Development of novel targeted drug formulations for the treatment of haematological malignancies

Initially, the synergistic pairing of ABT-737 and Purvalanol A was explored and validated in paediatric AML cell models. Then, a poly (lactic-co-glycolic acid) (PLGA)-based nanoformulation was developed for their ratiometric co-delivery, to overcome limitations such as their very poor hydrophilicity and severe side effects. The resulting dual drug-loaded NP revealed optimal physicochemical characteristics and therapeutic efficacy, demonstrated by significantly enhanced apoptotic cell death.

Gemtuzumab and its fragments were then employed as targeting moieties to develop CD33-targeted polymeric NPs (CD33 NPs), through maleimide-thiol coupling. CD33 NPs revealed specific and enhanced binding to CD33 and internalization in CD33-positive cells. Furthermore, CD33-targeted dual-loaded NPs retained desired physicochemical characteristics, and improved delivery of the entrapped payloads.

Finally, different nanoparticle- and ADC-based formats were explored to harness the unique therapeutic potential of α-amanitin. While the extremely hydrophilic nature of α-amanitin raised numerous challenges for its nanoencapsulation, a highly homogeneous anti-CD19 α-amanitin-based ADC was successfully developed. This ADC showed targeting selectivity and picomolar toxicity in CD19-positive cell lines, achieving up to 4,200-fold higher effectiveness than the free drug in B-cell ALL models. <br><i><br>Thesis embargoed until 31st December 2029 </i>