iRGD-Guided Silica/Gold Nanoparticles for Efficient Tumor-Targeting and Enhancing Antitumor Efficacy Against Breast Cancer

Abstract

Background: Breast cancer presents significant challenges due to the limited effectiveness of available treatments and the high likelihood of recurrence. iRGD possesses both RGD sequence and C-terminal sequence and has dual functions of targeting and membrane penetration. iRGD-modified nanocarriers can enhance drug targeting of tumor vascular endothelial cells and penetration of new microvessels, increasing drug concentration in tumor tissues.

Methods: The amidation reaction was carried out between SiO₂/AuNCs and iRGD/PTX, yielding a conjugated drug delivery system (SiO₂/AuNCs-iRGD/PTX, SAIP@NPs). The assessment encompassed the characterization of the morphology, particle size distribution, physicochemical properties, in vitro release profile, cytotoxicity, and cellular uptake of SAIP@NPs. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed using a small animal in vivo imaging system and a tumor-bearing nude mice model, respectively. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed utilizing a small animal in vivo imaging system and an in situ nude mice breast cancer xenograft model, respectively.

Results: The prepared SAIP@NPs exhibited decent stability and a certain slow-release effect in phosphate buffer (PBS, pH 7.4). In vitro studies had shown that, due to the dual functions of transmembrane and targeting of iRGD peptide, SAIP@NPs exhibited strong binding to integrin αvβ3, which was highly expressed on the membrane of MDA-MB-231 cells, improving the uptake capacity of tumor cells, inhibiting the rapid growth of tumor cells, and promoting tumor cell apoptosis. The results of animal experiments further proved that SAIP@NPs had longer residence time in tumor sites, stronger anti-tumor effect, and no obvious toxicity to major organs of experimental animals.

Conclusion: The engineered SAIP@NPs exhibited superior functionalities including efficient membrane permeability, precise tumor targeting, and imaging, thereby significantly augmenting the therapeutic efficacy against breast cancer with a favorable safety profile.

Keywords: breast cancer; gold nanoclusters; iRGD penetrating peptide; integrin αvβ3; silicon dioxide nanoparticles; tumor targeting.

Graphical abstract

Figure 1

Characterization of SAIP@NPs. (A) ¹H NMR spectra of MCA-PTX in DMSO-D₆, (B) ¹H NMR spectra iRGD/PTX in DMSO-D₆, (C) fluorescence spectra, (D) TEM image, (E) size distribution and (F) in vitro PTX release curves of SAIP@NPs.

Figure 2

In vitro cell cytotoxicity and cell apoptosis against MDA-MB-231 cells. (A) After incubation with MDA-MB-231 cells for 24 h, the cytotoxic effects of free iRGD and free PTX at different concentrations. (B) Comparison of cytotoxicity of free iRGD (40 μg/mL), free PTX (40 μg/mL), free PTX (40 μg/mL) + free iRGD (40 μg/mL), SAIP@NPs (including 40 μg/mL PTX) in vitro. **p<0.01, vs free iRGD; ^##p<0.01, vs free PTX. (C) Apoptosis detection of MDA-MB-231 cells.

Figure 3

Uptake of nanoparticles by MDA-MB-231 cells.

Figure 4

In vivo tumor targeting of Cy7-SAIP@NPs.

Figure 5

Antitumor effect of drug delivery system in vivo. Data were expressed as means ± SD (n = 5). (A) Body weight curves of mice, (B) tumor growth curves of mice, (C) tumor photos of mice, (D) tumor weight of mice. *p <0.05, **p <0.01 vs control, ^#p <0.05 vs PTX.

Figure 6

Histological inspection of heart, liver, spleen, lung, and kidney of MBD-MB-231 tumor-bearing mice after 14 days of intervention with different treatment strategies.