Preoccupation of Empty Carriers Decreases Endo-/Lysosome Escape and Reduces the Protein Delivery Efficiency of Mesoporous Silica Nanoparticles.
Wen-Qing LiLi-Ping SunYiqiu XiaSijie HaoGong ChengZhigang WangYuan WanChuandong ZhuHongzhang HeSi-Yang ZhengPublished in: ACS applied materials & interfaces (2018)
Endo-/lysosome escape is a major challenge in nanoparticle-based protein delivery for cancer therapy. To enhance the endo-/lysosomal escape and increase the efficacy of protein delivery, current strategies mainly focus on destroying endo-/lysosomes by employing modified nanoparticles, such as pH-sensitive polyplexes, cell-penetrating peptides, and photosensitive molecules. Herein, we hypothesize that pretreatment with empty nanocarriers might make endo-/lysosomes occupied and affect the endo/lysosomal escape of protein subsequently delivery by nanocarriers. We first treated breast carcinoma MDA-MB-231 cells with a high concentration of empty nanocarriers, mesoporous silica nanoparticles (MSN), to occupy the endo-/lysosome. After 2 h, we treated the cells with a lower concentration of fluorescein isothiocyanate-labeled MSN (MSN-FITC) and investigated the intracellular spatial and temporal distribution of MSN-FITC and their colocalization with endo-/lysosomes. We discovered the preoccupation of endo-/lysosomes by the empty nanocarriers did exist, mainly through changing the spatial distribution of the subsequently introduced nanocarriers. Furthermore, for the protein delivery, we observed reduced MSN-saporin delivery after endo-/lysosome preoccupation by MSN empty carriers. A similar result is observed for the delivery of cytochrome C by MSN but not for the small-molecule anticancer drug doxorubicin. The results show that the empty nanocarriers inhibit the endo-/lysosome intracellular trafficking process and decrease the endo-/lysosome escape of proteins subsequently delivered by the nanocarriers. This new discovered phenomenon of declined endo-/lysosome escape after endo-/lysosome preoccupation indicates that repeated treatment by nanomaterials with low protein-loading capacity may not yield a good cancer therapeutic effect. Therefore, it provides a new insightful perspective on the role of nanomaterial carriers in intracellular protein delivery.
Keyphrases
- cancer therapy
- drug delivery
- fluorescent probe
- protein protein
- small molecule
- living cells
- drug release
- amino acid
- induced apoptosis
- binding protein
- cell cycle arrest
- emergency department
- bone marrow
- mass spectrometry
- high resolution
- mesenchymal stem cells
- signaling pathway
- cell therapy
- endoplasmic reticulum stress
- papillary thyroid
- combination therapy
- pi k akt
- lymph node metastasis