Antitumor Activity of the Zinc Oxide Nanoparticles Coated with Low-Molecular-Weight Heparin and Doxorubicin Complex In Vitro and In Vivo

Abstract

Various metal oxide nanomaterials have been widely used as carriers to prepare pH-sensitive nanomedicines to respond to the acidic tumor microenvironment promoting antitumor efficiency. Herein, we used zinc oxide nanoparticles (ZnO NPs) as metal oxide nanomaterial coated with low-molecular-weight heparin (LMHP) and doxorubicin (DOX) complex (LMHP-DOX) to prepare ZnO-LD NPs for controllable pH-triggered DOX release on the targeted site. Our results indicated that the released DOX from ZnO-LD NPs was pH-sensitive. The oxygen produced by ZnO-LD NPs in H 2 O 2 solution was observed in in vitro experiment. The ZnO-LD NPs entered into both PC-3M and 4T1 tumor cells via clathrin-mediated endocytosis and micropinocytosis pathway. The intracellular reactive oxygen species (ROS) generated by ZnO-LD NPs could significantly increase the caspase 3/7 level, leading to tumor cell apoptosis. The in vitro and in vivo antitumor activity was confirmed in PC-3M and 4T1 cell lines or tumor-bearing mice models. The in vivo and in vitro tumor images via second-order nonlinearity of ZnO-LD NPs indicated that ZnO-LD NPs could penetrate deep into the tumor tissues. Therefore, the ZnO-LD NPs developed in our study could provide an efficient approach for the preparation of pH-sensitive nano delivery systems suitable for tumor therapy and imaging.

Albumin Nanoparticles Surface Decorated with a Tumor-Homing Peptide Help in Selective Killing of Triple-Negative Breast Cancer Cells

“…In cancerous 4T1, there was little to no role of caveolae-mediated endocytosis in the uptake of either the bare (FH) or peptide-modified (TFH) nanoparticles, which was consistent with the basal caveolin-1 expression levels in those cells. Both the bare (FH) and peptide-modified (TFH) nanoparticles seemed to be following a combination of clathrin- and lipid-raft-dependent endocytosis to be taken up by the cells, consistent with other reports of how nanoparticles are endocytosed in 4T1 . Mucin-1, a transmembrane mucin and known to be involved in cancer progression like Mucin-16, has been shown to predominantly follow the clathrin-mediated route for cellular entry …”

“…Both the bare (FH) and peptide-modified (TFH) nanoparticles seemed to be following a combination of clathrin-and lipid-raft-dependent endocytosis to be taken up by the cells, consistent with other reports of how nanoparticles are endocytosed in 4T1. 54 Mucin-1, a transmembrane mucin and known to be involved in cancer progression like Mucin-16, has been shown to predominantly follow the clathrin-mediated route for cellular entry. 55 Upon internalization, caveosomes, small grape-like multicaveolar structures, appear in the cytoplasm, which may be independent moieties never fusing with lysosomes.…”

ZnO nanomaterials target mitochondrial apoptosis and mitochondrial autophagy pathways in cancer cells

“…The findings revealed that ZnO LD NPs significantly increased intracellular ROS levels and the expression of caspase 3/7, leading to apoptosis of tumor cells. Thus, ZnO LD NPs can be considered as effective pH‐sensitive nanocarrier systems for tumor treatment and imaging 48 …”

“…Thus, ZnO LD NPs can be considered as effective pH-sensitive nanocarrier systems for tumor treatment and imaging. 48 ZnO NMts exhibit pH-dependent dissolution, particularly at low pH, leading to the release of Zn2+ ions. This dissolution process triggers the production of ROS in cancer cells, resulting in specific toxicity towards these cells.…”

Design and Evaluation of Periodic Mesoporous Organosilica/ZnO Nanocomposites as an Effective Drug Delivery System for Gemcitabine

“…Results show that, in comparison to anticancer drugs alone, the compounds ZnO and doxorubicin have strong therapeutic e cacy to inhibit the growth of lung cancer cells. Li et al [11] used zinc oxide nanoparticles coated with heparin and doxorubicin for controllable pH-triggered anticancer release on the targeted site. In-vitro and in-vivo results showed the effectiveness of the compound through endocytosis and ROS on tumor cells (PC-3M and 4T1).…”