Novel approaches and pharmacological considerations in melanoma treatment

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Melanoma is the most aggressive skin cancer, traditionally known to be extremely resistant to common chemotherapeutics, and difficult to treat once metastasised. The prognosis of malignant melanoma is strongly dependent on early detection and disease stage. Recently a number of promising anti-melanoma therapies have been developed, such as anti-CTLA4 and anti-PD-1 antibodies, which enhance tumour T-cell activity, and selective BRAF (DBF; dabrafenib) and MEK (TRA; trametinib) inhibitors, that block tumour growth in patients with active BRAF mutations. Although these therapies offer significant improvement in treating melanoma patients, they are associated with high toxicity and drug resistance.

Nano-medicine offers unique advantages in treating metastatic melanoma. Nanoparticles (NPs) enhance therapeutic efficacy, providing controlled release and prolonged drug circulation time. Active-targeting enables NP accumulation in tumours using targeting-moieties designed to recognise tumour-associated molecular markers.

Super-paramagnetic (SP) iron oxide nanoparticles (SPIONs) have been selected and synthesised in-house as a drug delivery platform.3 These nano-carriers can encapsulate anti-melanoma drugs, allowing the NPs to function as drug delivery systems. Additionally, SP iron oxide cores possess properties for magnetic resonance imaging (MRI) and magnetic hyperthermia therapy (MHT). SPIONs have been fully characterised, including entrapment and drug-release in a controlled environment. A α-melanocyte-stimulating hormone (α-MSH) was incorporated into SPIONs to improve tumour-targeting and demonstrated preferentially increased MC1-receptor mediated-endocytosis in melanoma cell lines.

Increased cytotoxicity was demonstrated in vitro using drug-loaded NPs, showing dose-dependent anti-proliferative effects in human and murine melanoma cell lines, using DBF or TRA and a synergistic combination. Drug-loaded NPs were efficacious in drug-sensitive and -resistant melanoma cells lines. In vivo, syngeneic studies with DBF, compared tumour growth with free- and NP-bound drug: mice were treated with DBF daily via oral gavage (31.5 mg/kg) or NP-bound DBF twice weekly via intravenous injection (2.5 mg/kg). Both treatments significantly reduced tumour volume, demonstrating the potential for NPs to decrease systemic toxicity and improve therapeutic efficacy.

SPIONs loaded with DBF and TRA, showed an increased in vitro toxicity in human and murine melanoma cells compared to the drug alone. Subsequently, NP-bound DBF significantly reduced tumour volume in syngeneic GEMM5555 tumour-bearing mouse models in vivo, acting as a drug-delivery platform and improving therapeutic efficacy whilst decreasing systemic toxicity commonly associated with conventional chemotherapies. Anti-melanoma SPIONs can represent a lead therapeutic for the treatment of unresectable/recurrent tumours in both patients with locoregional and distant melanoma metastasis.
Date of Award2021
Original languageEnglish
SupervisorColin Henderson (Supervisor), Roland Wolf (Supervisor) & Charlotte Proby (Supervisor)

Keywords

  • Nanoparticles
  • Melanoma
  • SPIONs
  • Toxicity
  • Tumour-targeting

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