Controlling Toxicity of Peptide–Drug Conjugates by Different Chemical Linker Structures

Böhme, David; Beck‐Sickinger, Annette G.

doi:10.1002/cmdc.201402514

Cited by 38 publications

(44 citation statements)

References 68 publications

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“…As modification point, the natural Lys 4 in [F 7 ,P 34 ]-NPY was chosen. In previous studies, modification of Lys 4 with toxic agents or carboranes did not change the activity and selectivity profile of the peptide [13,14]. To facilitate side-specific modification in pb12, the N ε -amino group of Lys 4 was orthogonally protected by Dde.…”

Section: Methodsmentioning

confidence: 99%

“…Despite its palmitic acid modification, known to increase resistance against proteolysis [32], [ 111 In]In-pb12 is rapidly metabolized potentially limiting its availability for tumor uptake. In a previous study, [F 7 , P 34 ]-NPY conjugated to methotrexate by the GFLGlinker exhibited much higher plasma stability [13]. Therefore, the reason for the fast degradation of [ 111 In]In-pb12 is most likely high susceptibility of the arginine/lysine-rich c-Myc NLS (PAAKRVKLD) to proteolysis and stabilization of this sequence is required for further application.…”

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confidence: 99%

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Design, synthesis, and biological evaluation of a multifunctional neuropeptide-Y conjugate for selective nuclear delivery of radiolanthanides

et al. 2020

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Background: Targeting G protein-coupled receptors on the surface of cancer cells with peptide ligands is a promising concept for the selective tumor delivery of therapeutically active cargos, including radiometals for targeted radionuclide therapy (TRT). Recently, the radiolanthanide terbium-161 (161 Tb) gained significant interest for TRT application, since it decays with medium-energy β-radiation but also emits a significant amount of conversion and Auger electrons with short tissue penetration range. The therapeutic efficiency of radiometals emitting Auger electrons, like 161 Tb, can therefore be highly boosted by an additional subcellular delivery into the nucleus, in order to facilitate maximum dose deposition to the DNA. In this study, we describe the design of a multifunctional, radiolabeled neuropeptide-Y (NPY) conjugate, to address radiolanthanides to the nucleus of cells naturally overexpressing the human Y 1 receptor (hY 1 R). By using solid-phase peptide synthesis, the hY 1 R-preferring [F 7 ,P 34 ]-NPY was modified with a fatty acid, a cathepsin B-cleavable linker, followed by a nuclear localization sequence (NLS), and a DOTA chelator (compound pb12). In this proof-of-concept study, labeling was performed with either native terbium-159 (nat Tb), as surrogate for 161 Tb, or with indium-111 (111 In). Results: [ nat Tb]Tb-pb12 showed a preserved high binding affinity to endogenous hY 1 R on MCF-7 cells and was able to induce receptor activation and internalization similar to the hY 1 R-preferring [F 7 ,P 34 ]-NPY. Specific internalization of the 111 In-labeled conjugate into MCF-7 cells was observed, and importantly, time-dependent nuclear uptake of 111 In was demonstrated. Study of metabolic stability showed that the peptide is insufficiently stable in human plasma. This was confirmed by injection of [ 111 In]In-pb12 in nude mice bearing MCF-7 xenograft which showed specific uptake only at very early time point. Conclusion: The multifunctional NPY conjugate with a releasable DOTA-NLS unit represents a promising concept for enhanced TRT with Auger electron-emitting radiolanthanides. Our research is now focusing on improving the reported concept with respect to the poor plasmatic stability of this promising radiopeptide.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Design, synthesis, and biological evaluation of a multifunctional neuropeptide-Y conjugate for selective nuclear delivery of radiolanthanides

et al. 2020

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“…Although selective tumor targeted imaging in breast cancer patients has been achieved successfully by using NPY analogs that specifically binding Y 1 subtype receptors, there is still a lack of therapeutics for clinical cancer therapy. Besides the reported Y receptor-based nanomedicine and radiopharmaceuticals, peptide-drug conjugate might be another choice to make Y receptor-based therapeutics as promising candidates for cancer therapy in clinic [ 65 , 66 ].…”

Section: Discussionmentioning

confidence: 99%

Neuropeptide Y receptors: a promising target for cancer imaging and therapy

Tian

2015

Regen Biomater

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Neuropeptide Y (NPY) was first identified from porcine brain in 1982, and plays its biological functions in humans through NPY receptors (Y1, Y2, Y4 and Y5). NPY receptors are known to mediate various physiological functions and involve in a majority of human diseases, such as obesity, hypertension, epilepsy and metabolic disorders. Recently, NPY receptors have been found to be overexpressed in many cancers, so they emerged as promising target in cancer diagnosis and therapy. This review focuses on the latest research about NPY and NPY receptors, and summarizes the current knowledge on NPY receptors expression in cancers, selective ligands for NPY receptors and their application in cancer imaging and therapy.

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“…In another study, the toxic agent MTX was coupled to the Lys 4 side‐chain of [F 7 ,P 34 ]‐NPY by different linker structures, including an amide, ester, disulfide, and enzymatically cleavable GFLG linkage. [ 187 ] The optimal conjugate [K 4 (GFLG‐MTX),F 7 ,P 34 ]‐NPY displayed high extracellular stability, paired with selective internalization into hY 1 R‐expressing cells and fast intracellular release of the (drug) cargo. Potent toxicity of this PDC against MDA‐MB‐468 breast cancer cells was observed with no effect on normal HEK293 cells.…”

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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Controlling Toxicity of Peptide–Drug Conjugates by Different Chemical Linker Structures

Cited by 38 publications

References 68 publications

Design, synthesis, and biological evaluation of a multifunctional neuropeptide-Y conjugate for selective nuclear delivery of radiolanthanides

Design, synthesis, and biological evaluation of a multifunctional neuropeptide-Y conjugate for selective nuclear delivery of radiolanthanides

Neuropeptide Y receptors: a promising target for cancer imaging and therapy

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

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