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*

*Corresponding author for this work

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
StatePublished - 15 Apr 2024


FundersFunder number
National Science Foundation2104558
National Science Foundation


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


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