Abstract
IGF1R and CD44 are overexpressed in most advanced melanomas so we designed chemotherapeutic nanoparticles to target those receptors. Tris(dibenzylideneacetone)dipalladium (Tris DBA-Pd) is a novel inhibitor of N-myristoyltransferase 1 (NMT-1) and has proven in vivo activity against melanoma. However, poor solubility impairs its effectiveness. To improve its therapeutic efficacy and overcome drug resistance in advanced melanomas, we synthesized Tris DBA-Pd hyaluronic acid nanoparticles (Tris DBA-Pd HANP) and evaluated them against in vivo xenografts of LM36R, an aggressive BRAF mutant human melanoma resistant to BRAF inhibitors. We treated xenografted mice in four arms: empty HANPs, free Tris DBA-Pd, Tris DBA-Pd HANPs, and Tris DBA-Pd HANPs with IGF1R antibody. The Tris DBA-Pd HANP group was the most responsive to treatment and showed the greatest depletion of CD44-positive cells on IHC. Surprisingly, the HANP containing IGF1R antibody was less effective than particles without antibody, possibly due to steric hindrance of IGF1R and CD44 binding. Tris DBA-Pd nanoparticles are an effective therapy for CD44-positive tumors like melanoma, and further development of these nanoparticles should be pursued.
Highlights
Metastatic melanoma remains a leading cause of morbidity and mortality
We examined two potential targets for our drug payload, CD44 and IGFR1 which are both implicated in the progression of metastatic melanoma
To confirm the encapsulation of Tris-palladium, 1 mg of hyaluronic acid nanoparticles (HANP)/Tris DBA complex was dissolved in 1 mL water and subjected to HPLC (C18, 5 μm, 250 × 4.6 mm) with a linear gradient from 20% to 95% acetonitrile/water (0.1% TFA) at a flow rate of 1 mL∙min-1 and the detection wavelength at 224 nm
Summary
Metastatic melanoma remains a leading cause of morbidity and mortality. Despite recent advances in targeted therapies and immunotherapy, survival is still dismal. Tris DBA-Pd has been shown to be efficacious against melanoma, but preclinical models of pancreatic cancer, chronic lymphocytic leukemia and multiple myeloma as well[8,9,10] This compound might have therapeutic benefit against a variety of cancers, and not limited to those with a specific mutation. Studies show treatment with anti-IGF1R antibody is able to reduce tumor growth in uveal melanoma, revealing its value as a potential target for novel chemotherapeutic agents[15]. With these two targets in mind, we hypothesized that nanoparticles synthesized with hyaluronic acid would carry the Tris DBA-Pd payload to cells that express CD44 surface receptors, especially those cells which overexpress CD44 and IGF1R such as metastatic melanoma
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