New somatostatin-drug conjugates for effective targeting pancreatic cancer

Ragozin, Elena; Hesin, Arkadi; Bazylevich, Andrii; Bovina, A.; Zahavi, Talia Shekhter; Oron‐Herman, Mor; Kostenich, Genady; Firer, Michael A.; Rubinek, Tami; Wolf, Ido; Luboshits, Galia; Sherman, Michael Y.; Gellerman, Gary

doi:10.1016/j.bmc.2018.06.032

Cited by 23 publications

(17 citation statements)

References 44 publications

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“…Short peptides have low oral bioavailability but are easily synthesized to homogeneity and allow for considerable flexibility resulting from the diversity of amino acid combinations, which enable the alteration of physiochemical properties, specificity, and stability, generally without immunogenic responses [ 29 , 50 , 51 ]. PDCs have shown promising anti-cancer activities in many difficult-to-treat malignancies, such as pancreatic cancer [ 52 ] and melanoma [ 17 ]. The Kaur group is developing peptide-doxorubicin conjugates in order to treat triple-negative breast cancer (TNBC) by targeting cell-surface keratin-1 (K1) or epidermal growth factor receptor (EGFR) in cancer cells [ 22 , 28 , 29 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

A Small Peptide Increases Drug Delivery in Human Melanoma Cells

et al. 2022

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Melanoma is the most fatal type of skin cancer and is notoriously resistant to chemotherapies. The response of melanoma to current treatments is difficult to predict. To combat these challenges, in this study, we utilize a small peptide to increase drug delivery to melanoma cells. A peptide library array was designed and screened using a peptide array-whole cell binding assay, which identified KK-11 as a novel human melanoma-targeting peptide. The peptide and its D-amino acid substituted analogue (VPWxEPAYQrFL or D-aa KK-11) were synthesized via a solid-phase strategy. Further studies using FITC-labeled KK-11 demonstrated dose-dependent uptake in human melanoma cells. D-aa KK-11 significantly increased the stability of the peptide, with 45.3% remaining detectable after 24 h with human serum incubation. Co-treatment of KK-11 with doxorubicin was found to significantly enhance the cytotoxicity of doxorubicin compared to doxorubicin alone, or sequential KK-11 and doxorubicin treatment. In vivo and ex vivo imaging revealed that D-aa KK-11 distributed to xenografted A375 melanoma tumors as early as 5 min and persisted up to 24 h post tail vein injection. When co-administered, D-aa KK-11 significantly enhanced the anti-tumor activity of a novel nNOS inhibitor (MAC-3-190) in an A375 human melanoma xenograft mouse model compared to MAC-3-190 treatment alone. No apparent systemic toxicities were observed. Taken together, these results suggest that KK-11 may be a promising human melanoma-targeted delivery vector for anti-melanoma cargo.

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Section: Discussionmentioning

confidence: 99%

A Small Peptide Increases Drug Delivery in Human Melanoma Cells

et al. 2022

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“…The somatostatin receptor (SSTR) is expressed in human gastrointestinal tumours, including pancreatic cancer [30]. It prevents angiogenesis and has anti-proliferative effects on both cancerous and healthy cells.…”

Section: Somatostatin Receptormentioning

confidence: 99%

The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

García-Sampedro

Gaggia

Ney

et al. 2021

JCM

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Pancreatic cancer is a devastating disease with very poor prognosis. Currently, surgery followed by adjuvant chemotherapy represents the only curative option which, unfortunately, is only available for a small group of patients. The majority of pancreatic cancer cases are diagnosed at advanced or metastatic stage when surgical resection is not possible and treatment options are limited. Thus, novel and more effective therapeutic strategies are urgently needed. Molecular profiling together with targeted therapies against key hallmarks of pancreatic cancer appear as a promising approach that could overcome the limitations of conventional chemo- and radio-therapy. In this review, we focus on the latest personalised and multimodal targeted therapies currently undergoing phase II or III clinical trials. We discuss the most promising findings of agents targeting surface receptors, angiogenesis, DNA damage and cell cycle arrest, key signalling pathways, immunotherapies, and the tumour microenvironment.

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“…[ 175–179 ] Furthermore, octreotide analogs conjugated to different toxic agents, including CPT, the anti‐mitotic agent combretastatin‐A4, and the alkylating agent chlorambucil (CLB), via carbamate or amide linkers were developed. [ 180,181 ] One CPT conjugate displayed good in vitro toxicity and specific uptake into SSTR2‐positive pancreatic tumors in a mouse xenograft model. [ 181 ] Recently, the integrin‐targeting cyclic peptides c(RGDfK) and c(RGDfS) were conjugated to CPT and CLB by a carbamate and ester linkage, respectively.…”

Section: Variation Of the Drug Cargo In Receptor‐targeting Peptide‐drmentioning

confidence: 99%

“…[ 180,181 ] One CPT conjugate displayed good in vitro toxicity and specific uptake into SSTR2‐positive pancreatic tumors in a mouse xenograft model. [ 181 ] Recently, the integrin‐targeting cyclic peptides c(RGDfK) and c(RGDfS) were conjugated to CPT and CLB by a carbamate and ester linkage, respectively. Both PDCs showed growth inhibition in cancer cell lines expressing the integrin αvβ3.…”

Section: Variation Of the Drug Cargo In Receptor‐targeting Peptide‐drmentioning

confidence: 99%

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

2020

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Specifically addressing cell surface molecules on cancer cells facilitates targeted cancer therapies that offer the potential to selectively destroy malignant cells, while sparing healthy tissue. Thus, undesired side-effects in tumor patients are highly reduced. Peptide-binding receptors are frequently overexpressed on cancer cells and therefore promising targets for selective tumor therapy. In this review, peptidebinding receptors for anti-cancer drug delivery are summarized with a focus on peptide ligands as delivery agents. In the first part, some of the most studied peptidebinding receptors are presented, and the ghrelin receptor and the Y 1 receptor are introduced as more recent targets for cancer therapy. Furthermore, nonpeptidic small molecules for receptor targeting on cancer cells are outlined. In the second part, peptide conjugates for the delivery of therapeutic cargos in cancer therapy are described.The essential properties of receptor-targeting peptides are specified, and recent developments in the fields of classical peptide-drug conjugates with toxic agents, radiolabeled peptides for radionuclide therapy, and boronated peptides for boron neutron capture therapy are presented. K E Y W O R D SBNCT, G protein-coupled receptor, internalization, peptide drug conjugate, tumor targeting

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New somatostatin-drug conjugates for effective targeting pancreatic cancer

Cited by 23 publications

References 44 publications

A Small Peptide Increases Drug Delivery in Human Melanoma Cells

A Small Peptide Increases Drug Delivery in Human Melanoma Cells

The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

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