Drug Conjugation to Cyclic Peptide–Polymer Self‐Assembling Nanotubes

Blunden, Bianca M.; Chapman, Robert; Danial, Maarten; Lu, Hongxu; Jolliffe, Katrina A.; Perrier, Sébastien; Stenzel, Martina H.

doi:10.1002/chem.201403130

Cited by 44 publications

(38 citation statements)

References 32 publications

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“…37 Conjugation of water-soluble polymers to these peptides enables control over the size and the functionality of the nanotubes. Although first cell studies indicated that nanotubes possess great potential as nanosized drug delivery systems, [38][39][40] their in vivo behaviour has yet to be explored.…”

Section: Introductionmentioning

confidence: 99%

Cyclic peptide-poly(HPMA) nanotubes as drug delivery vectors: In vitro assessment, pharmacokinetics and biodistribution

et al. 2018

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Size and shape have progressively appeared as some of the key factors influencing the properties of nanosized drug delivery systems. In particular, elongated materials are thought to interact differently with cells and therefore may allow alterations of in vivo fate without changes in chemical composition. A challenge, however, remains the creation of stable self-assembled materials with anisotropic shape for delivery applications that still feature the ability to disassemble, avoiding organ accumulation and facilitating clearance from the system. In this context, we report on cyclic peptide-polymer conjugates that self-assemble into supramolecular nanotubes, as confirmed by SANS and SLS. Their behaviour ex and in vivo was studied: the nanostructures are non-toxic up to a concentration of 0.5 g L and cell uptake studies revealed that the pathway of entry was energy-dependent. Pharmacokinetic studies following intravenous injection of the peptide-polymer conjugates and a control polymer to rats showed that the larger size of the nanotubes formed by the conjugates reduced renal clearance and elongated systemic circulation. Importantly, the ability to slowly disassemble into small units allowed effective clearance of the conjugates and reduced organ accumulation, making these materials interesting candidates in the search for effective drug carriers.

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Section: Introductionmentioning

confidence: 99%

Cyclic peptide-poly(HPMA) nanotubes as drug delivery vectors: In vitro assessment, pharmacokinetics and biodistribution

et al. 2018

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“…Perpendicular to the plane of the cyclic peptide ring, the amide bonds participate in hydrogen bonding to form a nanotubular assembly . These systems have gained much attention due to their potential biological applications as antimicrobial materials, biosensors, and drug delivery vehicles . Conjugation of water‐soluble polymers to these peptides significantly improves their solubility, further widening the range of biological applications.…”

Section: Introductionmentioning

confidence: 99%

Probing the Dynamic Nature of Self‐Assembling Cyclic Peptide–Polymer Nanotubes in Solution and in Mammalian Cells

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et al. 2017

Adv Funct Materials

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Self-assembling cyclic peptide-polymer nanotubes have emerged as a fascinating supramolecular system, well suited for a diverse range of biomedical applications. Due to their well-defined diameter, tunable peptide anatomy, and ability to disassemble in situ, they have been investigated as promising materials for numerous applications including biosensors, antimicrobials, and drug delivery. Despite this continuous effort, the underlying mechanisms of assembly and disassembly are still not fully understood. In particular, the exchange of units between individual assembled nanotubes has been overlooked so far, despite its knowledge being essential for understanding their behavior in different environments. To investigate the dynamic nature of these systems, cyclic peptide-polymer nanotubes are synthesized, conjugated with complementary dyes, which undergo a Förster resonance energy transfer (FRET) in close proximity. Model conjugates enable to demonstrate not only that their self-assembly is highly dynamic and not kinetically trapped, but also that the self-assembly of the conjugates is strongly influenced by both solvent and concentration. Additionally, the versatility of the FRET system allows studying the dynamic exchange of these systems in mammalian cells in vitro using confocal microscopy, demonstrating the exchange of subunits between assembled nanotubes in the highly complex environment of a cell. Nanotubes

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“…For example, IC 50 values of 15 and 51 μM were observed against the A2780 cell line relative to 271 μM for RAPTA-C. Fluorescence microscopy indicated that the micelles co-localized within the lysosomes (A2780 cell line, 3 h incubation) and ICP-MS revealed higher intracellular ruthenium concentrations in cells incubated with the micelles compared to RAPTA-C (up to a 12-fold increase in uptake). Synthetic route to PTA-containing polymers and polymers loaded with the RAPTA unit via the PTA ligand [72, 73].Further studies resulted in the development of cyclic peptide-polymer nanotubes as carrier systems of RAPTA-C[74]. Two p(HEA 58 -co-CEMA 10 ) polymers were coupled to a cyclic peptide via an alkyne end-group, followed by exchange of the chloride groups of the CEMA side chains to iodide groups using the Finkelstein reaction.RAPTA-C was then covalently attached to the polymer via reaction of PTA with the iodide side-chains followed by addition of [RuCl 2 (η 6 -p-cymene)] 2 .…”

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confidence: 99%