bims-cepepe 2024-11-10 papers

bims-cepepe

Biomed News

on Cell-penetrating peptides

Issue of 2024‒11‒10
thirteen papers selected by
Henry Lamb, Queensland University of Technology

Methyl-β-cyclodextrin Enhances Tumor Cellular Uptake and Accumulation of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles.
Recalibration of MARTINI-3 Parameters for Improved Interactions between Peripheral Proteins and Lipid Bilayers.
β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide.
Polysaccharide-Based Coacervate Microgel Bearing Cationic Peptides That Achieve Dynamic Cell-Membrane Structure Alteration and Facile Cytosolic Infusion of IgGs.
Construction of a novel amphiphilic peptide paclitaxel rod micelle: Demonstrating that the nano-delivery system shape can affect the cellular uptake efficiency of paclitaxel and improve the therapeutic efficacy for breast cancer.
Disulfide-Rich Self-Assembling Peptides Based on Aromatic Amino Acid.
Macropinocytosis-targeted peptide-docetaxel conjugate for bystander pancreatic cancer treatment.
A LANA peptide inhibits tumor growth by inducing CHD4 protein cleavage and triggers cell death.
Targeting HER2 in breast cancer with brain metastases: a pharmacological point of view with special focus on the permeability of blood-brain barrier to targeted treatments.
Lipidation and PEGylation strategies to prolong the in vivo half-life of a nanomolar EphA4 receptor antagonist.
Lasso peptides realm: Insights and applications.
Targeting RAF1 gene fusions with MEK inhibition in metastatic melanoma.
Peptide Receptor Radionuclide Therapy and clinical associations with renal and hematological toxicities and survival in patients with neuroendocrine tumors: an analysis from two U.S. medical centers.

Mol Pharm. 2024 Nov 04.

Methyl-β-cyclodextrin Enhances Tumor Cellular Uptake and Accumulation of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles.

Meiqi Xu, Junwei Liu, Jianming Yu, Jingwen Wang, Hui Li, Ting Zhong, Yanli Hao, Zhuoyue Li, Jingru Wang, Xu Huang, Hui Wang, Yubo Tian, Heng Zhao, Qingchao Wei, Xuan Zhang.

  Improving nanomedicine uptake by tumor cells is key to achieving intracellular drug delivery. In this study, we found that methyl-β-cyclodextrin (MβCD) can significantly promote the intracellular accumulation of nanoparticulated α-linolenic acid-paclitaxel conjugates (ALA-PTX NPs) via enhanced clathrin-mediated endocytosis and limited degradation in lysosomes. Our in vitro results indicated that MβCD not only reduced the plasma membrane cholesterol content and increased plasma membrane fluidity, leading to ALA-PTX NPs being more easily incorporated into the plasma membrane, further enhancing membrane fluidity and making the plasma membrane more susceptible to tensile deformation, forming intracellular vesicles to enhance ALA-PTX NP cellular uptake, but also destroyed lysosomes and then limited ALA-PTX NPs' degradation in lysosomes. In HepG2 tumor-bearing mice, MβCD was also able to enhance the antitumor activity of ALA-PTX NPs in vivo. Moreover, we found that MβCD specifically promoted PUFA-paclitaxel conjugate NP cellular uptake. The cellular uptake of PTX liposome which shares an endocytosis pathway with ALA-PTX NPs could be enhanced by MβCD combined with ALA or ALA-PTX NPs. Therefore, we suggested that MβCD combined with polyunsaturated fatty acid-conjugation would be an effective strategy for improving intracellular delivery of nanoparticulated chemotherapeutic drugs used for combination administration to enhance antitumor efficiency.

Keywords:  cellular uptake; clathrin-mediated endocytosis; membrane fluidity; methyl-β-cyclodextrin; α-linolenic acid-paclitaxel conjugate nanoparticles

DOI:  https://doi.org/10.1021/acs.molpharmaceut.4c00190
J Chem Theory Comput. 2024 Nov 03.

Recalibration of MARTINI-3 Parameters for Improved Interactions between Peripheral Proteins and Lipid Bilayers.

Jatin Soni, Shivam Gupta, Taraknath Mandal.

The MARTINI force field is one of the most used coarse-grained models for biomolecular simulations. Many limitations of the model including the protein-protein overaggregation have been improved in its latest version, MARTINI-3. In this study, we investigate the efficacy of the MARTINI-3 parameters for capturing the interactions of peripheral proteins with model plasma membranes. Particularly, we consider two classes of proteins, namely, annexin and epsin, which are known to generate negative and positive membrane curvatures, respectively. We find that current MARTINI-3 parameters are not able to correctly describe the protein-membrane interface and the protein-induced membrane curvatures for any of these proteins. The problem arises due to the lack of proper hydrophobic interactions between the protein residues and lipid tails. Making systematic adjustments, we show that a combination of reduction in the protein-water interactions and enhancement of protein-lipid hydrophobic interactions is essential for accurate prediction of the interfacial structure including the protein-induced membrane curvature. Next, we apply our model to a couple of other peripheral proteins, namely, Snf7, a core component of the ESCRT-III complex, and the PH domain of evectin-2. We find that our model captures the protein-membrane interfacial structure much more accurately than the MARTINI-3 model for all of the peripheral proteins considered in this study. However, the strategy described in this study may not be suitable for oligomeric transmembrane proteins where protein-protein hydrophobic interactions should be increased instead of protein-lipid hydrophobic interactions.

DOI: https://doi.org/10.1021/acs.jctc.4c00645
J Pharm Sci. 2024 Nov 02. pii: S0022-3549(24)00493-3. [Epub ahead of print]

β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide.

Negar Jafari, Justin T Douglas, Sarah A Neuenswander, Payam Kelich, Michael J Hageman.

  Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated. NMR spectroscopy was used to examine the interaction between β-cyclodextrin derivatives and specific residues of lanreotide. It was observed that the hydrophobic side chain of aromatic residues in the lanreotide sequence can be fit into the cavity of both β-cyclodextrin derivatives. Additionally, NMR revealed a lower diffusion coefficient and higher hydrodynamic radius of complex, indicative of binding to the cavities. Each aromatic residue was individually studied by substituting alanine in lanreotide to measure its association binding with both β-cyclodextrin derivatives. The alanine-substitute study indicated a stronger binding of SBEβ-CD to Lanreotide compared to HPβ-CD. Docking studies suggested that the 1:1 inclusion complex is more favorable than higher order complexes due to the steric hindrance and size considerations. The docking analysis indicated the stable conformation of all three aromatic side chains with both β-cyclodextrin derivatives, SBEβ-CDand HPβ-CD.

Keywords:  NMR; association binding; cyclic peptide drug; cyclodextrin; fluorescence spectroscopy; lanreotide

DOI:  https://doi.org/10.1016/j.xphs.2024.10.042
Bioconjug Chem. 2024 Nov 05.

Polysaccharide-Based Coacervate Microgel Bearing Cationic Peptides That Achieve Dynamic Cell-Membrane Structure Alteration and Facile Cytosolic Infusion of IgGs.

Junya Michibata, Yoshimasa Kawaguchi, Hisaaki Hirose, Akiko Eguchi, Sayaka Deguchi, Kazuo Takayama, Wei Xu, Takuro Niidome, Yoshihiro Sasaki, Kazunari Akiyoshi, Shiroh Futaki.

Conjugates of the biocompatible polysaccharide pullulan with a cell membrane permeabilizing peptide L17E (PL-L17Es) were prepared with the aim of producing complex coacervates with pronounced intracellular antibody (IgG) delivery activity and stable structures. Coacervates with diameters of a few μm were formed simply by mixing PL-L17Es with IgG labeled with negatively charged fluorescent moieties of Alexa Fluor 488 [IgG(AF488)]. The coacervate resulted in a pronounced cytosolic infusion of IgG(AF488) and IgG binding to the target proteins inside the cell. The droplet structures were maintained even under high salt conditions, and the fluorescence in the droplet was not recovered after photobleaching, suggesting the formation of complex coacervate microgels. Dynamic changes in cell membrane structure to entrap the coacervate microgels were captured by confocal and electron microscopy, resulting in cytosolic IgG infusion. The use of M-lycotoxin instead of L17E resulted in a coacervate microgel with marked IgG delivery activity even in the presence of serum. Successful IgG delivery to primary hepatocytes, undifferentiated induced pluripotent stem (iPS) cells, and iPS cell-derived intestinal epithelial cells was also achieved. The construction of complex coacervate microgels with design flexibility and the validity of intracellular IgG delivery with high salt stability were thus demonstrated.

DOI: https://doi.org/10.1021/acs.bioconjchem.4c00344
Biomater Adv. 2023 Oct 25. pii: S2772-9508(23)00396-5. [Epub ahead of print]155 213673

Construction of a novel amphiphilic peptide paclitaxel rod micelle: Demonstrating that the nano-delivery system shape can affect the cellular uptake efficiency of paclitaxel and improve the therapeutic efficacy for breast cancer.

Tangyong Xiang, Yu Liu, Shan Xu, Weixi Zhong, Zhengzhou Sha, Jian Zhang, Linwei Chen, Yarong Li, Weidong Li, Zheng Yan, Zhipeng Chen, Liu Xu.

  Recent studies have shown that the morphology of nano-delivery systems has become a key factor affecting their anti-tumor effects. Although it has been demonstrated that rod-like nanoparticles are more easily absorbed by tumor cells, the application of rod-like nanoparticles is still limited by the lack of safe vector in vivo. In this study, a biocompatible amphiphilic peptide (IIQQQQ, I2Q4), was designed to form rod-like micelles. The key forces of the self-assembly mechanism were investigated. Driven by hydrogen bonds, the hydrophilic segment of the peptide formed a β-sheet structure, and the molecules accumulated and extended along the side chain direction to form a rod-like structure. Using paclitaxel (PTX) as the model drug, a PTX rod-like nano-drug delivery system, PTX@I2Q4, was constructed. PTX exists in a randomly coiled state in the hydrophobic cavity formed by the peptide. Compared to PTX and spherical PTX albumin nanoparticles, PTX@I2Q4 showed higher entry efficiency and better antitumor effects in vivo and in vitro. This was mainly because PTX@I2Q4 not only allowed more efficient entry into cells via macro-pinocytosis, but also significantly prolonged the t1/2 of PTX. The results confirmed the feasibility of regulating the morphology of nanoparticles to improve the efficacy of PTX and provide a reference for further research on the influence of the morphology of the nano-drug delivery system on the efficacy of antitumor effects.

Keywords:  Breast cancer; Paclitaxel; Rod-like micelle; Self-assembly peptide

DOI:  https://doi.org/10.1016/j.bioadv.2023.213673
Small. 2024 Nov 03. e2407464

Disulfide-Rich Self-Assembling Peptides Based on Aromatic Amino Acid.

Wenjing Huang, Huilei Dong, Qipeng Yan, Tingfen Deng, Xiaoxu Li, Zhe Zhao, Zenghui Li, Mingshui Wang, Chunhui Zhang, Bo Kong, Junfeng Shi, Dan Yuan.

  Aromatic residues in assembling peptides play a crucial role in driving peptide self-assembly through π-π stacking and hydrophobic interactions. Although various aromatic capping groups have been extensively studied, systematic investigations into the effects of single aromatic amino acids in assembling peptides remain limited. In this study, the influence of aromatic-aromatic interactions on disulfide-rich assembling peptides is systematically investigated by incorporating three different aromatic amino acids. Their folding propensity, self-assembling properties, and rheological behaviors are evaluated. These results indicate that different aromatic-aromatic interactions have a significant effect on self-assembly abilities, as determined by critical aggregation concentration (CAC) measurements. Furthermore, the biocompatibility of these hydrogels is assessed, and their potential for 3D cell culture is explored. The injectable F1-ox hydrogel demonstrate excellent biocompatibility for SHED and NIH3T3 cells and exhibit a porous structure that facilitates nutrient and cellular metabolic waste exchange. This work provides new insights into the molecular design of peptide-based biomaterials, with a focus on the impact of aromatic residues on disulfide-rich assembling peptides.

Keywords:  3D cell culture; aromatic interaction; hydrogel; peptide; self‐assembly

DOI:  https://doi.org/10.1002/smll.202407464
J Control Release. 2024 Nov 05. pii: S0168-3659(24)00743-0. [Epub ahead of print]376 829-841

Macropinocytosis-targeted peptide-docetaxel conjugate for bystander pancreatic cancer treatment.

Young Seok Cho, Hanhee Cho, Ha Rin Kim, Seong Jin Park, Joo Hye Yeo, Yoon Gun Ko, Jinu Lee, Sang Yoon Kim, Kwangmeyung Kim, Youngro Byun.

  Oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are highly prevalent in pancreatic ductal adenocarcinoma (PDAC) and have garnered attention as potential targets for targeted therapies, such as KRAS inhibitors. However, the limited therapeutic efficacy of KRAS allele-specific inhibitors necessitate an efficient pan-KRAS cancer cell killing strategy. Here, we have examined enhanced macropinocytosis pathway in KRAS mutant cancer cells and report improved intracellular delivery of albumin-based therapeutics. We further established an albumin-binding peptide-docetaxel conjugate platform (MPD3), which has a caspase-3 cleavable feature, for macropinocytosis-targeted bystander payload delivery and realization of bystander killing of pan-KRAS cancer cells, complemented with caspase-3 mediated activation of MPD3 to bolster tumoral accumulation of cytotoxic payloads. Utilization of in vitro co-culture system of pan-KRAS cancer cells and pharmacodynamic marker staining revealed potent bystander killing effects of MPD3, highlighting MPD3 as an efficient delivery platform against pan-KRAS cancer. Moreover, MPD3 elicited robust anti-tumor activities in both local and liver metastatic PDAC tumor models in mice. Overall, this work establishes a paradigm for developing translational pan-KRAS cancer treatment and broadens the applicability of albumin binding peptide-drug conjugate against albumin-metabolism enriched cancers.

Keywords:  Bystander killing; KRAS mutation; Macropinocytosis; Pancreatic cancer; Peptide-drug conjugate

DOI:  https://doi.org/10.1016/j.jconrel.2024.10.070
Cell Chem Biol. 2024 Oct 26. pii: S2451-9456(24)00438-0. [Epub ahead of print]

A LANA peptide inhibits tumor growth by inducing CHD4 protein cleavage and triggers cell death.

Hiroki Miura, Kang-Hsin Wang, Tomoki Inagaki, Frank Chuang, Michiko Shimoda, Chie Izumiya, Tadashi Watanabe, Ryan R Davis, Clifford G Tepper, Somayeh Komaki, Ken-Ichi Nakajima, Ashish Kumar, Yoshihiro Izumiya.

  Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection, and viral genes are poised to be transcribed in the latent chromatin. In the poised chromatins, KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4) and inhibits viral promoter activation. CHD4 is known to regulate cell differentiation by preventing enhancers from activating promoters. Here, we identified a putative CHD4 inhibitor peptide (VGN73) from the LANA sequence corresponding to the LANA-CHD4 interaction surface. The VGN73 interacts with CHD4 at its PHD domain with a dissociation constant (KD) of 14 nM. Pre-treatment with VGN73 enhanced monocyte differentiation into macrophages and globally altered the repertoire of activated genes in U937 cells. Furthermore, the introduction of the peptide into the cancer cells induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in a xenograft mouse model. The VGN73 may facilitate cell differentiation therapy.

Keywords:  CHD4; KSHV; LANA; apoptosis; autophagy; cancer; cell differentiation; leukemia; monocyte; peptide

DOI:  https://doi.org/10.1016/j.chembiol.2024.10.003
Eur J Pharmacol. 2024 Oct 30. pii: S0014-2999(24)00766-0. [Epub ahead of print] 177076

Targeting HER2 in breast cancer with brain metastases: a pharmacological point of view with special focus on the permeability of blood-brain barrier to targeted treatments.

Giorgio Guglielmi, Caludio Zamagni, Marzia Del Re, Romano Danesi, Stefano Fogli.

  Understanding the capability of a drug to penetrate the blood-brain barrier (BBB) is an unmet medical need in patients with positive human epidermal growth factor receptor 2 (HER2 positive) and brain metastases. The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. Predicting the BBB permeability of these therapeutic agents is a pharmacological challenge due to the various factors involved in the barrier functions. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.

Keywords:  ADCs; Brain metastases; HER2 positive breast cancer; TKIs

DOI:  https://doi.org/10.1016/j.ejphar.2024.177076
Eur J Med Chem. 2023 Oct 16. pii: S0223-5234(23)00843-7. [Epub ahead of print]262 115876

Lipidation and PEGylation strategies to prolong the in vivo half-life of a nanomolar EphA4 receptor antagonist.

Maricel Gomez-Soler, Erika J Olson, Elena Rubio de la Torre, Chunxia Zhao, Ilaria Lamberto, Dillon T Flood, Waleed Danho, Bernhard C Lechtenberg, Stefan J Riedl, Philip E Dawson, Elena B Pasquale.

  The EphA4 receptor tyrosine kinase plays a role in neurodegenerative diseases, inhibition of nerve regeneration, cancer progression and other diseases. Therefore, EphA4 inhibition has potential therapeutic value. Selective EphA4 kinase inhibitors are not available, but we identified peptide antagonists that inhibit ephrin ligand binding to EphA4 with high specificity. One of these peptides is the cyclic APY-d3 (βAPYCVYRβASWSC-NH2), which inhibits ephrin-A5 ligand binding to EphA4 with low nanomolar binding affinity and is highly protease resistant. Here we describe modifications of APY-d3 that yield two different key derivatives with greatly increased half-lives in the mouse circulation, the lipidated APY-d3-laur8 and the PEGylated APY-d3-PEG4. These two derivatives inhibit ligand induced EphA4 activation in cells with sub-micromolar potency. Since they retain high potency and specificity for EphA4, lipidated and PEGylated APY-d3 derivatives represent new tools for discriminating EphA4 activities in vivo and for preclinical testing of EphA4 inhibition in animal disease models.

Keywords:  Cancer; Eph receptor; Ephrin; Nerve injury; Neurodegeneration; Peptide antagonist

DOI:  https://doi.org/10.1016/j.ejmech.2023.115876
Peptides. 2024 Nov 01. pii: S0196-9781(24)00170-0. [Epub ahead of print]182 171317

Lasso peptides realm: Insights and applications.

Othman Al Musaimi.

  Lasso peptides exhibit a range of bioactivities, including antiviral effects, inhibition of the glucagon receptor, blockade of the endothelin type B receptor, inhibition of myosin light chain kinase, and modulation of the atrial natriuretic factor, as well as notable antimicrobial properties. Intriguingly, lasso peptides exhibit remarkable proteolytic and thermal stability, addressing one of the key challenges that traditional peptides often face. The challenge in producing those valuable peptides remains the main hurdle in the way of producing larger quantities or even modifying them with more potent analogues. Genome mining and heterologous expression approaches have greatly facilitated the production of lasso peptides, moving beyond mere isolation techniques. This advancement not only allows for larger quantities but also enables the creation of additional analogues with improved stability and potency. This review aims to explore the unique bioactivities and stability of lasso peptides, along with recent advancements in genome mining and heterologous expression that address production challenges and open pathways for engineering potent analogues.

Keywords:  Antagonists; Anticancer; Antimicrobial; Antiviral; Lasso peptides; Proteolytic stability

DOI:  https://doi.org/10.1016/j.peptides.2024.171317
Oncologist. 2024 Nov 06. pii: oyae297. [Epub ahead of print]

Targeting RAF1 gene fusions with MEK inhibition in metastatic melanoma.

Karam Khaddour, Rizwan Haq, Elizabeth I Buchbinder, David Liu, Michael P Manos, Patrick A Ott, F Stephen Hodi, Megan L Insco.

  The biological and clinical relevance of gene fusions in melanoma is unknown. Reports and preclinical data have suggested that tumor cells with specific rearrangements such as RAF1 gene fusions could be therapeutically targeted. To investigate the relevance of targeted therapy in patients with melanoma harboring RAF1 gene fusions, we reviewed records of 1268 melanoma patients with targeted sequencing data at the Dana-Farber Cancer Institute. We identified 9 cases and report here on their clinicopathologic characteristics. We describe the favorable outcome of 2 patients who received MEK inhibitor therapy, including 1 patient with a durable response. We coalesced our data with published reports of patients with RAF1 gene fusions who were treated with targeted therapy. We find that single-agent MEK inhibition has anti-tumor activity in melanoma patients harboring an RAF1 gene fusion, and we propose that patients with RAF1 gene fusions should be considered for single-agent MEK inhibitor therapy.

Keywords:   RAF1 gene fusion; MEK inhibition; melanoma; targeted therapy

DOI:  https://doi.org/10.1093/oncolo/oyae297
J Cancer Res Clin Oncol. 2024 Nov 02. 150(11): 485

Peptide Receptor Radionuclide Therapy and clinical associations with renal and hematological toxicities and survival in patients with neuroendocrine tumors: an analysis from two U.S. medical centers.

Tao Xu, Joseph S Dillon, Mary A Maluccio, Dawn E Quelle, Sarah H Nash, Hyunkeun Cho, Kristen E Limbach, Nicholas J Skill, Yvette Bren-Mattison, Michael A O'Rorke.

  PURPOSE: Renal and hematological toxicity are side effects and dose-limiting factors of Peptide Receptor Radionuclide Therapy (PRRT). We aimed to assess the changes in renal and hematological function and associations with survival in neuroendocrine tumor (NET) patients treated with PRRT.METHODS: A retrospective cohort of 448 NET patients treated with either 177Lu-DOTATATE or 90Y-DOTATOC were followed for changes of renal and hematological function. Renal function was assessed by monitoring changes in serum creatinine, blood urea nitrogen and estimated glomerular filtration rate. Hematological function was determined by examining changes in white blood cell counts (WBC), platelet counts, and hemoglobin levels over time. Piecewise linear mixed effect models were applied to model the longitudinal repeated measurements of renal and hematological function. Overall survival (OS) and progression-free survival (PFS) were modelled using Cox proportional hazard regressions.
RESULTS: Of the 448 PRRT treated patients, 335 received 177Lu-DOTATATE (74.78%) and 113 were treated with 90Y-DOTATOC (25.22%). Comparing patients treated with 177Lu-DOTATATE to those treated with 90Y-DOTATOC, renal function did not differ significantly prior to, during or after PRRT. Compared with patients treated with 90Y-DOTATOC, significantly decreased indicators of hematological function were observed in those treated with 177Lu-DOTATATE prior to and during PRRT treatment (WBC: estimate, -0.10, 95% CI, -0.15 to -0.05; P < 0.001; platelet count: estimate, -2.53, 95% CI, -3.83 to -1.24; P < 0.001), and no significant recovery was observed in hematological function post PRRT. Individuals who received 177Lu-DOTATATE tended to have a longer PFS (hazard ratio, 0.47, 95%CI: 0.28-0.79, P = 0.004) compared with 90Y-DOTATOC, but there was no difference in OS.
CONCLUSION: There was no significant renal, but minor hematological toxicity, in patients treated with 177Lu-DOTATATE compared with 90Y-DOTATOC. Compared to 90Y-DOTATOC, 177Lu-DOTATATE appears to enhance PFS, but not OS. Treatment with 177Lu-DOTATATE may necessitate follow-up for hematological toxicity irrespective of other therapies prior to PRRT.

Keywords:  Hematological toxicity; Neuroendocrine tumors; Peptide Receptor Radionuclide Therapy; Renal toxicity; Survival

DOI:  https://doi.org/10.1007/s00432-024-06020-w