The surface charge of nanocarriers inevitably affects drug delivery efficiency; however, the cancer cell specificity, anti-inflammatory effects, and charge-reversal points remain to be further addressed in biomedical applications. The aim of this study was to comprehensively assess the cancer cell specificity of DOX-loaded mesoporous silica-chitosan oligosaccharide-carboxymethyl chitosan nanoparticles (DOX@MSNs-COS-CMC) in MCF-7 and HeLa cells, inhibit the production of inflammatory cytokines, and improve the drug accumulation in the tumor site. Intracellular results reveal that the retention time prolonged to 48 h in both HeLa and MCF-7 cells at pH 7.4. However, DOX@MSNs-COS-CMC exhibited a cell type-dependent cytotoxicity and enhanced intracellular uptake in HeLa cells at pH 6.5, due to the clathrin-mediated endocytosis and macropinocytosis in HeLa cells in comparison with the vesicular transport in MCF-7 cells. Moreover, Pearson’s correlation coefficient value significantly decreased to 0.25 after 8 h, prompting endosomal escape and drug delivery into the HeLa nucleus. After the treatment of MSNs-COS-CMC at 200 μg/mL, the inflammatory cytokines IL-6 and TNF-α level decreased by 70% and 80%, respectively. Tumor inhibition of DOX@MSNs-COS-CMC was 0.4 times higher than free DOX, alleviating cardiotoxicity and inflammation in the HeLa xenograft tumor model. Charge-reversible DOX@MSNs-COS-CMC could be a possible candidate for clinical therapy of cervical carcinoma.
Bozhen Wu,Shunshu Deng,Shihao Zhang,Jia Jiang,Baosan Han,Yulin Li
The surface/interface state of nanomaterials plays a key role on their biomedical applications. Nanotechnology offers a versatile means to develop nanoparticles with well-defined architecture. In this study, mesoporous silica nanoparticles were firstly loaded with an anticancer drug (doxorubicin, DOX), which were then decorated with a cationic oligomer (low molecular weight polyethyleneimine, LPEI) to acquire an increased surface charge. The resulting particles were further self-assembled with negative-charged bovine serum albumin (BSA) as natural protein nanoblocks to offer surface charge tunability. The resulting mesoporous nanohybrids (MDPB) acquired charge-reversal ability, which presented negative charge under biological conditions (beneficial to biocompatibility), while displaying a positive-charged state under acidic conditions mimicking the tumor extracellular microenvironment (favoring cell uptake or tumor penetration). Furthermore, the nanohybrids not only allowed for an effective loading of DOX drug, but also accelerated its release under acidic tumor microenvironments in a sustainable way. In vitro biological study indicated that the DOX-free nanoparticles were biocompatible, while MDPB exerted good cytotoxicity against cancer cells, suggesting their promise for therapeutic delivery application.
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