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.
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Acknowledgements
The work is supported by the National Science Foundation (DMR 1255281), USA. We thank National Institutes of Health (NIH) for funding Andrew G CHEETHAM (T-32CA130840). We acknowledge the use of the Johns Hopkins Department of Chemistry NMR and Mass Spectrometry Shared Facilities and the Integrated Imaging Center for access to the relevant instrumentation. Financial support for MALDI-Tof analysis was provided by NSF Grant CHE-0840463. We thank Dr Phil MORTIMER for assistance with LC-MS and Prof Kalina HRISTOVA for use of the CD spectropolarimeter.
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Supplementary information 1H and 13C NMR, HPLC chromatograms and mass spectrometric characterization of the purified materials can be found in the Supplementary Information on the website of Acta Pharmacologica Sinica.
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Comparison of dCPT-buSS-Tau and dCPT-buSS-Sup35 (DOC 1385 kb)
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Cheetham, A., Lin, Ya., Lin, R. et al. Molecular design and synthesis of self-assembling camptothecin drug amphiphiles. Acta Pharmacol Sin 38, 874–884 (2017). https://doi.org/10.1038/aps.2016.151
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DOI: https://doi.org/10.1038/aps.2016.151
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