Co-Assembly of Cancer Drugs with Cyclo-HH Peptides: Insights from Simulations and Experiments

Anastasia Vlachou, Vijay Bhooshan Kumar, Om Shanker Tiwari, Sigal Rencus-Lazar, Yu Chen, Busra Ozguney, Ehud Gazit, Phanourios Tamamis

Research output: Contribution to journalArticlepeer-review


Peptide-based nanomaterials can serve as promising drug delivery agents, facilitating the release of active pharmaceutical ingredients while reducing the risk of adverse reactions. We previously demonstrated that Cyclo-Histidine-Histidine (Cyclo-HH), co-assembled with cancer drug Epirubicin, zinc, and nitrate ions, can constitute an attractive drug delivery system, combining drug self-encapsulation, enhanced fluorescence, and the ability to transport the drug into cells. Here, we investigated both computationally and experimentally whether Cyclo-HH could co-assemble, in the presence of zinc and nitrate ions, with other cancer drugs with different physicochemical properties. Our studies indicated that Methotrexate, in addition to Epirubicin and its epimer Doxorubicin, and to a lesser extent Mitomycin-C and 5-Fluorouracil, have the capacity to co-assemble with Cyclo-HH, zinc, and nitrate ions, while a significantly lower propensity was observed for Cisplatin. Epirubicin, Doxorubicin, and Methorexate showed improved drug encapsulation and drug release properties, compared to Mitomycin-C and 5-Fluorouracil. We demonstrated the biocompatibility of the co-assembled systems, as well as their ability to intracellularly release the drugs, particularly for Epirubicin, Doxorubicin, and Methorexate. Zinc and nitrate were shown to be important in the co-assembly, coordinating with drugs and/or Cyclo-HH, thereby enabling drug-peptide as well as drug-drug interactions in successfully formed nanocarriers. The insights could be used in the future design of advanced cancer therapeutic systems with improved properties.

Original languageEnglish
Pages (from-to)2309-2324
Number of pages16
JournalACS Applied Bio Materials
Issue number4
Early online date13 Mar 2024
StatePublished - 15 Apr 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society


E.G. acknowledges support from NSF-BSF Joint Funding Research Grants (no. 2020752). P.T. acknowledges support from the National Science Foundation (Award Number 2104558; NSF-BSF: Computational and Experimental Design of Novel Peptide Nanocarriers for Cancer Drugs). All MD simulations and energy calculations were performed using computational resources at the High Performance Research Computing facility, the College of Engineering, and the Artie McFerrin Department of Chemical Engineering at Texas A&M University.

FundersFunder number
National Science Foundation2104558


    • cancer drugs
    • drug encapsulation
    • molecular dynamics simulations
    • peptide co-assembly with drugs
    • peptide self-assembly


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