Platinum-acridine hybrid agents show high activity in non-small cell lung cancer (NSCLC) and other solid tumors at low-nanomolar concentrations but prove to be quite toxic in test animals. To improve the tolerability of these agents, we are currently pursuing various delivery and prodrug strategies. We reasoned that nanoencapsulation of the dicationic, hydrophilic platinum-acridines in the aqueous core of liposomes may alter the pharmacokinetic properties of the agents by prolonging their circulation times and delivering the payload to the tumor site. To this end, the most cytotoxic analogue (IC<sub>50</sub> = 1.3 nM in NCI-H460 cells) was successfully loaded into liposomes prepared from DPPG, HSPC, and DSPE-mPEG<sub>2k</sub>. This combination of lipids yields liposomes with a diameter of 120 nm and a drug loading of 20 % (based on Pt-to-lipid ratio, wt/wt). The formulation shows improved cytotoxicity compared to the free agent, and confocal microscopy images of cancer cells treated with liposome suggest a distinct mechanism of cellular uptake. Another strategy to overcome systemic toxicity are newly designed ester-based prodrugs, in which hydroxyl-modified derivatives have been masked with a cleavable lipophilic acyl moiety. Two distinct pathways by which the target compounds undergo effective ester hydrolysis, the proposed activating step, have been confirmed using spectroscopic and analytical methods: (i) platinum-assisted, self-immolative ester cleavage in a low-chloride environment and (ii) enzymatic cleavage by human carboxylesterase-2 (hCES-2). Among the derivatives, the valproic acid ester analogue shows excellent chemical stability and reduced systemic toxicity in vivo. Furthermore, to produce less genotoxic and more selective agents, modifications are introduced that allow targeting of nucleolar nucleic acids (rDNA and rRNA) involved in ribosome biogenesis. This can be achieved by minimizing the reactivity of platinum with the dsDNA of chromatin and by conjugating the cytotoxic agent to the vectors that selectively deliver the cargo to the nucleolus.

Novel strategies for improving the pharmacological properties of platinum-acridine anticancer agents

249th National Meeting (2015)

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