Albumin-Oxanorbornadiene Conjugates Formed ex Vivo for the Extended Circulation of Hydrophilic Cargo

Abstract

Oxanorbornadiene dicarboxylate (OND) reagents were explored for the purpose of binding and releasing chemical cargos from endogenous circulating serum albumins. ONDs bearing gadolinium chelates as model cargos exhibited variable conjugation efficiencies with albumin in rat subjects that are consistent with the observed reactivity of each linker and their observed stability toward serum hydrolases in vitro. The terminal elimination rate from circulation was dependent on the identity of the OND used, and increased circulation time of gadolinium cargo was achieved for linkers bearing electrophilic fragments designed to react with cysteine-34 of circulating serum albumin. This binding of and release from endogenous albumin highlights the potential of OND linkers in the context of optimizing the pharmacokinetic parameters of drugs or diagnostic agents.

Azabicyclic vinyl sulfones for residue-specific dual protein labelling

“…S8 and S9† for NMR spectroscopic monitoring). Compound 2 has a half-life of ≈16 h, which is nearly half of the longest half-life reported for the corresponding oxanorbornadiene derivative 22. As reported, the rDA fragmentation has a tuneable rate depending upon the substituents of the norbornene so we decided to modulate the stability of our reagent.…”

“…Having shown the chemoselectivity of 1 towards cysteine residues, we then studied the stability of the formed thioether because we were concerned by some rDA reports of cleavage with similar bicyclic systems 22,31–34. Thus, fragmentation of azanorbornene 2 into N -Boc-pyrrole and thio-vinyl sulfone 9 was studied by 1 H NMR spectroscopy at 37 °C in CDCl 3 (Table 1, entry 1; see Fig.…”

“…1a). 20,21 After cysteine ligation on the protein, oxanorbornadiene undergoes a controllable retro-Diels–Alder (rDA) fragmentation that allowed their use as drug delivery systems 22. Strained [2.2.1]bicyclic systems, especially oxanorbornadiene and norbornene systems,19 have also been widely used in the field of bioorthogonal chemistry as handles, for example, for fast reactions with tetrazines in iEDDA 23.…”

Strategies for Preparing Albumin-based Nanoparticles for Multifunctional Bioimaging and Drug Delivery

“…As a natural biomacromolecule measuring 6.67 ± 0.57 nm, albumin also exhibits possible EPR effect on tumors (controversial); a larger size displays excellent EPR effect 138 - 140 . In addition, a single albumin possesses long blood circulation and high biocompatibility, which facilitate the maintenance of high blood drug concentration for long periods 16 , 141 . Thus, a single albumin could be used as a scaffold to be functionalized for effective drug delivery and bioimaging 142 .…”

Programmable multistage drug delivery to lymph nodes

“… 28 , 29 To this platform we bring thiol-reactive oxanorbornadiene (OND) linkers that fragment by a first-order retro-Diels-Alder mechanism in a pH- and solvent-insensitive manner with programmable half-lives ranging from hours to days. 30 – 32 We demonstrate in vivo that this two-stage system facilitates improved lymphatic delivery and access of small and medium-sized molecules to lymphocyte subpopulations poorly accessed with conventional drug formulations. Large increases were observed in the total number of LN-resident cells receiving the cargo, as well as in the delivered dose to those cells, with timing controlled by the half-life of intralymphatic release.…”