Bench to Bedside: Albumin Binders for Improved Cancer Radioligand Therapies

Abstract

Radioligand therapy (RLT) relies on the use of pharmacophores to selectively deliver ionization energy to cancers to exert its tumoricidal effects. Cancer cells that are not directly targeted by a radioconjugate remain susceptible to RLT because of the crossfire effect. This is significant given the inter- and intra-heterogeneity of tumors. In recent years, reversible albumin binders have been used as simple “add-ons” for radiopharmaceuticals to modify pharmacokinetics and to enhance therapeutic efficacy. In this Review, we discuss recent advances in albumin binder platforms used in RLT, with an emphasis on 4-(p-iodophenyl)­butyric acid and Evans blue derivatives. We focus on four biological systems pertinent to oncology that utilize this class of compounds: folate receptor, integrin αvβ3, somatostatin receptor, and prostate-specific membrane antigen. Finally, we offer our perspectives on albumin binders for RLT, highlighting future areas of research that will help propel the technology further for clinical use.

Molecular, Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy

“…An equally successful biological counterpart is albumin, the most abundant protein in human plasma, characterized with a phenomenal circulation half‐life of around three weeks . Drug conjugates and supramolecular noncovalent adducts with albumin are successful in their own right, the latter of which are increasingly popular because of the decreased handling of the biomolecule and the incredibly broad spectrum of synthetic opportunities to define affinity to albumin and the pharmacokinetics of the therapeutic molecule . Indeed, the overall majority of covalent conjugates to albumin pursue the same chemistry of maleimide‐to‐Cys34 conjugation .…”

“…Indeed, the overall majority of covalent conjugates to albumin pursue the same chemistry of maleimide‐to‐Cys34 conjugation . In contrast, the arsenal of noncovalent binders contains dozens of ligands and spacers with associated opportunities to fine‐tune pharmacokinetics of the (pro)drug …”

“…As a drug, we used monomethyl auristatin E (MMAE), one of the most potent toxins used in medicinal practice . Finally, the protraction arm R was introduced at a late stage of the synthesis and varied between PEG 2,000 Da and PEG 20,000 Da (tools of polymer therapeutics), as well as 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine (DSPE), 4‐( p ‐iodophenyl)butyric acid (AlbuTag), and the trityl group (Tr), the latter of which are known albumin binders …”

“…Whereas toxicity of treatment was much improved over MMAE monotherapy, improvement in the therapeutic effect was not observed (Figure 2 C 1,2 ,D 1,2 ). This observation was rather surprising and indicates that otherwise successful tools of nanomedicine, such as DSPE‐PEG, PEG, and AlbuTag failed to facilitate translocation of the glucuronide prodrugs to the tumor in sufficient quantities required for a successful i ‐EPT, at least with the chosen sparse s.c. drug administration schedule. Worthy of note, the prodrug with a PEG 20k ( 8 ) protraction arm exhibited statistically significant suppression of the tumor growth rate and this prodrug scaffold deserves further optimization.…”

“…Analysis of the structure–activity relationship for the panel of molecular, macromolecular, and supramolecular prodrugs employed in this work reveals the Tr‐PEG protraction arm to be the most effective tool to achieve enhanced tumor localization of the prodrug with ensuing tumor growth suppression. The likely mechanism of this pharmacokinetic phenomenon is that this prodrug associates noncovalently with albumin, as is the case for the DSPE and AlbuTag counterpart . However, affinity of the trityl group to albumin at this point is only conjecture as limited prior art exists to support this notion .…”