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, 54 (23), 8078-84

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


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

Natalie M Barkey et al. J Med Chem.


The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engineered to overexpress MC1R, MC4R, or MC5R. Of these, compound 1 (4-phenylbutyryl-His-dPhe-Arg-Trp-NH(2)) exhibited high (0.2 nM) binding affinity for MC1R and low (high nanomolar) affinities for MC4R and MC5R. Functionalization of the ligand at the C-terminus with an alkyne for use in Cu-catalyzed click chemistry was shown not to affect the binding affinity. Finally, formation of the targeted polymer, as well as the targeted micelle formulation, also resulted in constructs with low nanomolar binding affinity.


Figure 1
Figure 1
Representative competitive binding assays for (A) 4-targeted polymer; (B) untargeted polymer; (C) 4-targeted micelles; (D) untargeted micelles and (E) 4 against HCT116/hMC1R cells. X-axis concentrations for (A), (C) and (E) were normalized to the targeting ligand. Concentrations for the ligand in (A), (C) and (E) and polymer and micelle in (B) and (D) were deliberately chosen to be the same for all assays.
Scheme 1
Scheme 1
Synthetic route for compounds 1–8. a) (i) Fmoc-AA-OH (3eq), HOCt or HOBt (3eq), and DIC (3eq) in DMF/DCM (10 mL/1g of resin) for amino acid couplings; (iii) Piperidine/DMF (1:10, 2 + 20 minutes); (iv) 4-phenylbutyric acid (6eq), and DIC (3eq) in DMF/DCM; b) (i) Pd(0)tetrakistriphenylphosphine (0.01eq), N,N′-dimethylbarbituric acid (5eq) in degassed DCM (2 × 30 minutes) (ii) 5-hexynoic acid (5eq) and DIC (3eq) in DMF/DCM for compound 1; S-Trt-3-propanoic acid (5eq) and DIC (3eq) in DMF/DCM for compound 2; c) (i) TFA-scavengers cocktail (91% TFA, 3% water, 3% thioanisole, 3% ethanedithiol); (ii) ether extraction; d) purification.
Scheme 2
Scheme 2
Synthesis of targeted, stabilized micelle system.

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