Cyclic
RGD (cRGD) peptide-conjugated boronated albumin was developed
to direct toward integrin αvβ3, which
overexpresses on many cancer cells. A stepwise conjugation of c[RGDfK(Mal)]
and maleimide-conjugated closo-dodecaborate (MID)
to bovine serum albumin (BSA) afforded cRGD-MID-BSA, which was noncytotoxic
toward both U87MG and A549 cells. As compared with l-BPA,
selective antitumor activity of cRGD-MID-BSA toward U87MG cells overexpressing
integrin αvβ3 was identified after
thermal neutron irradiation. In vivo fluorescence live imaging of
Cy5-conjugated cRGD-MID-BSA and MID-BSA revealed that both cRGD-MID-BSA
and MID-BSA similarly reached the maximum accumulation during 8–12
h after injection. The selective accumulation and retention of Cy5-cRGD-MID-BSA
was more pronounced than Cy5-MID-BSA after 24 h. An in vivo boron
neutron capture therapy (BNCT) study revealed that the cRGD peptide
ligand combination enhanced accumulation of MID-BSA into tumor cells
in U87MG xenograft models. The significant tumor growth suppression
was observed in U87MG xenograft models at a dose of 7.5 mg [10B]/kg after neutron irradiation.
Maleimide-functionalized closo-dodecaborate (MID) and isothiocyanate-functionalized closo-dodecaborate (ISD) were synthesized from closo-dodecaborate via ring opening reaction of 1,4-dioxane-closo-dedecaborate complex 1 with ammonia. MID was found to possess highest conjugation efficacy to bovine serum albumin among three closo-dodecaborate derivatives, MID, ISD, and 1. The conjugation reaction of MID to human serum albumin (HSA) proceeded under PBS buffer conditions (pH 7.4). Boron distribution studies in colon 26 tumor-bearing mice revealed that HSA-MID was highly accumulated in tumor (23 ppm B), whereas boron concentrations in other organs such as liver, kidney and spleen were low (3~8 ppm B).
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