Huperzine A (Hup-A) is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion (SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration-time curve (AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension (P<0.01). The absorption rate constant (Ka) and the apparent permeability coefficient (Papp) for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of Ka and Papp of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration (Cmax) of the blocking model were significantly lower than those of the control model (P<0.05). The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%, respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

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.