Research on quantitatively controlling the ligand density on the surface of nanocarriers is in the frontier and becomes a technical difficulty for targeted delivery system designing. In this study, we developed an improved pre-conjugation (Imp) strategy, in which herceptin as a ligand was pre-conjugated with DSPE-PEG2000-Mal via chemical cross-linking, followed by conjugation onto the surface of pre-prepared paclitaxel-loaded PLGA/DODMA nanoparticles (PDNs) through hydrophobic interaction and electrostatic attraction for paclitaxel delivery. Compared with the post-conjugation (Pos) strategy, in which the ligand was conjugated onto the nanoparticle surface after the preparation of the nanoparticles, it realized a precise control targeting effect via adjustment of the herceptin density on the surface of the nanoparticles. Within the range of 0–20% of DSPE-PEG2000-herceptin in the blend, it showed a linear relation with the ligand density on the surface of the nanoparticles. The Imp strategy protected the bioactivity of the ligand during the preparation of nanoparticles. At the same time it avoided the waste of an excess amount of herceptin to drive the conjugation reaction in comparison with the post-conjugation (Pos) strategy. The nanoparticles from the Imp strategy showed much better cytotoxicity (p < 0.001), tumor targeting and cellular uptake efficiency (p < 0.001) than that of the other strategies in BT474 cells, in which BT474 cells were HER2 receptor over-expression breast cancer cell lines. A significant reduction in cellular uptake of the nanoparticles from the Imp strategy was observed in the presence of sucrose and cytochalasin D, indicating that clathrin-mediated and caveolae-dependent endocytosis was as a primary mechanism of cellular entry for these antibody-modified nanoparticles.
Yehong Liu,Miaoxin Chen,Gaoyang Li,Shouhong Xu,Honglai Liu
In this study, a pH/reduction dual responsive carrier containing 42nt-nucleic acid HApt based on mesoporous silica nanoparticles (MSNs) was designed. Two kinds of low molecular weight oligomeric hyaluronic acid (HA) were used to graft onto MSN for better drug encapsulation. Crosslinked MSN-HA3000gel and MSN-HA11000gel were prepared by crosslinking the HA chain through the sulfhydrylization of the carboxyl group on the HA side chain. An appropriate amount of sulfhydryl nucleic acid (HApt-SH) was added during the crosslinking reaction, which realized the targeting ability and apoptosis function to cancer cells overexpressing the HER2 receptor. Crosslinked HA had a good effect on decreasing the side effect of DOX that the drug leakage was less than 20% under a normal body environment. However, it could realize rapid and efficient drug release in a tumor environment. As to the release of HApt, it exhibited a good response to GSH. The cytotoxicity test showed that HApt contained in HAgel had a great targeting effect and significant cytotoxicity to SKBR3 cells. As a whole, this MSN-HAgel enabled the combination of gene therapy and chemotherapy, showing the synergistic effect of “1 + 1 > 2”, providing a novel idea for cancer treatments.
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