Melanogenesis Exploitation and Melanoma Nanomedecine: Utilization of Melanogenesis Substrate, NPrCAP for Exploiting Melanoma-Targeting Drug and its Conjugation with Magnetite Nanoparticles for Developing Melanoma Chemo-Thermo-Immunotherapy

Abstract

Exploitation of a specific biological property is one of the best approaches for developing novel cancer-targeted drugs. Melanogenesis substrate, N-propionyl cysteaminylphenol (NPrCAP: amine analog of tyrosine) may provide a unique drug delivery system (DDS) because of its selective incorporation into melanoma cells. It may also act as a melanoma-targeted therapeutic drug because of its production of highly reactive free radicals (melanoma-targeted chemotherapy). Utilization of magnetite nanoparticles can also be a good platform to develop thermo-immunotherapy because of heat shock protein (HSP) generation upon exposure to the alternating magnetic field (AMF). This study shows the feasibility of this approach in experimental study using in vivo and in vitro B16 melanoma cells and preliminary clinical study to a limited number of advanced melanoma patients. The therapeutic protocol against the primarily transplanted tumor with or without AMF once a day every other day for a total of three treatments not only inhibited the growth of primary transplant, but also prevented the growth of the secondary, re-challenge transplant and increased life span of the host mice. HSP70 production at the site of primary transplant and CD8 + T cell infiltration at the site of the rechallenge melanoma transplant were seen. Four patients entered in the preliminary clinical trial by following the basic outline of this animal protocol and two of them showed PR and CR. We hope to establish in situ vaccination immunotherapy for melanoma metastases by melanogenesis-targeted chemo-and thermotherapy.

Immunomodulation of Melanoma by Chemo-Thermo-Immunotherapy Using Conjugates of Melanogenesis Substrate NPrCAP and Magnetite Nanoparticles: A Review

“…We synthesized four NPrCAP derivatives bound to MNP as shown in Figure 5 for CTI therapy, and we have already reported the synthetic methods for three of these derivatives (NPrCAP/MNP, NPrCAP/PEG/MNP and NPCMD) [ 8 , 24 , 25 , 26 ]. In this review, we report a new method for the synthesis of NPrCAP/PEG/APTES/DNM, which is described below.…”

Elucidation of Melanogenesis Cascade for Identifying Pathophysiology and Therapeutic Approach of Pigmentary Disorders and Melanoma

“…Primarily treated skin metastases were totally excised after three rounds of the CTI therapy. The histopathological finding showed infiltration of lymphocytes and macrophages in and around the necrotic tumor tissue [ 12 ].…”

“…This review discusses certain aspects of current progresses in major pathways of melanogenesis cascade which include (1) melanocyte development and differentiation, (2) melanosome biosynthesis and intracellular trafficking, and (3) melanin pigment-type switching, and then introduces the possibility of applying the knowledge of melanogenesis cascade for elucidating the pathophysiology of pigmentary disorders and developing a novel therapeutic approach for malignant neoplasia of melanocytes, melanoma [ 12 ].…”

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development

“…We provided new evidence that CTI therapy can be developed by combining NPrCAP with magnetic nanoparticles, exploiting the unique melanogenesis cascade. For this purpose, we developed three nanoparticles: (1) NPrCAP encapsulated in magnetite cationic liposomes (NPrCAP/MCL) [ 44 ], (2) direct conjugation of magnetite nanoparticles with NPrCAP (NPrCAP/M) [ 45 , 46 , 47 , 48 ], and (3) conjugation of NPrCAP with magnetite nanoparticles via polyethylene glycol (NPrCAP/PEG/M). We first prepared NPrCAP/MCL to test the combined effects of chemotherapy using NPrCAP and magnetic hyperthermia on melanoma.…”

“…We found that NPrCAP-conjugated magnetite nanoparticles selectively accumulate in melanoma tissues in vivo when administered locally or systemically, as well as in in vitro cultured cells. Specifically, when administered intraperitoneally, NPrCAP/M accumulated in melanosomes, which contain the final products of melanogenesis and accumulate intracellularly in melanoma [ 45 ] ( Figure 1 ).…”