title: Synthesis and Self-Assembly of a Mikto-Arm Star Dual Drug Amphiphile Containing both Paclitaxel and Camptothecin.
abstract: Self-assembly of anticancer therapeutics into discrete nanostructures provides an innovative way to develop a self-delivering nanomedicine with a high, quantitative drug loading. We report here the synthesis and assembly of a mikto-arm star dual drug amphiphile (DA) containing both a bulky paclitaxel (PTX) and a planar camptothecin (CPT). The two anti-cancer drugs of interest were stochastically conjugated to a β-sheet forming peptide (Sup35) and under physiologically-relevant conditions the dual DA could spontaneously associate into supramolecular filaments with a fixed 41% total drug loading (29% PTX and 12% CPT). Transmission electron microscopy imaging and circular dichroism spectroscopy studies reveal that the bulkiness of the PTX, as well as the π-π interaction preference between the CPT units, has a significant impact on the assembly kinetics, molecular level packing, and nanostructure morphology and stability. We found that the DA containing two PTX units assembled into non-filamentous micelle-like structures, in contrast to the filamentous structures formed by the hetero dual DA and the DA containing two CPTs. The hetero dual DA was found to effectively release the two anticancer agents, exhibiting superior cytotoxicity against PTX-resistant cervical cancer cells. The presented work offers a potential method to generate well-defined entwined filamentous nanostructures and provides the basis for a future combination therapy platform.
authors: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA ; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors: A G
authors: AG
authors: Cheetham
authors: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors: P
authors: P
authors: Zhang
authors: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA ; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors: Y-A
authors: YA
authors: Lin
authors: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors: R
authors: R
authors: Lin
authors: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA ; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors: H
authors: H
authors: Cui