Abstract
Treatment of hepatocellular carcinoma (HCC) requires sustained suppression of tumor cell growth and metastasis for long‐term efficacy. However, traditional intratumoral drug delivery system always exhibits burst release with less therapeutic outcomes. Here, a new self‐assembling amphiphilic peptide drug conjugate (SAAPDC) is fabricated as a “two‐in‐one” nanofiber system comprising a hexapeptide as a matrix metalloproteinases (MMP) inhibitor and doxorubicin (DOX) for the treatment of HCC. The results indicate that doxorubicin‐conjugated peptide (DOX‐KGFRWR) self‐assembles to form long nanofibers showing sustained release property for inhibiting the enzymatic activities of MMP‐2 and MMP‐9. This nanofiber not only inhibits tumor growth in situ but also effectively prevents pulmonary metastasis in an SMMC7721 cell line–based mouse model. In summary, this hexapeptide‐based supermolecule system represents a promising nanoscale platform to sustain drug release with high loading capacity for intratumoral administration. Moreover, the delivery of chemotherapeutic drugs via drug‐bearing supramolecular MMP inhibitor nanofibers simultaneously inhibits metastasis and tumor growth to achieve synergistic effects for metastatic HCC therapy.
Highlights
Sion of tumor cell growth and metastasis for long-term efficacy
The hexapeptide KGFRWR possesses alternating hydrophobic–hydrophilic side-chain functionalities that form nanofiber structures when conjugated to a larger hydrophobic moiety, and even form nanofibers
We evaluated the sustained release of DOX from the DOX– KGFRWR nanofiber to evaluate the long-lasting effects of this system
Summary
The conjugation of suitable amino acids to antitumor drugs such as DOX was shown to significantly improve cellular uptake and drug resistance compared to the free drug.[16]. The hexapeptide KGFRWR possesses alternating hydrophobic–hydrophilic side-chain functionalities that form nanofiber structures when conjugated to a larger hydrophobic moiety, and even form nanofibers. According to the results of the gelation test, KGFRWR and amphiphilic DOX–KGFRWR conjugates formed stable, colorless transparent, or red nanofibers, respectively, at a concentration of 1.5 × 10−3 m (Figure 1). KGFRWR and DOX–KGFRWR self-assembled to form long nanofibers with average widths of 6.67 and 10.51 nm (Figure 1a), respectively, where the difference in the diameter between the two nanofibers is approximately the size of DOX. The hydrophobic tryptophan group in the predominantly hydrophilic plane may facilitate the packing and lead to an increase in the interfacial curvature, favoring a fiber-like structure at concentrations exceeding the critical aggregation concentration
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