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    Home > Nano letter, Yuanzhi research group, Nankai University: pH sensitive reversible double ligand mutual masking system used to enhance the enrichment of nanodrug tumors

    Nano letter, Yuanzhi research group, Nankai University: pH sensitive reversible double ligand mutual masking system used to enhance the enrichment of nanodrug tumors

    • Last Update: 2019-03-19
    • Source: Internet
    • Author: User
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    The targeted ligand modified nanodrug delivery system can enhance drug enrichment and reduce side effects, but the specificity of these targeted groups is not strong, which may be recognized and cleared by the immune system Therefore, researchers have developed a masking / de masking strategy for tumor microenvironment response Usually, the target molecules are protected by the coupling agent of tumor microenvironment response fracture, and then exposed in the tumor site However, once the target molecules are exposed on the surface of nanoparticles, the nanoparticles may still be recognized by other cells after leaving the tumor For this reason, researchers have developed a reversible masking / de masking system, which is mainly realized by reversible assembly of pH sensitive thermosensitive molecules or polymers, but in these processes, the shrinkage and expansion of polymers are slow, while the assembly of polymers is related to the concentration, which may not reach the assembly concentration after several cycles Therefore, the research team of Professor Yuan Zhi of Nankai University has developed a new pH sensitive double ligand mutual masking / de masking strategy, which uses the presence of pH sensitivity in the binding force of two targeted molecules to achieve the surface targeted molecular masking and de masking of nanoparticles, significantly enhancing the tumor enrichment and anti-cancer effect of nanoparticles Relevant research results have been published on nano letter recently, with the title of "reversible shielding between dual lives for enhanced tumoraccumulation of ZnPc loaded miles" (DOI: 10.1021 / ACS Nanolet 8b04645) (photo source: nano letter) firstly, PEG-PCL, pba-pcl and gal-pcl modified by phenylboric acid and galactose were synthesized, and PBA / gal (scheme 1) was prepared by mixing them Among them, PBA can specifically recognize sialic acid residues (such as me-sa), gal can specifically recognize tumor cells with high expression of asialoglycoprotein receptor (ASGPR) Under normal physiological conditions (pH 7.4), PBA and gal can form borate ester bond to realize mutual shielding of double ligands However, in the environment of tumor micro acid (pH 6.8), the binding force of PBA and gal is weakened, resulting in PBA more inclined to bind to me sa on the surface of tumor cells, while the uncovered gal will bind to ASGPR on the surface of cells to achieve double ligand targeting Once PBA leaves the tumor cells and enters the normal tissues, it will form borate ester bond with gal again to realize double ligand masking Meanwhile, this reversible reaction has nothing to do with the concentration of micelles Taking zinc phthalocyanine complex (ZnPc, a hydrophobic photosensitizer, which can absorb near-infrared light and produce singlet oxygen with high quantum yield) as a model drug, PBA / gal micelles were prepared by self-assembly Meanwhile, PBA micelles and gal micelles in the control group and galcopba micelles (directly adding gal and PBA in PBA micelle solution) were prepared The particle size of both was about 120 nm, and the drug loading was 7.9% and 7.8%, respectively In order to test whether the nanoparticles can achieve reversible double ligand masking / de masking process, the author tested the ratio of gal exposed under different conditions The results showed that when pH decreased from 7.4 to 6.8, the ratio of gal exposed increased by 1.9 times, while after five cycles of pH change, the ratio of gal exposed at pH 6.8 was still higher than that at pH 7.4 At the same time, when different concentrations of me-sa were added, the ratio of gal exposed on the surface of micelles at pH 6.8 was higher than that at pH 7.4, which indicated that the binding between PBA and gal was pH responsive in the presence of me-sa In general, these data show that the double ligand micelles have reversible mutual masking / de masking effects (Figure 2) in response to pH (photo source: nano letter) next, we used HepG2, a human HCC cell line overexpressed with me sa and ASGPR, to study the cell uptake and cell killing of double ligand micelles at different pH (Figure 3) Flow cytometry (FACS) analysis showed that the uptake of PBA / gal micelles at pH 6.8 was 4.3 times higher than that at pH 7.4, while the uptake of uncovered PBA or gal micelles was not different The uptake of PBA / gal micelles at pH 6.8 was significantly reduced by adding gal or PBA The results of laser confocal microscopy (CLSM) are similar to those of FACS All of these data show that the double ligands can be removed to enhance cell uptake by reducing pH, which is caused by the interaction between two target ligands and corresponding receptors on cell surface In order to prove the reversibility of this system, the uptake of PBA / gal micelles and galco PBA micelles by cells under different conditions were compared After 5 pH cycles, the uptake of PBA / gal micelles by HepG2 at pH 7.4 was still significantly lower than that at pH 6.8, but there was no significant difference in the uptake of galcopba micelles by HepG2 at pH 7.4 and 6.8 after only one cycle At pH 7.4, the uptake of PBA / gal micelles by macrophages was also significantly different After two pH cycles, the uptake of PBA / gal micelles by macrophages at pH 7.4 was not significantly different, but the uptake of galcopba micelles was significantly increased This shows that PBA / gal micelles have reversible pH sensitive double ligand masking / de masking effect, which can enhance the uptake of micelles by tumor cells and significantly reduce the uptake of micelles by macrophages at pH 7.4 The level of singlet oxygen in PBA / gal micelles was significantly enhanced by 660 nm laser irradiation compared with that without photography, while the level of singlet oxygen in PBA / gal micelles was much higher at pH 6.8 At the same time, this kind of micelle is almost non-toxic to cells under no light, which indicates that it has better safety, while under the condition of light, PBA / gal micelle has stronger cytotoxicity at pH 6.8 (photo source: nano letter) further, the author conducted in vivo experiments to study the pharmacokinetics of the new system in rats (Figure 4) We synthesized cy5.5-labeled PEG-PCL and mixed it into micelles for fluorescence labeling, then injected it into healthy rats through tail vein Through in vivo imaging, the authors found that the blood clearance rate of PBA / gal micelles was slower than that of galco PBA micelles, and the blood circulation time was longer The half-life and AUC of PBA / gal micelles were 1.8 times and 1.5 times of that of galco PBA micelles, respectively (photo source: nano letter) finally, the authors studied the distribution of micelles in vivo and tumor inhibition effect (Figure 5) in Kunming mice with heterotopic H22 Tumor Transplantation After injecting cy5.5 labeled micelles into tail vein, the distribution of micelles in vivo was studied by in vivo imaging The concentration of galcopba in tumor peaked at 24 hours, then began to decrease, while the concentration of PBA / gal in tumor peaked at 36 hours In addition, the PBA / gal micelles of the tumor injected with glucose were more abundant, which indicated that the tumor acidity and pH dependent cell uptake played an important role in tumor enrichment After the liver and tumor were taken out for fluorescence imaging, it was found that the concentration of PBA / gal micelles in the liver was less than that of galcopba micelles, while the concentration of PBA / gal micelles in the tumor was the opposite The results of quantitative analysis showed that the content of PBA / gal micelles in liver was 54% lower than that of galco PBA micelles and 40% higher in tumor These results indicate that this reversible double ligand masking system can significantly inhibit liver clearance and enhance tumor accumulation The results showed that the tumor growth of mice in PBS group (+ laser) and PBA / gal micelle group (- laser) was the fastest, indicating that the laser itself had no antitumor effect, while ZnPc alone (+ laser) had only a certain degree of antitumor effect PBA / gal micelles (+ laser) and galcopba micelles (+ laser) have significant antitumor effects, which are due to the EPR effect of tumor promoting the enrichment of micelles in tumor However, the antitumor effect of PBA / gal micelles was significantly better than that of galcopba micelles, and the results of tumor removal and weighing after the experiment were similar The results show that the reversible double ligand system is better than the irreversible system in tumor enrichment and tumor inhibition (photo source: nano letter) in summary, based on the pH sensitive characteristics of the binding force between PBA and gal, a reversible masking / de masking micelle with dual ligand targeting pH sensitivity was developed Compared with irreversible micelles, this kind of micelles can significantly enhance the uptake of micelles by tumor cells at pH 6.8, and inhibit the uptake of micelles by the immune system at pH 7.4, which ultimately leads to the decrease of micelle clearance by the liver, while the accumulation of micelles in tumors is significantly increased Under 660 nm laser irradiation, the therapeutic effect of this kind of micelle is significantly better than that of the non reversible masking group.
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