Molecular design and synthesis of self-assembling camptothecin drug amphiphiles

Abstract

The conjugation of small molecular hydrophobic anticancer drugs onto a short peptide with overall hydrophilicity to create self-assembling drug amphiphiles offers a new prodrug strategy, producing well-defined, discrete nanostructures with a high and quantitative drug loading. Here we show the detailed synthesis procedure and how the molecular structure can influence the synthesis of the self-assembling prodrugs and the physicochemical properties of their assemblies. A series of camptothecin-based drug amphiphiles were synthesized via combined solid- and solution-phase synthetic techniques, and the physicochemical properties of their self-assembled nanostructures were probed using a number of imaging and spectroscopic techniques. We found that the number of incorporated drug molecules strongly influences the rate at which the drug amphiphiles are formed, exerting a steric hindrance toward any additional drugs to be conjugated and necessitating extended reaction time. The choice of peptide sequence was found to affect the solubility of the conjugates and, by extension, the critical aggregation concentration and contour length of the filamentous nanostructures formed. In the design of self-assembling drug amphiphiles, the number of conjugated drug molecules and the choice of peptide sequence have significant effects on the nanostructures formed. These observations may allow the fine-tuning of the physicochemical properties for specific drug delivery applications, ie systemic vs local delivery.

Self-assembling prodrugs

“…To study the effect of the peptide segment on morphology, Cui and coworkers replaced the Tau peptide sequence with a more hydrophilic β-sheet forming peptide derived from the Sup35 yeast prion (NNQQNY). 197 Similar nanofilaments were observed in both cases however, in comparison to dCPT-buSS-Tau, the nanofilaments of dCPT-buSS-Sup35 were slightly wider yet considerably longer. Moreover, a significant distinction was seen in the critical assembly concentration (CAC) where the more hydrophilic peptide showed a lower propensity to assemble into micelles, as evidenced by the higher CAC value, which could be a result of increased monomer solubility.…”

Coarse-grained molecular dynamics studies of the structure and stability of peptide-based drug amphiphile filaments

“…20 When exposed to mild sonication, dissociation was observed in the case of a similar DA called qCPT-Sub 35 which has four CPT drugs conjugated to a Sub 35 peptide. 90–92 After relaxing the computational system for 200 ns at 300 K, the filament is 0.576 μm. When the temperature is elevated to 350 K, the disassembly process starts quickly with three distinct behaviours: kinking, thinning, and budding as shown in Fig.…”

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

“…Cui and co‐workers conjugated hydrophilic peptides to camptothecin ( Figure 4A). Besides the simply hydrophobic interactions, this design also takes advantages of the highly predictable self‐assemble properties of peptides, by which multiple molecular interactions including van der Waals forces, ionic bonds, hydrogen bonds are involved in the self‐assembly . The addition of a reducible disulfide linker allows the release of CPT upon tumor cell uptake and internalization, resulting greater cytotoxic effect in vitro …”