Transforming Small-Molecule Nanoaggregation into Functional Drug Delivery Platforms

The development of stimuli-responsive nanoaggregates
offers a transformative
approach to cancer therapy, addressing the challenges of selectivity
and efficacy. The spontaneous formation of nanoscale aggregates of
small organic molecules through self-assembly is a major hurdle in
early-stage drug discovery. However, this disadvantage can be transformed
with a meticulous design into a functional drug delivery platform.
Here, we report Nano-CC1-Acl, a nanoaggregate engineered
for targeted anticancer activity. CC1 and CC1-Acl, benzimidazole derivatives, undergo self-assembly in aqueous environments
to generate Nano-CC1 (235.2 ± 28.2 nm; IC50 > 100 μM) and Nano-CC1-Acl (110.6 ± 23.1
nm; IC50 = 2.88–3.40 μM) nanoaggregates. The
IC50 value of Nano-CC1-Acl further decreases
to 0.20 ± 0.16 μM in the presence of cysteine, a biothiol.
Triggered by intracellular biothiols, Nano-CC1-Acl disassembles
to release CC1, a potent microtubule-targeting agent
that disrupts microtubule polymerization. Results presented here indicate
that small molecule nanoaggregation can be utilized to develop functional
drug delivery platforms.