Abstract
In this study, we synthesized a peptide of Nap-GFFYGRGD, which could self-assemble into supramolecular nanofibers. The peptide itself could only form nanofibers but not hydrogels due to the relative weak inter-fiber interactions. The resulting nanofibers were then utilized as the vehicles for anticancer drug doxorubicin. It was found that the nanofibers of Nap-GFFYGRGD could not encapsulate doxorubicin, whereas the drug formed nanospheres, which were located at the surface of the nanofibers. Due to the electrostatic interactions between the negatively charged nanofibers and the positively charged doxorubicin nanospheres, the doxorubicin nanospheres were able to serve as a cross-linker to increase the inter-fiber interactions, leading to the formation of stable three-dimentional fiber networks and hydrogels. The resulting doxorubicin-peptide hydrogels were capable of releasing the drug in a sustained manner, which also showed comparable cytotoxicity as compared to free doxorubicin against a variety of cancer cell lines including HeLa and MCF-7 cancer cells. Therefore, this successful example using drug as the peptide nanofiber cross-linkers provided a new strategy for fabricating supramolecular hydrogelation for controlled delivery of anticancer drugs.
Highlights
In this study, we synthesized a peptide of Nap-GFFYGRGD, which could self-assemble into supramolecular nanofibers
We opted to use supramolecular nanofibers of peptides to deliver doxorubicin and we chose the peptide of NapGFFYGRGD (Fig. 1), because the peptide could self-assemble into nanofibers with good water solubility
Nap-GFFYGRGD was synthesized by standard solid-phase 9-fluorenyl-methoxycarbonyl (Fmoc) peptide chemistry, and its purity and identity were characterized by 1H NMR and LC-MS (Supplementary Fig. S1 and S2)
Summary
For gels with more amounts of doxorubicin, the diameter of nanospheres was larger and the diameter of peptide nanofibers remained similar to that, suggesting that the nanospheres were probably formed by doxorubicin (Fig. 3C). The results indicated that the zeta potential of the peptide solution in the absence of doxorubicin was about 244 mV, which was significantly neutralized with the increase of doxorubicin amount in the peptide solution Based on these observations, we proposed a possible illustration for hydrogelations in our system (Fig. 3E). The diameter of both nanospheres and nanofibers changed to be smaller (Supplementary Fig. S5), suggesting that both the peptide and DOX got released from the gel. These observations suggested that our hydrogels might be applied for controlled delivery of doxorubicin
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