•Good solubility and stability of HA-PTX was obtained by one step method of directly linking the PTX to HA via the ester bond.•The tLyP-1 was used to modify HA-PTX and guided the formed conjugate to penetrate multiple bio-barriers into tumor cells.•The tLyP-1 expanded the anticancer scope of tLyP-1-HA-PTX from tumor cells expressing CD44 to those of expressing NRP1.•Good stability and safety of conjugates were proved via FT-IR, 1H NMR, in vitro stability studies and hemolysis test.•Enhanced targeting and accumulation of conjugates were certified by in vitro cellular uptake studies.A novel tLyP-1-HA-PTX conjugate is designed for combining the solubilization capacity of Paclitaxel (PTX) and tumor tissue targeting – penetration effect of hyaluronic acid (HA) as well as cell penetration peptide (tLyP-1). In addition, through modifying by tLyP-1, the anticancer scope of tLyP-1-HA-PTX conjugate was expanded from tumor cells expressing CD44 receptors to those of expressing NRP1 receptors. In vitro antitumor ability of tLyP-1-HA-PTX conjugate and cellular uptake tests were conducted to testify the tumor-targeting behavior of the conjugates. The results showed that both HA-PTX and tLyP-1-HA-PTX conjugates gained better solubility, better stability and specific tumor sites ability and showed high safety in vitro cytotoxicity tests. The tLyP-1-HA-PTX conjugate was especially endowed with efficient cell-penetrating and tumor NRP1 receptor targeting ability and compensate for the decreasing of uptake caused by suppression of CD44 receptor, which is more significant when NRP1 receptor is highly expressed.

Tyroservatide (YSV) is a tripeptide that has been approved for clinical testing, as a new anticancer drug. In the current study, YSV-stearic acid (YSV-SA) was inserted into the surface of d-alpha-tocopheryl polyethylene glycol 1000 succinate monoester (TPGS)-modified paclitaxel (PTX) liposomes (TP-Lip) to form YSV-conjugated TP-Lip (TYP-Lip). Both in vivo imaging and in vitro cell uptake analysis indicated that these modifications could increase tumor-targeting and cell uptake of the liposomes. Optimal antitumor effects were achieved via tail vein injections of TYP-Lip in MB-231 tumor-bearing nude mice. Overall, the formed TYP-Lip not only achieved a synergistic anticancer effect through YSV and PTX, but also improved tumor-targeting and exhibited further antitumor capabilities. These results indicated that combining biological (YSV) and chemotherapeutic (PTX) agents is an efficient combinatorial delivery strategy for enhanced tumor targeting and synergistic antitumor effects.1Tyroservatide is an effective targeting ligand for breast cancer treatment.2TYP-Lip is a promising strategy that combines tyroservatide-targeting with a well-known paclitaxel into a single nanovehicle for co-delivery with targeted and synergistic effects.3This co-delivery approach enhanced efficacy and reduced toxicity both in vitro and in vivo.Download high-res image (161KB)Download full-size image