Design of the New Closo-Dodecarborate-Containing Gemcitabine Analogue for the Albumin-Based Theranostics Composition

Abstract

Combination therapy is becoming an increasingly important treatment strategy because multi-drugs can maximize therapeutic effect and overcome potential mechanisms of drug resistance. A new albumin-based theranostic containing gemcitabine closo-dodecaborate analogue has been developed for combining boron neutron capture therapy (BNCT) and chemotheraphy. An exo-heterocyclic amino group of gemcitabine was used to introduce closo-dodecaborate, and a 5′-hydroxy group was used to tether maleimide moiety through an acid-labile phosphamide linker. The N-trifluoroacylated homocysteine thiolactone was used to attach the gemcitabine analogue to human serum albumin (HSA) bearing Cy5 or Cy7 fluorescent dyes. The half-maximal inhibitory concentration (IC50) of the designed theranostic relative to T98G cells was 0.47 mM with the correlation coefficient R = 0.82. BNCT experiments resulted in a decrease in the viability of T98G cells, and the survival fraction was ≈ 0.4.

Development of theranostics albumin auristatin conjugates for combining chemotherapy with boron neutron capture therapy

“…We previously reported using the reactivity of a thiolactone homocysteine (a cyclic thioester) as a latent thiol functionality in thiol-'click' chemistry for the synthesis of HSA-based theranostic agents [6, 7,23,24,38]. The thiol was released by nucleophilic ring-opening (aminolysis) by amino groups on the HSA and subsequently reacted with a thiol 'scavenger' (a maleimide of the drug).…”

“…Currently, some research groups developed maleimide-functionalized closo-dodecaborate and aimed to conjugate it to albumin [20][21][22][23][24]. Conjugation of albumin with undecahydro-closo-dodecaborate did not signi cantly affect cell viability in the absence of irradiation, as compared with the unmodi ed protein.…”

In Vivo Application of Carboranes for Boron Neutron Capture Therapy (BNCT): Structure, Formulation and Analytical Methods for Detection

“…Receptor-targeted BNCT or the use of therapeutic nucleic acids [204,[206][207][208][209] may represent innovative approaches to improve the selectivity of boron agents. Biocompatible delivery systems, based on biomolecules such as proteins (i.e., albumin) or antibodies, will allow for better bioretention and bioavailability of the investigated boron agents [104,158,[210][211][212][213][214][215].…”