Development of Melanoma-Targeted Polymer Micelles by Conjugation of a Melanocortin 1 Receptor (MC1R) Specific Ligand

Barkey, Natalie; Tafreshi, Narges K.; Josan, J.S.; Silva, Channa R. De; Sill, Kevin; Hruby, Victor J.; Gillies, Robert J.; Morse, David L.; Vagner, Josef

doi:10.1021/jm201226w

Cited by 41 publications

(80 citation statements)

References 38 publications

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“…27 Finally, the use of different types of nanomaterials, such as liposomes and dendrimers, conjugated with multiple copies of αMSH analogs, has generally resulted in only modest increases in in vitro MC1-R binding affinities. 28 Although preliminary in vivo MC1-R targeting studies utilizing larger diameter αMSH-conjugated particles, such as polymer micelles 29 ( i.e. , ~100 nm) and hollow gold nanospheres 30 ( i.e.…”

Section: Introductionmentioning

confidence: 99%

Melanocortin-1 Receptor-Targeting Ultrasmall Silica Nanoparticles for Dual-Modality Human Melanoma Imaging

Chen¹,

Zhang

et al. 2018

ACS Appl. Mater. Interfaces

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The poor prognosis associated with malignant melanoma has not changed substantially over the past 30 years. Targeted molecular therapies, such as immunotherapy have shown promise, but suffer from resistance and off-target toxicities, underscoring the need for alternative therapeutic strategies that can be used in combination with existing protocols. Moreover, peptides targeting melanoma-specific markers, like the melanocortin-1 receptor (MC1-R), for imaging and therapy exhibit high renal uptake that limits clinical translation. In the current study, the application of ultrasmall fluorescent (Cy5) silica nanoparticles (C′ dots), conjugated with MC1-R targeting alpha melanocyte stimulating hormone (αMSH) peptides on the polyethylene glycol (PEG) coated surface, is examined for melanoma-selective imaging. αMSH peptide sequences, evaluated for conjugation to the PEG-Cy5-C′ dot nanoparticles, bound to MC1-R with high affinity, and targeted melanoma in syngenetic and xenografted melanoma mouse models. Results demonstrated a 10-fold improvement in MC1-R affinity over the native peptide alone following surface attachment of the optimal αMSH peptide. Systematic in vivo studies further demonstrated favorable in vivo renal clearance kinetics as well as receptor-mediated tumor cell internalization of as-developed radiolabeled particle tracers in B16F10 melanoma bearing mice. These findings highlight the ability of αMSH-PEG-Cy5-C′ dots to overcome previous hurdles that prevented clinical translation of peptide and antibody-based melanoma probes, and reveal the potential of αMSH-PEG-Cy5-C′ dots for melanoma selective imaging, image-guided surgery, and therapeutic applications.

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Section: Introductionmentioning

confidence: 99%

Melanocortin-1 Receptor-Targeting Ultrasmall Silica Nanoparticles for Dual-Modality Human Melanoma Imaging

Chen¹,

Zhang

et al. 2018

ACS Appl. Mater. Interfaces

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“…In 2011 and 2013, Barkey et al . attached hMC1R selective α-MSH analogs to stabilized triblock polymer micelles through Cu-catalyzed click chemistry [267, 268]. Though the ligand decreased binding affinity of the polymer micelles after attachment, it increased specificity for the hMC1R over the hMC4R and hMC5R [268].…”

Section: Bivalent and Multivalent Melanocortin Ligandsmentioning

confidence: 99%

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Ericson

Lensing

Fleming

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress.

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“…This may be due to a larger entropy penalty for 9 upon binding to CCK2R or to hydrophobic interactions between the PEG spacer and the CCK4 ligand which hinder binding to the receptor. 40,41 For these reasons, lower affinity ligands are currently being identified for incorporation into multivalent molecules targeting CCK2R.…”

Section: Discussionmentioning

confidence: 99%

Development of a time-resolved fluorescence probe for evaluation of competitive binding to the cholecystokinin 2 receptor

Elshan

Jayasundera

Weber

et al. 2015

Bioorganic & Medicinal Chemistry

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The synthesis, characterization, and use of Eu-DTPA-PEGO-Trp-Nle-Asp-Phe-NH2 (Eu-DTPA-PEGO-CCK4), a luminescent probe targeted to cholecystokinin 2 receptor (CCK2R, aka CCKBR), are described. The probe was prepared by solid phase synthesis. A Kd value of 17 ± 2 nM was determined by means of saturation binding assays using HEK-293 cells that overexpress CCK2R. The probe was then used in competitive binding assays against Ac-CCK4 and three new trivalent CCK4 compounds. Repeatable and reproducible binding assay results were obtained. Given its ease of synthesis, purification, receptor binding properties, and utility in competitive binding assays, Eu-DTPA-PEGO-CCK4 could become a standard tool for high-throughput screening of compounds in development targeted to cholecystokinin receptors.

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Development of Melanoma-Targeted Polymer Micelles by Conjugation of a Melanocortin 1 Receptor (MC1R) Specific Ligand

Cited by 41 publications

References 38 publications

Melanocortin-1 Receptor-Targeting Ultrasmall Silica Nanoparticles for Dual-Modality Human Melanoma Imaging

Melanocortin-1 Receptor-Targeting Ultrasmall Silica Nanoparticles for Dual-Modality Human Melanoma Imaging

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Development of a time-resolved fluorescence probe for evaluation of competitive binding to the cholecystokinin 2 receptor

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