Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells

Su, Hao; Zhang, Pengcheng; Cheetham, Andrew G.; Koo, Jin Mo; Lin, Ran; Masood, Asad; Schiapparelli, Paula; Quiñones‐Hinojosa, Alfredo; Cui, Honggang

doi:10.7150/thno.15420

Cited by 60 publications

(39 citation statements)

References 69 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

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

2017

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Peptide-based supramolecular filaments, in particular filaments self-assembled by drug amphiphiles (DAs), possess great potential in the field of drug delivery. These filaments possess one hundred percent drug loading, with a release mechanism that can be tuned based on the dissociation of the supramolecular filaments and the degradation of the DAs [Cheetham et al., J. Am. Chem. Soc. 135 (8), 2907 (2013)]. Recently, much attention has been drawn to the competing intermolecular interactions that drive the self-assembly of peptide-based amphiphiles into supramolecular filaments. Recently, we reported on long-time atomistic molecular dynamics simulations to characterize the structure and growth of chiral filaments by the self-assembly of a DA containing the aromatic anti-cancer drug camptothecin [Kang et al., Macromolecules 49 (3), 994 (2016)]. We found that the π–π stacking of the aromatic drug governs the early stages of the self-assembly process, while also contributing towards the chirality of the self-assembled filament. Based on these all-atomistic simulations, we now build a chemically accurate coarse-grained model that can capture the structure and stability of these supramolecular filaments at long time-scales (microseconds). These coarse-grained models successfully recapitulate the growth of the molecular clusters (and their elongation trends) compared with previously reported atomistic simulations. Furthermore, the interfacial structure and the helicity of the filaments are conserved. Next, we focus on characterization of the disassembly process of a 0.675 μm DA filament at microsecond time-scales. These results provide very useful tools for the rational design of functional supramolecular filaments, in particular supramolecular filaments for drug delivery applications.

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Section: Resultsmentioning

confidence: 99%

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

2017

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“…Camptothecin, the first small molecule targeting Top I for the treatment of advanced digestive carcinoma in clinical2331, which stabilizes the DNA cleavable complex to block the transient breaking and rejoining of DNA173233 and has been used as the Top I poison for the treatment of many digestive solid tumors widely34, was served as the positive control. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Chen

Tian

et al. 2016

Sci Rep

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Crude Amaryllidaceae alkaloids (AAs) extracted from Lycoris radiata are reported to exhibit significant anti-cancer activity. However, the specific alkaloids responsible for the pharmacodynamic activity and their targets still remain elusive. In this context, we strived to combine affinity ultrafiltration with topoisomerase I (Top I) as a target enzyme aiming to fish out specific bioactive AAs from Lycoris radiata. 11 AAs from Lycoris radiata were thus screened out, among which hippeastrine (peak 5) with the highest Enrichment factor (EF) against Top I exhibited good dose-dependent inhibition with IC50 at 7.25 ± 0.20 μg/mL comparable to camptothecin (positive control) at 6.72 ± 0.23 μg/mL. The molecular docking simulation further indicated the inhibitory mechanism between Top I and hippeastrine. The in vitro antiproliferation assays finally revealed that hippeastrine strongly inhibited the proliferation of HT-29 and Hep G2 cells in an intuitive dose-dependent manner with the IC50 values at 3.98 ± 0.29 μg/mL and 11.85 ± 0.20 μg/mL, respectively, and also induced significant cellular morphological changes, which further validated our screening method and the potent antineoplastic effects. Collectively, these results suggested that hippeastrine could be a very promising anticancer candidate for the therapy of cancer in the near future.

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“…More recently, Cui and coworkers have reported a novel class of peptide–drug conjugates that can form nanostructures through a true self-assembly pathway. These PDCs, termed drug amphiphiles (DAs), are formed by covalently conjugating one or more anticancer drugs to a rationally designed/chosen peptide through a biodegradable linker [84, 114, 134–137]. The peptides in the resultant conjugates act as the functionally active and guiding unit, which modulate DAs to form a variety of supramolecular morphologies in aqueous solutions.…”

Section: Self-assembling Peptide–drug Conjugatesmentioning

confidence: 99%

Peptide–drug conjugates as effective prodrug strategies for targeted delivery

Wang

Cheetham

Angacian

et al. 2017

Advanced Drug Delivery Reviews

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Peptide–drug conjugates (PDCs) represent an important class of therapeutic agents that combine one or more drug molecules with a short peptide through a biodegradable linker. This prodrug strategy uniquely and specifically exploits the biological activities and self-assembling potential of small molecule peptides to improve the treatment efficacy of medicinal compounds. We review here the recent progress in the design and synthesis of peptide–drug conjugates in the context of targeted drug delivery and cancer chemotherapy. We analyze carefully the key design features in choosing the peptide sequence and linker chemistry for the drug of interest, as well as the strategies to optimize the conjugate design. We highlight the recent progress in the design and synthesis of self-assembling peptide-drug amphiphiles to construct supramolecular nanomedicine and nanofiber hydrogels for both systemic and topical delivery of active pharmaceutical ingredients.

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Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells

Cited by 60 publications

References 69 publications

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

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

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Peptide–drug conjugates as effective prodrug strategies for targeted delivery

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