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.