Reducing Interstitial Fluid Pressure and Inhibiting Pulmonary Metastasis of Breast Cancer by Gelatin Modified Cationic Lipid Nanoparticles

Interstitial fluid pressure (IFP) in tumor is much higher than that in normal tissue, and it constitutes a great obstacle for the delivery of antitumor drugs, thus becoming a potential target for cancer therapy. In this study, cationic nanostructured lipid carriers (NLCs) were modified by low molecular weight gelatin to achieve the desirable reduction of tumor IFP and improve the drug delivery. In this way, the chemotherapy of formulations on tumor proliferation and pulmonary metastasis was further improved. The nanoparticles were used to load three drugs, docetaxel (DTX), quercetin (Qu), and imatinib (IMA), with high encapsulation efficiency of 89.54%, 96.45%, and 60.13%, respectively. GNP-DTX/Qu/IMA nanoparticles exhibited an enzyme-sensitive drug release behavior, and the release rate could be mediated by matrix metalloproteinases (MMP-9). Cellular uptake and MTT assays showed that the obtained GNP-DTX/Qu/IMA could be internalized into human breast 4T1 cells effectively and exhibited the strongest cytotoxicity. Moreover, GNP-DTX/Qu/IMA demonstrated obvious advantages in inducing apoptosis and mediating the expression of apoptosis-related proteins (Caspase 3, Caspase 9, and bcl-2). In the wound-healing assay, GNP-DTX/Qu/IMA exhibited evidently inhibition of cell migration. The benefits of tumor IFP reduction induced by GNP-DTX/Qu/IMA were further proved after a continuous administration to 4T1 tumor-bearing mice. Finally, in the in vivo antitumor assays, GNP-DTX/Qu/IMA displayed stronger antitumor efficiency as well as suppression on pulmonary metastasis. In conclusion, the GNP-DTX/Qu/IMA system might be a promising strategy for metastatic breast cancer treatment.