Department of Dermatology, Emory University School of Medicine, Atlanta, GA, 30322, Georgia.
Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, Georgia.
Sci Rep. 2019 Mar 1;9(1):3255. doi: 10.1038/s41598-019-40258-6.
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.
IGF1R 和 CD44 在大多数晚期黑色素瘤中过度表达，因此我们设计了化疗纳米颗粒来靶向这些受体。三（二苄叉丙酮）二钯（Tris DBA-Pd）是一种新型的 N-豆蔻酰转移酶 1（NMT-1）抑制剂，已被证明对黑色素瘤具有体内活性。然而，较差的溶解性降低了它的效果。为了提高其治疗效果并克服晚期黑色素瘤中的耐药性，我们合成了三（二苄叉丙酮）二钯透明质酸纳米颗粒（Tris DBA-Pd HANP），并对其进行了评价，以评估其对 LM36R 的体内异种移植的作用，LM36R 是一种对 BRAF 抑制剂有抗药性的侵袭性 BRAF 突变的人黑色素瘤。我们在四个实验组中治疗异种移植的小鼠：空 HANP、游离 Tris DBA-Pd、Tris DBA-Pd HANP 和携带 IGF1R 抗体的 Tris DBA-Pd HANP。Tris DBA-Pd HANP 组对治疗的反应最敏感，在 IHC 上显示出 CD44 阳性细胞的最大耗竭。令人惊讶的是，含有 IGF1R 抗体的 HANP 不如没有抗体的颗粒有效，这可能是由于 IGF1R 和 CD44 结合的空间位阻所致。Tris DBA-Pd 纳米颗粒是治疗 CD44 阳性肿瘤（如黑色素瘤）的有效方法，应进一步开发这些纳米颗粒。
