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  • br The physical properties of micelles are listed


    The physical properties of λ-Carrageenan are listed in Table 1. All types of nanocarriers are about 15 nm in diameter with PDI less than 0.2, and negatively charged. The TEM images showed that both 7pep-M-RAP and 7pep-M-PTX were spherical in shape and about 15 nm with a narrow distribution, which were consistent with the results determined by DLS (Fig. 1A and B, Supporting Information Figs. S4 and S5). The entrapment efficiencies (EEs) of both RAP and PTX formulations were consistently greater than 90%. There was no obvious difference in physical properties be-tween modified and non-modified nanocarriers, which was favorable for their following comparison in vitro and in vivo tests. Besides, the experiment of dilution stability revealed that drug-loaded micelles were resistant to about 100 times dilutions (Supporting Information Table S1). r> Fig. 1C displays the XRD patterns of RAP powder, blank micelles, physical mixture of RAP plus blank micelles, and lyophilized RAP-loaded micelles, respectively. RAP powder dis-played a series of distinct sharp peaks, and similar characteristic peaks of RAP were also observed in the physical mixture of RAP and blank micelles. While no crystal peaks of RAP were seen in the profiles of both RAP-loaded micelles and blank micelles. Similarly, the XRD spectra of PTX-loaded micelles exhibited
    Table 1 Characteristics of various drug-loaded micelles.
    Formulation Size (nm) PDI Zeta potential (mV) EE (%)
    Please cite this article as: Mei D et al., Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer, Acta Pharmaceutica Sinica B,
    + MODEL
    Figure 1 The characteristics of 7pep-modified nanomedicines. (A) Particle size distribution of 7pep-M-RAP. (B) Morphology of 7pep-M-RAP by TEM. (C) Powder X-ray diffraction patterns of various RAP preparations, including RAP powder, blank PMs, physical mixture of RAP plus blank PMs, and lyophilized RAP-loaded micelles. (D) In vitro release of RAP and from micelles in 1.0 mol/L sodium sa-licylate at 37 C (mean SD, n Z 3).
    showed no diffraction peaks assigned to PTX powder (Supporting Information Fig. S6), implying that both RAP and PTX might exist as amorphous or molecular state in their polymeric micelles.
    Moreover, the CMCs of PEG-DSPE and 7pep-PEG-DSPE were 2.425 and 2.567 mg/mL, respectively, which were close to the previously reported values33, and were low enough to maintain the micelle state for the materials during the experimental pro-cesses. The in vitro release of RAP and PTX from micelles 1.0 mol/L sodium salicylate is presented in Fig. 1D and 
    Supporting Information Fig. S7. No burst release was observed, and similar kinetics was observed between 7pep-modified and non-modified micelles.
    3.2. Active targeting effect of 7pep-modified-micelles in vitro
    Firstly, the TfR expression in human breast-cancer cell line MCF-7 was confirmed by flow cytometry. Supporting Information Fig. S8 shows the plots of MCF-7 cells after incubation with TfR antibody, indicating that the TfR was obviously expressed in MCF-7 cells.
    In order to investigate the targeting efficiency of 7pep modi-fication on the micelle internalization, C6-loaded micelles modi-fied with different densities of 7pep were prepared to trace the cellular uptake of PMs. As seen in Supporting Information Fig. S9, the cellular uptake of 7pep-M-C6 was much higher than that of M-C6, and the amount of its accumulation in MCF-7 cells increased with the modification density of 7pep. Given this, micelles modified with 15% of 7pep were constructed for further experiments. The results of receptor competitive experiment showed in Fig. 2A and Supporting Information Fig. S10 revealed that the enhanced cellular uptake by 7pep modification was obviously decreased in the presence of excess antibody, suggest-ing that the enhanced cellular uptake was probably mediated by the existence of TfR on MCF-7 cells.