Toward innovative anticancer therapies: modulation of tumour cells and microenvironment with unconventional ADCs or novel Platinum(II)-NHC complexes

This doctoral thesis explores innovative chemical strategies for overcoming pharmacokinetic limitations, off-target effects and resistance mechanisms in cancer therapy, with a focus on developing next-generation targeted anticancer agents. The first part explores the use of antibody-drug conjugates (ADCs) as a platform for repurposing unconventional bioactive molecules to selectively modulate tumour cells and the tumour microenvironment. Cyclopamine, a natural Smoothened inhibitor of the Hedgehog (Hh) signalling pathway with poor pharmacokinetics, was successfully conjugated to cetuximab to create new ADCs that target Hh-activated, epidermal growth factor receptor (EGFR)-expressing melanoma cells. The use of an acid-cleavable linker enabled the controlled intracellular release of cyclopamine, resulting in the effective inhibition of Gli1 and Gli2 expression, reduced proliferation and the induction of apoptosis in melanoma cell lines, whilst maintaining plasma stability. To address tumour heterogeneity and microenvironment-driven drug resistance, antibody-drug conjugate (ADC)-based strategies were developed to achieve dual targeting of malignant cells and tumour-associated macrophages (TAMs). CSF-1R-directed ADCs were designed to deliver kinase inhibitors selectively to CSF-1R-expressing mesothelioma cells and TAMs by exploiting both cleavable and non-cleavable linkers. These constructs demonstrated promising in vitro activity, showing the potential of ADCs to suppress tumour growth and modulate pro-tumourigenic macrophage populations. The second part of the thesis focuses on designing, synthesising and biologically evaluating novel platinum(II)-N-heterocyclic carbene (Pt(II)-NHC) complexes as anti-cancer agents. To overcome the limitations of classical platinum drugs, dithiocarbamate-functionalised Pt(II)-NHC complexes and derivatives inspired by Marinetti’s series were developed, revealing structure-activity relationships and highlighting the feasibility of targeted platinum-based therapeutic strategies.