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Author Spotlight: Assessing the Potential of Circulating Tumor Cells in Leptomeningeal Disease Research
Published on: March 29, 2024
Cell-targeted c(AmpRGD)-sunitinib molecular conjugates impair tumor growth of melanoma
Francesca Bianchini1, Elisabetta Portioli2, Francesca Ferlenghi2
1Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
Abstract:
Drug resistance and off-organ toxicity remain unsolved issues in chemotherapy of advanced-stage melanoma patients. Thus, the creation of new molecular conjugates able to combine a selective accumulation, high ability of internalization and signaling pathway inhibition, are highly requested. Recently, we reported a new class of molecular conjugates, compounds 1-3, where the anti-αVβ3 integrin peptidomimetic c(AmpRGD), which is a selective ligand for αVβ3 integrin, was covalently bound to the tyrosine kinase inhibitor sunitinib. Here, we report that these c(AmpRGD)-sunitinib conjugates and, in particular, compound 3, are selectively internalized by human melanoma cells through αVβ3 receptor-mediated endocytosis. Compound 3 is more effective than sunitinib in reducing in vitro melanoma cells proliferation, cloning efficiency, migration, and invasion. More interestingly, compound 3 is able to significantly reduce the growth of xenografted melanoma tumor developed in immune-compromised mice, more efficiently than an equimolar dose of sunitinib. Indeed, its targeting ability was demonstrated by the selective localization at the tumor level with respect to healthy tissues. Thus, c(AmpRGD)-sunitinib conjugates such as compound 3 could serve as intriguing multiple-target agents to selectively reach melanoma cells and interfere with the progression of the disease.
Insights
New molecular conjugates targeting melanoma cells show promise. Compound 3 selectively targets and inhibits melanoma growth, outperforming sunitinib in vitro and in vivo, offering a potential new therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Drug resistance and off-organ toxicity are significant challenges in advanced melanoma chemotherapy.
- There is a need for novel molecular conjugates that selectively accumulate, internalize, and inhibit signaling pathways in cancer cells.
Purpose of the Study:
- To evaluate the efficacy of novel c(AmpRGD)-sunitinib conjugates, specifically compound 3, in targeting and inhibiting human melanoma cells.
- To assess the in vitro and in vivo anti-melanoma activity of compound 3 compared to sunitinib.
Main Methods:
- Synthesis of c(AmpRGD)-sunitinib molecular conjugates.
- Assessment of selective internalization by human melanoma cells via αVβ3 receptor-mediated endocytosis.
- In vitro evaluation of proliferation, cloning efficiency, migration, and invasion inhibition.
- In vivo efficacy study using xenografted melanoma models in immune-compromised mice.
Main Results:
- Compound 3 demonstrated selective internalization into human melanoma cells through αVβ3 receptor-mediated endocytosis.
- Compound 3 significantly inhibited melanoma cell proliferation, cloning efficiency, migration, and invasion in vitro, surpassing sunitinib's effects.
- Compound 3 effectively reduced xenografted melanoma tumor growth in mice more efficiently than an equimolar dose of sunitinib.
- Selective localization of compound 3 at the tumor site was confirmed, with minimal distribution in healthy tissues.
Conclusions:
- c(AmpRGD)-sunitinib conjugates, particularly compound 3, represent a promising class of agents for targeted melanoma therapy.
- Compound 3 exhibits superior anti-melanoma activity and targeted delivery compared to sunitinib, addressing key challenges in melanoma treatment.
- These conjugates hold potential as multiple-target agents for selectively reaching melanoma cells and impeding disease progression.
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