Self-assembly of a 5-fluorouracil and camptothecin dual drug dipeptide conjugate.

Nano-formulated, combinatory therapeutics that control the spatiotemporal aspects of drug release have potential to overcome many of the challenges faced in cancer therapy. Herein, we describe a peptide nanotube functionalized with two anticancer drugs, 5-fluoruracil (5-FU) and camptothecin (CPT). The nanotube was formed via peptide self-assembly, which positioned 5-FU on the surface at the aqueous interface; whereas, CPT was sequestered within the hydrophobic walls. Thus, two different release profiles were observed: rapid release of 5-FU, followed by slower, sustained production of CPT. This profile emerged from the rapid hydrolytic cleavage of 5-FU at the aqueous/nanotube interface, which produced a smaller nanotube comprised of the peptide fragment.

The self-assembly of a camptothecin-lysine nanotube.

A simple, low molecular weight camptothecin-lysine conjugate is reported to self-assemble into nanotubes with diameters of 70-100nm and a drug loading level of 60.5%. The nanotubes exhibited promising in vitro cytotoxicity against cancer cell lines A549, NCI-H460 and NCI-H23. The release of active camptothecin was highly dependent on conjugate concentration, temperature and pH of the solution.

The self-assembly of anticancer camptothecin-dipeptide nanotubes: a minimalistic and high drug loading approach to increased efficacy.

20-(S)-Camptothecin (CPT)-conjugated dipeptides are reported that preassemble into nanotubes with diameters ranging from 80-120 nm. These nanoassemblies maintain a high (∼47 %) drug loading and exhibit greater drug stability (i.e., resistance to lactone hydrolysis), and consequently greater efficacy against several human cancer cells (HT-29, A549, H460, and H23) in vitro compared with the clinically used prodrug irinotecan. A key and defining feature of this system is the use of the CPT-conjugated dipeptide as both the drug and precursor to the nanostructured carrier, which simplifies the overall fabrication process.

Self-assembly of a robust, reduction-sensitive camptothecin nanotube.

The self-assembly and covalent crosslinking of a camptothecin (CPT) tetrapeptide nanotube is reported. Intermolecular disulfide bond formation of a self-assembled CPT-peptide reversibly stabilized the nanotubes toward dissociation at low concentrations, resulting in inhibited release of CPT. In the presence of dithiothreitol (DTT), the release of CPT was significantly accelerated. The crosslinked nanotubes also exhibited in vitro cytotoxicity against human non-small cell lung cancer cell lines A549 and H460.

Controlling the length of self-assembled nanotubes by sonication followed by polymer wrapping.

This work demonstrates that sonication, followed by polymer-wrapping, is an effective strategy to modulate the length of self-assembled nanotubes. The length distributions of the nanotubes were controlled by varying the amplitude of sonication. Wrapping the nanotubes with ionic polymers suspended the propensity of the nanotube fragments to re-assemble over time into their elongated precursors.

Self-assembly of a 5-fluorouracil-dipeptide hydrogel.

The self-assembly of 5-fluorouracil dilysine conjugates into self-supporting hydrogels, comprised of entangled nanofibers or rigid nanotubes with diameters of 10 and 16 nm, respectively, is reported. The rate of release of 5-Fu from the conjugates was highly dependent on concentration in solution, whereas, release from the fully formed hydrogels was significantly slower. The 5-Fu conjugate also exhibited promising in vitro cytotoxicity against human tumor cell lines A549, H460 and H23.