A Comparison of Di- and Trinuclear Platinum Complexes Interacting with Glycosaminoglycans for Targeted Chemotherapy.

Heparan sulfate proteoglycans (HSPGs) and their associated proteins aid in tumor progression through modulation of biological events such as cell invasion, angiogenesis, metastasis, and immunological responses. Metalloshielding of the anionic heparan sulfate (HS) chains by cationic polynuclear platinum complexes (PPCs) prevents the HS from interacting with HS-associated proteins and thus diminishes the critical functions of HSPG. Studies herein exploring the PPC-HS interactions demonstrated that a series of PPCs varying in charge, nuclearity, distance between Pt centers, and hydrogen-bonding ability influence HS affinity. We report that the polyamine-linked complexes have high HS affinity and display excellent in vivo activity against breast cancer metastases and those arising in the bone and liver compared to carboplatin. Overall, the PPC-HS niche offers an attractive approach for targeting HSPG-expressing tumor cells.

Substitution-inert polynuclear platinum compounds inhibit human cytomegalovirus attachment and entry.

Human cytomegalovirus (HCMV) infects up to 90-100% of the world population. Although HCMV infection is not a concern for immunocompetent patients, it can be life threatening for immunocompromised individuals. Additionally, congenital HCMV infections can cause serious neurological deficits in neonates. Since viral resistance mutations arise for all current treatments, new treatments targeting novel processes are needed. A well-defined target for HCMV is heparan sulfate, a highly sulfated glycosaminoglycan (GAG) necessary for virion/host cell attachment. In this study, we investigated as possible antiviral agents substitution-inert cationic polynuclear platinum complexes (PPCs) that demonstrate charge-dependent high affinity for GAGs (Katner et al., 2018; Peterson et al., 2017). Certain PPCs had anti-HCMV activities in low micromolar concentrations and antiviral activity correlated with their GAG-binding affinity. Time of addition, removal, and mechanistic studies were consistent with PPCs binding to cells and blocking HCMV virion attachment; however, evidence also suggested that PPC/virion interactions could inhibit fibroblast but not epithelial cell infection. We hypothesize that the PPC-heparan sulfate interaction described here is a general approach to inhibition of virion/host cell attachment and viral entry mediated by other anionic GAGs and sialic acids on the cell surface. Through metalloshielding of the critical sulfate receptors, PPCs offer an attractive alternative to current antiviral compounds, with the potential to target a broad spectrum of viruses that utilize GAGs for attachment and entry.

Substitution-Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate.

Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumour-related events including angiogenesis, cell invasion, and metastasis. Metalloshielding of heparan sulfate (HS) by positively charged polynuclear platinum complexes (PPCs) effectively inhibits physiologically critical HS functions. Studies using bacterial P. heparinus heparinase II showed that a library of Pt complexes varying in charge and nuclearity and the presence or absence of a dangling amine inhibits the cleavage activity of the enzyme on the synthetic pentasaccharide, Fondaparinux (FPX). Charge-dependent affinity of PPC for FPX was seen in competition assays with methylene blue and ethidium bromide. The dissociation constant (Kd ) of TriplatinNC for FPX was directly measured by isothermal titration calorimetry (ITC). The trend in DFT calculated interaction energies with heparin fragments is consistent with the spectroscopic studies. Competitive inhibition of TAMRA-R9 internalization in human carcinoma (HCT116) cells along with studies in HCT116, wildtype CHO and mutant CHO-pgsA745 (lacking HS/CS) cells confirm that HSPG-mediated interactions play an important role in the cellular accumulation of PPCs.