056 and ProBOMB5 with 4,4-difluoroproline (diF-Pro) to obtain an agonist LW02060 (DOTA-Pip-[D-Phe⁶,Tle¹⁰,NMe-His¹²,diF-Pro¹⁴]Bombesin(6–14)) and an antagonist LW02080 (DOTA-Pip-[D-Phe⁶,NMe-Gly¹¹,Leu¹³(ψ)diF-Pro¹⁴]Bombesin(6–14)), respectively. Methods/Results: The binding affinities (K_i) of Ga-LW02060, Ga-LW02080, Lu-LW02060, and Lu-LW02080 were measured by in vitro competition binding assays using PC-3 cells and were found to be 5.57 ± 2.47, 21.7 ± 6.69, 8.00 ± 2.61, and 32.1 ± 8.14 nM, respectively. The ⁶⁸Ga- and ¹⁷⁷Lu-labeled ligands were obtained in 36–75% decay-corrected radiochemical yields with >95% radiochemical purity. PET imaging, SPECT imaging, and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Both [⁶⁸Ga]Ga-LW02060 and [⁶⁸Ga]Ga-LW02080 enabled clear tumor visualization in PET images at 1 h post-injection (pi). Tumor uptake values of [⁶⁸Ga]Ga-LW02060 and [⁶⁸Ga]Ga-LW02080 at 1 h pi were 16.8 ± 2.70 and 7.36 ± 1.33 %ID/g, respectively, while their pancreas uptake values were 3.12 ± 0.89 and 0.38 ± 0.04 %ID/g, respectively. Compared to [¹⁷⁷Lu]Lu-LW02080, [¹⁷⁷Lu]Lu-LW02060 showed higher tumor uptake at all time points (1, 4, 24, 72, and 120 h pi). However, fast tumor clearance was observed for both [¹⁷⁷Lu]Lu-LW02060 and [¹⁷⁷Lu]Lu-LW02080. Conclusions: Our data demonstrate that [⁶⁸Ga]Ga-LW02060 is promising for clinical translation for the detection of GRPR-expressing tumor lesions. However, further optimizations are needed for [¹⁷⁷Lu]Lu-LW02060 and [¹⁷⁷Lu]Lu-LW02080 to prolong tumor retention for therapeutic applications. Full article

Background/Objectives: Prostate cancer (PC) represents the second most diagnosed form of cancer in men on a global scale. Despite the theranostic efficacy of prostate-specific membrane antigen (PSMA) radioligands, there is a spectrum of PC disease in which PSMA expression is low or absent. The gastrin-releasing peptide receptor (GRPR), also known as the bombesin type 2 receptor, has been identified as a target in both the early and advanced stages of PC. The objective of this study was to prepare and preclinically evaluate [^99mTc]Tc-iPSMA-Bombesin ([^99mTc]Tc-iPSMA-BN), estimate dosimetry in healthy subjects, and assess the diagnostic efficacy of the radiotracer in patients with metastatic PC, with the hypothesis of non-inferiority to one of the gold standards, [¹⁸F]-PSMA-1007. Moreover, the potential of [^99mTc]Tc-iPSMA-BN as a theranostic pair with [¹⁷⁷Lu]Lu-iPSMA-BN was investigated. Methods: [^99mTc]Tc-iPSMA-BN was prepared under GMP conditions with radiochemical purities > 95%, showing specific recognition by PSMA and GRP receptors in prostate cancer cells and mice bearing PC tumors. Six healthy volunteers were enrolled, and [^99mTc]Tc-iPSMA-BN SPECT/CT imaging (740 MBq) was performed to estimate the dosimetry. The pilot clinical study included seven mCRPC and four mCSPC patients with prior androgen deprivation therapy. All patients had a recent [¹⁸F]-PSMA-PET/CT scan and were enrolled in this prospective study on their own signed behalf. Volumetric lesion target-to-background ratios (TBRs) were obtained from PET/CT and SPECT/CT images. Results: [^99mTc]Tc-iPSMA-BN effective radiation dose was 1.94 ± 0.39 mSv/740 MBq. A total of 178 lesions were detected via CT, 162 via [¹⁸F]-PSMA-1007 PET, and 155 via [^99mTc]Tc-iPSMA-BN SPECT. Three patients with mCRPC had higher TBR values on SPECT than on PET. [^99mTc]Tc-iPSMA-BN appears to have better lesion detection in patients with aggressive histologic transformation. Two-way ANOVA analysis revealed a significant difference in TBR values between patients with mCRPC and mCSPC (p < 0.05) but no difference between [¹⁸F]-PSMA-1007 and [^99mTc]Tc-iPSMA-BN (p > 0.05). In one patient, [¹⁷⁷Lu]Lu-iPSMA-BN showed a high correlation with [^99mTc]Tc-iPSMA-BN for lesions that concentrated radioactivity. Conclusions: [^99mTc]Tc-iPSMA-BN SPECT/CT is a promising alternative not only for diagnostic purposes but also for broadening the spectrum of PC patients who may benefit from radionuclide theranostics. The results justify the development of a clinical trial involving a significant number of patients with PC. Full article

We developed a novel site-specific bimodal MRI/fluorescence nanoparticle contrast agent targeting gastrin-releasing peptide receptors (GRPrs), which are overexpressed in aggressive prostate cancers. Biocompatible ultra-small superparamagnetic iron oxide (USPIO) nanoparticles were synthesized using glucose and casein coatings, followed by conjugation with a Cy7.5-K-8AOC-BBN [7-14] peptide conjugate. The resulting USPIO(Cy7.5)-BBN nanoparticles were purified by 100 kDa membrane dialysis and fully characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared (FTIR) spectroscopy, and magnetic resonance imaging (MRI) relaxivity, as well as evaluated for in vitro and in vivo binding specificity and imaging efficacy in PC-3 prostate cancer cells and xenografted tumor-bearing mice. The USPIO(Cy7.5)-BBN nanoparticles had a core diameter of 4.93 ± 0.31 nm and a hydrodynamic diameter of 35.56 ± 0.58 nm. The r₂ relaxivity was measured to be 70.2 ± 2.5 s⁻¹ mM⁻¹ at 7T MRI. The Cy7.5-K-8AOC-BBN [7-14] peptide-to-nanoparticle ratio was determined to be 21:1. The in vitro GRPr inhibitory binding (IC₅₀) value was 2.5 ± 0.7 nM, indicating a very high binding affinity of USPIO(Cy7.5)-BBN to the GRPr on PC-3 cells. In vivo MRI showed significant tumor-to-muscle contrast enhancement in the uptake group at 4 h (31.1 ± 3.4%) and 24 h (25.7 ± 2.1%) post-injection compared to the blocking group (4 h: 15.3 ± 2.0% and 24 h: −2.8 ± 6.8%; p < 0.005). In vivo and ex vivo near-infrared fluorescence (NIRF) imaging revealed significantly increased fluorescence in tumors in the uptake group compared to the blocking group. These findings demonstrate the high specificity of bimodal USPIO(Cy7.5)-BBN nanoparticles towards GRPr-expressing PC-3 cells, suggesting their potential for targeted imaging in aggressive prostate cancer. Full article

The design and development of hybrid compounds as a new class of drug candidates remains an excellent opportunity to improve the pharmacological properties of drugs (including enzymatic stability, efficacy and pharmacokinetic and pharmacodynamic profiles). In addition, considering various complex diseases and/or disorders, the conjugate chemistry approach is highly acceptable and justified. Opioids have long been recognized as the most potent analgesics and serve as the basic pharmacophore for potent hybrid compounds that may be useful in pain management. However, a risk of tolerance and physical dependence exists. Since dopamine receptors have been implicated in the aforementioned adverse effects of opioids, the construction of a hybrid with dual action at opioid and dopamine receptors is of interest. Herein, we present nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation results for LENART01, an opioid–ranatensin hybrid peptide. Apart from molecular docking, protein–ligand interactions were also assessed in vitro using a receptor binding assay, which proved LENART01 to be bound to mu-opioid and dopamine receptors, respectively. Full article

Despite the tremendous development of oncology, prostate cancer remains a debilitating malignancy. One of the most promising approaches to addressing this issue is to exploit the advancements of nanomedicine in combination with well-established nuclear medicine and radiotherapy. Following this idea, we have developed a radioisotope nanocarrier platform of electron-beam-synthesized nanogels based on poly(acrylic acid). We have developed a functionalization protocol, showing the very high (>97%) efficiency of the conjugation in targeting a ligand–bombesin derivative. This engineered peptide can bind gastrin-releasing peptide receptors overexpressed in prostate cancer cells; moreover, it bears a radioisotope-chelating moiety. Our nanoplatform exhibits very promising performance in vitro; the radiolabeled nanocarriers maintained high radiochemical purity of >90% in both the labeling buffer and human serum for up to 14 days. The application of the targeted nanocarrier allowed also effective and specific uptake in PC-3 prostate cancer cells, up to almost 30% after 4 h, which is a statistically significant improvement in comparison to carrier-free radiolabeled peptides. Although our system requires further studies for more promising results in vivo, our study represents a vital advancement in radionanomedicine—one of many steps that will lead to effective therapy for castration-resistant prostate cancer. Full article

Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on the surface of various cancer cells. However, their biological properties proceed far beyond this, given a broad spectrum of activity. Bombesin receptor ligands are effective drugs for the treatment of rheumatoid arthritis or gastrointestinal diseases. However, most diseases are complex, and the use of polytherapy may lead to pharmacokinetic and pharmacodynamic drug–drug interactions, resulting in side effects. Therefore, there is a need to develop effective compounds that also contain BN or its analogs, which are combined with other structural entities, thus generating a so-called hybrid drug. Hybrid drugs that contain bombesin pharmacophore(s) may be proposed as a solution to the problem of polytherapy or the lack of an effective cure. Such structures have now demonstrated the desired efficacy, though information on these aforementioned compounds is relatively scarce. Therefore, our paper aims to encourage researchers to focus on bombesins. Herein, we indicate that the hybrid approach should also be firmly applied to bombesins and the BN receptor family. This paper’s structure is divided into two main sections demonstrating bombesins and their properties, as well as recent data on bombesin-based hybrid compounds and their potential usefulness in medicine. Overall, it refers to the discovery and synthesis of modified bombesin-based hybrid compounds. Full article

The clinical success of radiolabeled somatostatin analogs in the diagnosis and therapy—“theranostics”—of tumors expressing the somatostatin subtype 2 receptor (SST₂R) has paved the way for the development of a broader panel of peptide radioligands targeting different human tumors. This approach relies on the overexpression of other receptor-targets in different cancer types. In recent years, a shift in paradigm from internalizing agonists to antagonists has occurred. Thus, SST₂R-antagonist radioligands were first shown to accumulate more efficiently in tumor lesions and clear faster from the background in animal models and patients. The switch to receptor antagonists was soon adopted in the field of radiolabeled bombesin (BBN). Unlike the stable cyclic octapeptides used in the case of somatostatin, BBN-like peptides are linear, fast to biodegradable and elicit adverse effects in the body. Thus, the advent of BBN-like antagonists provided an elegant way to obtain effective and safe radiotheranostics. Likewise, the pursuit of gastrin and exendin antagonist-based radioligands is advancing with exciting new outcomes on the horizon. In the present review, we discuss these developments with a focus on clinical results, commenting on challenges and opportunities for personalized treatment of cancer patients by means of state-of-the-art antagonist-based radiopharmaceuticals. Full article

Angiogenesis-related cell-surface molecules, including integrins, aminopeptidase N, vascular endothelial growth factor, and gastrin-releasing peptide receptor (GRPR), play a crucial role in tumour formation. Radiolabelled imaging probes targeting angiogenic biomarkers serve as valuable vectors in tumour identification. Nowadays, there is a growing interest in novel radionuclides other than gallium-68 (⁶⁸Ga) or copper-64 (⁶⁴Cu) to establish selective radiotracers for the imaging of tumour-associated neo-angiogenesis. Given its ideal decay characteristics (E_β⁺_average: 632 KeV) and a half-life (T_1/2 = 3.97 h) that is well matched to the pharmacokinetic profile of small molecules targeting angiogenesis, scandium-44 (⁴⁴Sc) has gained meaningful attention as a promising radiometal for positron emission tomography (PET) imaging. More recently, intensive research has been centered around the investigation of ⁴⁴Sc-labelled angiogenesis-directed radiopharmaceuticals. Previous studies dealt with the evaluation of ⁴⁴Sc-appended a_vb₃ integrin–affine Arg-Gly-Asp (RGD) tripeptides, GRPR-selective aminobenzoyl–bombesin analogue (AMBA), and hypoxia-associated nitroimidazole derivatives in the identification of various cancers using experimental tumour models. Given the tumour-related hypoxia- and angiogenesis-targeting capability of these PET probes, ⁴⁴Sc seems to be a strong competitor of the currently used positron emitters in radiotracer development. In this review, we summarize the preliminary preclinical achievements with ⁴⁴Sc-labelled angiogenesis-specific molecular probes. Full article

The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [^99mTc]Tc-maSSS-PEG₂-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 µg of [^99mTc]Tc-maSSS-PEG₂-RM26 (600–700 MBq). No adverse events or pathological changes were observed. The rapid blood clearance of [^99mTc]Tc-maSSS-PEG₂-RM26 was observed with predominantly hepatobiliary excretion. The effective doses were 0.0053 ± 0.0007 for male patients and 0.008 ± 0.003 mSv/MBq for female patients. The accumulation of [^99mTc]Tc-maSSS-PEG₂-RM26 in tumors was observed in four out of six PCa and in seven out of seven BCa patients. In four BCa patients, a high uptake of the agent into the axillary lymph nodes was detected. Immunohistochemistry revealed positive GRPR expression in 60% of primary PCa, 71.4% of BCa tumors, and 50% of examined BCa lymph nodes. In conclusion, a single administration of [^99mTc]Tc-maSSS-PEG₂-RM26 was safe and well tolerated. [^99mTc]Tc-maSSS-PEG₂-RM26 SPECT may be useful for tumor detection in PCa and BCa patients, pending further studies. Full article

With overexpression in various cancers, the gastrin-releasing peptide receptor (GRPR) is a promising target for cancer imaging and therapy. However, the high pancreas uptake of reported GRPR-targeting radioligands limits their clinical application. Our goal was to develop ⁶⁸Ga-labeled agonist tracers for detecting GRPR-expressing tumors with positron emission tomography (PET), and compare them with the clinically validated agonist PET tracer, [⁶⁸Ga]Ga-AMBA. Ga-TacBOMB2, TacBOMB3, and TacBOMB4, derived from [Thz¹⁴]Bombesin(7–14), were confirmed to be GRPR agonists by a calcium mobilization study, and their binding affinities (K_i(GRPR)) were determined to be 7.62 ± 0.19, 6.02 ± 0.59, and 590 ± 36.5 nM, respectively, via in vitro competition binding assays. [⁶⁸Ga]Ga-TacBOMB2, [⁶⁸Ga]Ga-TacBOMB3, and [⁶⁸Ga]Ga-AMBA clearly visualized PC-3 tumor xenografts in a PET imaging study. [⁶⁸Ga]Ga-TacBOMB2 showed comparable tumor uptake but superior tumor-to-background contrast ratios when compared to [⁶⁸Ga]Ga-AMBA. Moreover, [⁶⁸Ga]Ga-TacBOMB2 and [⁶⁸Ga]Ga-TacBOMB3 showed a much lower rate of uptake in the pancreas (1.30 ± 0.14 and 2.41 ± 0.72%ID/g, respectively) than [⁶⁸Ga]Ga-AMBA (62.4 ± 4.26%ID/g). In conclusion, replacing Met¹⁴ in the GRPR-targeting sequence with Thz¹⁴ retains high GRPR-binding affinity and agonist properties. With good tumor uptake and tumor-to-background uptake ratios, [⁶⁸Ga]Ga-TacBOMB2 is promising for detecting GRPR-expressing tumors. The much lower pancreas uptake of [⁶⁸Ga]Ga-TacBOMB2 and [⁶⁸Ga]Ga-TacBOMB3 suggests that [Thz¹⁴]Bombesin(7–14) is a promising targeting vector for the design of GRPR-targeting radiopharmaceuticals, especially for radioligand therapy application. Full article

Advances in nanomedicine bring the attention of researchers to the molecular targets that can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical, and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby, the recent advances in the field of applications of various nanoplatforms that are able to reach the GRPR-expressing cells are reviewed. Full article

Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. Among several receptors upregulated in cancer cells, the gastrin-releasing peptide receptor (GRP-R) has recently emerged as a promising target for cancer imaging, diagnosing and treatment due to its overexpression on cancerous tissues such as breast, prostate, pancreatic and small-cell lung cancer. Herein, we report on the in vitro and in vivo selective delivery of the cytotoxic drug daunorubicin to prostate and breast cancer, by targeting GRP-R. Exploiting many bombesin analogues as homing peptides, including a newly developed peptide, we produced eleven daunorubicin-containing peptide–drug conjugates (PDCs), acting as drug delivery systems to safely reach the tumour environment. Two of our bioconjugates revealed remarkable anti-proliferative activity, an efficient uptake by all three tested human breast and prostate cancer cell lines, high stability in plasma and a prompt release of the drug-containing metabolite by lysosomal enzymes. Moreover, they revealed a safe profile and a consistent reduction of the tumour volume in vivo. In conclusion, we highlight the importance of GRP-R binding PDCs in targeted cancer therapy, with the possibility of further tailoring and optimisation. Full article