Abstract

Background: The benzothiazole structure is important in medicinal chemistry, and
5‐fluoro‐2‐(3,4‐dimethoxyphenyl) benzothiazole (GW 610) is of particular interest as
it shows outstanding anticancer activity in sensitive breast and colorectal carcinoma
cell lines via generation of lethal DNA adducts in sensitive cancer cells. Despite
promising activity, poor water solubility limits its applications. The apoferritin (AFt)
protein cage has been proposed as a robust and biocompatible drug delivery vehicle.
Aims: Here, we aim to enhance solubility of GW 610 by developing amino acid
prodrug conjugates and utilizing the AFt capsule as drug delivery vessel.
Methods and results: The potent experimental antitumour agent, GW 610, has
been successfully encapsulated within AFt with more than 190 molecules per AFt
cage. The AFt‐GW 610 complex exhibits dose‐dependent growth inhibition and is
more potent than GW 610 alone in 5/7 cancer cell lines. To enhance both aqueous
solubility and encapsulation efficiency, a series of amino acid esters of GW 608
prodrug were synthesized via N,N′‐dicyclohexylcarbodiimide ester coupling to produce
molecules with different polarity. A dramatic increase in encapsulation efficiency
was achieved, with more than 380 molecules of GW 608‐Lys molecules per AFt cage.
Release studies show sustained release of the cargo over 12 hours at physiologically
relevant pH. The AFt‐encapsulated amino acid modified GW 608 complexes are
sequestered more rapidly and exhibit more potent anticancer activity than
unencapsulated agent.
Conclusion: These results indicate that AFt‐encapsulation of GW 610 prodrug provides
a biocompatible delivery option for this potent, selective experimental
antitumour agent and for amino acid‐modified GW 608. Of particular interest is the
encapsulation efficiency and in vitro antitumour activity of AFt‐GW 608‐Lys, which
warrants further preclinical evaluation.