Antibody-Targeted Drug Delivery and Arsenic Trioxide

Antibody-Targeted Drug Delivery and Arsenic Trioxide-based
Agents for the Treatment of Metastatic Brain Cancer
Thomas V. O’Halloran, PhD
The Chemistry of Life Processes Institute; Robert H. Lurie Comprehensive
Cancer Center; Departments of Chemistry and Molecular Biosciences
Northwestern University, Evanston Il 60208-3113
Arsenic-containing compounds have been used in the treatment of disease for
over 3000 years. A resurgence of interest in the therapeutic application of
arsenicals has been driven by the discovery that low doses of an aqueous
solution of arsenic trioxide (i.e. arsenous acid) leads to complete remission of
certain types of leukemia. Since FDA approval of arsenic trioxide (As 2O3 or ATO)
for treatment of acute promyelocytic leukemia (APL) in 2000, it has become a
front line therapy in this indication. There are currently over 100 active clinical
trials involving arsenic compounds registered with the FDA for the treatment of
cancers. New generations of arsenic-based agents with enhanced activity or
targeted cytotoxicity are being developed to overcome some of the shortcomings
of arsenic therapeutics, namely short plasma half-lives, narrow therapeutic
window and limited efficacy against solid tumors. A family of lipid-encased
nanocrystalline drugs known as nanobins will be discussed (Ahn et al. Clin.
Cancer Res. 2010, 16(14) 3607-17). In these agents, aquacisplatin and As2O3
react with in a liposomal delivery vehicle to produce crystalline nanoparticles
stabilized by a novel type of PtII-AsIII adduct (Chen et al., Angew. Chem. Int. Ed.
2009, 48, 9295-9299). Inspired with that discovery, we have synthesized and
structurally characterized the first compounds containing the aqueous form of
ATO directly bound to platinum as an As(OH)2 moiety – arsenoplatins
(Miodragović et al., Angew. Chem. Int. Ed, 2013, 52, 10749-10752).
Arsenoplatins form in water-nitrile solution, retain a Pt-As(OH)2 core, and exhibit
potent cytotoxic activity against different cancer cell lines. This allows the
targeted delivery of drugs to tumors with significant efficacy in mouse models of
basal-like breast cancers that are not easily treated using traditional cytotoxic
chemotherapy. The drug payload of these nanobins is stabilized as a
nanocrystalline material, and drug release is negligible until triggered by intracellular thiols. The NB(Pt,As) both inhibited tumor growth and reduced the
number of lung metastasis. Progress towards the next generation of receptortargeted nanobins will be discussed. Targeted systems include the tumorassociated urokinase plasminogen activator receptor (uPAR) and transferring
receptor pathways and these agents exhibit significant preclinical activity in
animal models of triple negative breast cancer that have metastasized to the