Subcellular Organelle-Targeted Nanostructured Lipid Carriers for the Treatment of Metastatic Breast Cancer

Background: Subcellular organelle targeted nano-formulations for cancer treatment are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off-target side effects. The nucleus and mitochondria, as the main subcellular organelles, are the significant organelles responsible for maintaining cell operation and metabolism. They can be involved in many essential physiological and pathological processes such as cell proliferation, organism metabolism, intracellular transportation, and play a critical role in regulating cell biology. Meanwhile, breast cancer metastasis is one of the leading causes of death in breast cancer patients. With the development of nanotechnology, nanomaterials have been widely used in tumor therapy.Methods: We designed a subcellular organelle targeted nanostructured lipid carriers (NLC) to deliver paclitaxel (PTX) and gambogicResults: Due to the surface of NLC being modified by subcellular organelle targeted peptide, the PTX and GA co-loaded NLC can accurately release PTX and GA in tumor cells. This property makes NLC able to easy to enter tumor site and target the specific subcellular organelle. The modified NLC can efficiently inhibit the growth of 4T1 primary tumor and lung metastasis, which may be related to the down-regulation of matrix metalloproteinase-9 (MMP-9) and BCL-2 levels, up-regulation of E-cadherin level, and antagonized PTX-induced increase of C-C chemokine ligand 2 (CCL-2) levels by GA. Meanwhile, the synergistic anti-tumor effect of GA and PTX has also been verified in vitro and in vivo experiments.Conclusion: The subcellular organelle targeted peptide modified PTX+GA multifunctional nano-drug delivery system has a good therapeutic effect on tumors, and this study provides significant insights into the role of different subcellular organelles in inhibiting tumor growth and metastasis and inspires researchers to develop highly effective cancer therapeutic strategies through subcellular organelle targeted drugs.