Melanoma-Targeted Chemothermotherapy and In Situ Peptide Immunotherapy through HSP Production by Using Melanogenesis Substrate, NPrCAP, and Magnetite Nanoparticles
Exploitation of biological properties unique to cancer cells may provide a novel approach to overcome difficult challenges to the treatment of advanced melanoma. In order to develop melanoma-targeted chemothermoimmunotherapy, a melanogenesis substrate, N-propionyl-4-S-cysteaminylphenol (NPrCAP), sulfur-amine analogue of tyrosine, was conjugated with magnetite nanoparticles. NPrCAP was exploited from melanogenesis substrates, which are expected to be selectively incorporated into melanoma cells and produce highly reactive free radicals through reacting with tyrosinase, resulting in chemotherapeutic and immunotherapeutic effects by oxidative stress and apoptotic cell death. Magnetite nanoparticles were conjugated with NPrCAP to introduce thermotherapeutic and immunotherapeutic effects through nonapoptotic cell death and generation of heat shock protein (HSP) upon exposure to alternating magnetic field (AMF). During these therapeutic processes, NPrCAP was also expected to provide melanoma-targeted drug delivery system. 1. Introduction The incidence of melanoma is increasing worldwide at an alarming rate [1, 2]. As yet, management of metastatic melanoma is an extremely difficult challenge. Less than 10% with metastatic melanoma patients survive currently for five years because of the lack of effective therapies [3]. There is, therefore, an emerging need to develop innovative therapies for the control of metastatic melanoma. The major advance of drug discovery for targeted therapy to cancer cells can be achieved by exploiting their unique biological property. The biological property unique to the melanoma cell resides in the biosynthesis of melanin pigments, that is, melanogenesis occuring within specific compartments, melanosomes. Melanogenesis begins with the conversion of amino acid, tyrosine to dopa and subsequently to dopaquinone in the presence of tyrosinase. This pathway is uniquely expressed by all melanoma cells. It is well known that the clinically “amelanotic” melanoma tissues always have tyrosinase activity to some extent, and that “in vitro amelanotic” melanoma cells become “melanotic” ones when they are regrown in the in vivo condition. Melanin precursors are inherently cytotoxic through reacting with tyrosinase to form unstable quinone derivatives [4]. Thus, tyrosine analogues that are tyrosinase substrates can be good candidates for developing drugs to melanoma-targeting therapies [5]. N-propionyl and N-acetyl derivatives (NPr- and NAcCAP) of 4-S-cysteaminylphenol, that is, sulfur-amine analogue of tyrosine, were synthesized as possible
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