Orlistat, an FDA-approved drug for obesity treatment, demonstrates certain anticancer abilities by inhibiting of fatty acid synthesis. However, the anticancer activity of orlistat is low and varies greatly as tested <i>in vivo</i>. We reported the synergistic effect between orlistat and polydopamine in cancer treatment recently. This study we synthesized orlistat-dopamine conjugates (ODC) with a defined chemistry structure. Orlistat-dopamine conjugates by design underwent auto-oxidation in the presence of organic bases to polymerize and self-assemble into nano-sized particles (Nano-ODC). The resulted Nano-ODCs were well dispersed in solutions to form stable Nano-ODC suspensions. Because of the bio-adhesive property of catechol moieties, once incubated with cancer cells, Nano-ODCs were quickly accumulated on cell surfaces and efficient uptake by cancer cells through the endocytosis. In the cytoplasm, partially crystallized Nano-ODC experienced a biphasic dissolution followed by spontaneous hydrolysis to release intact orlistat and dopamine, which was regulated by pH values. Co-localized dopamine triggered mass production of reactive oxygen species and yielded synergistic effects on the cytotoxicity of orlistat. As a result, Nano-ODC demonstrated good cytotoxicity through a new cell lysis mechanism, and thus killed drug-sensitive and resistant cancer cells indistinguishably. Nano-ODC-enabled orlistat repurposing will contribute to the drug resistance overcome and the improvement of cancer chemotherapy.

Anticancer activity of nano-formulated orlistat-dopamine conjugates through self-assembly

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