Folate Receptor Targeting and Cathepsin B-Sensitive Drug Delivery System for Selective Cancer Cell Death and Imaging

Jin, Xiangmei; Zhang, Jun; Jin, Xiaoyan; Liu, Lan; Tian, Xizhe

doi:10.1021/acsmedchemlett.0c00031

Cited by 35 publications

(24 citation statements)

References 40 publications

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“…On the other hand, folate receptors are highly expressed on the surface of cancer cells. Therefore, FA could be a potent ligand of nanocarriers because of its high affinity to its receptor (Alibolandi et al., 2017 ; Muhamad et al., 2018 ; Jin et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy

Tan

Chu

et al. 2021

Drug Delivery

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Breast cancer is one of the most common types of cancer in female patients with high morbidity and mortality. Multi-drug chemotherapy has significant advantages in the treatment of malignant tumors, especially in reducing drug toxicity, increasing drug sensitivity and reducing drug resistance. The objective of this research is to fabricate lipid nanoemulsions (LNs) for the co-delivery of PTX and docosahexaenoic acid (DHA) with folic acid (FA) decorating (PTX/DHA-FA-LNs), and investigate the anti-tumor activity of the PTX/DHA-FA-LNs against breast cancer both in vitro and in vivo . PTX/DHA-FA-LNs showed a steady release of PTX and DHA from the drug delivery system (DDS) without any burst effect. Furthermore, the PTX/DHA-FA-LNs exhibited a dose-dependent cytotoxicity and a higher rate of apoptosis as compared with the other groups in MCF-7 cells. The cellular uptake study revealed that this LNs were more readily uptaken by MCF-7 cells and M2 macrophages in vitro . Additionally, the targeted effect of PTX/DHA-FA-LNs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. The anti-tumor efficiency results showed that PTX/DHA-FA-LNs significant inhibited tumor volume growth, prolonged survival time, and reduced toxicity when compared with the other groups. These results indicated that DHA increases the sensitivity of tumor cells and tumor-associated macrophages (ATM2) to PTX, and synergistic effects of folate modification in breast cancer treatment, thus PTX/DHA-FA-LNs may be a promising nanocarrier for breast cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy

Tan

Chu

et al. 2021

Drug Delivery

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“…To avoid any minor possibility of mistargeting, we decided to attach the R 9 -peptide to the autophagic vesicle-targeting peptide sequence via a protease-cleavable amino acid sequence G-F-L-G, which could be cleaved by Cathepsin B, a cellular protease (Scheme ). − The final cell-permeable autophagosome-targeting peptide sequence was W-T-H-L-G-F-L-G-R 9 (Scheme a). Additionally, the peptide sequence W-T-H-L was used to confirm the requirement of R 9 .…”

Section: Resultsmentioning

confidence: 99%

Spatio-Temporal Autophagy Tracking with a Cell-Permeable, Water-Soluble, Peptide-Based, Autophagic Vesicle-Targeted Sensor

et al. 2021

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Autophagy is an essential cellular degradation process. Impaired autophagy has been linked to multiple disorders, including cancer and neurodegeneration. Tracking the autophagic flux in living cells will provide mechanistic insights into autophagy and will allow rapid screening of autophagy modulators as potential therapeutics. Imaging autophagy to track the autophagic flux demands a cell-permeable probe that can specifically target autophagic vesicles and report on the extent of autophagy. Existing fluorescent protein-based probes for imaging autophagy target autophagic vesicles but are cell-impermeable and degrade with the progress of autophagy resulting in ambiguous information on the later stages of autophagy. Although small-molecule-based autophagy probes can be cell-permeable, they are mostly water-insoluble and often target lysosomes instead of autophagic vesicles leading to incomplete evidence of the early stages of the process. Hence, there is a major gap in the ability to link the imaging data obtained by applying fluorescent sensors to the real extent of autophagy in living cells. To address these challenges, we have combined the desirable features of targetability and cell permeability to develop a novel water-soluble, cell-permeable, visible-light excitable, peptide-based, fluorescent sensor, HCFP, for imaging autophagy and tracking the autophagic flux. The probe readily enters living cells within 30 min of incubation, distinctly targets autophagic vesicles, and spatio-temporally tracks the entire autophagy pathway in living cells via a ratiometric pH-sensitive detection scheme. The salient features of the probe combining targetability with cell permeability should provide an edge in high-throughput screening of autophagy modulators by tracking autophagy live.

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“…The alkyne-GFLG-PABOH synthesis step was the same as previously described. 32 The mixture was filtered and concentrated using a rotary evaporator. Silica gel column chromatography was used to purify the residue.…”

Section: Methodsmentioning

confidence: 99%

Antitumor Activity of a Novel Double-Targeted System for Folate Receptor-Mediated Delivery of Mitomycin C

Jin

Zhang

et al. 2020

ACS Omega

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In this study, we designed, formulated, and investigated the potential antitumor activity of a folate receptor (FR)-mediated double-targeted drug delivery system. The system comprised of the FR ligand folic acid (FA), glycine-phenylalanine-leucine-glycine (Gly-Phe-Leu-Gly, GFLG), which can be specifically cleaved by cathepsin B, and the anticancer drug mitomycin C (MMC). The antitumor effect of FA-GFLG-MMC was compared to that of MMC. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that FA-GFLG-MMC has a significantly higher inhibitory effect on HeLa, SiHa, and PC9 cells (high FR expression) than that on 16HBE and A549 cells (low FR expression). Furthermore, FA-GFLG-MMC inhibited cancer cell proliferation in a dose-dependent manner. Free MMC was toxic to both cancer and normal cells. Apoptosis of the HeLa, SiHa, and PC9 cells was higher than that of the A549 cells; however, the apoptotic effect on 16HBE cells was minimal. Proapoptotic protein bcl-2-associated X-protein (BAX) and antiapoptotic protein BCL-2 play critical roles in cellular defense and apoptotic signal transduction. BAX/BCL-2 ratio is used to determine the intensity of an apoptotic signal and assess whether a cell will survive or undergo apoptosis. BAX and BCL-2 expression in cells treated with 5 μM FA-GFLG-MMC was studied by Western blotting. FA-GFLG-MMC increased the BAX/BCL-2 ratio in HeLa, SiHa, and PC9 cells. The results show that FA-GFLG-MMC can effectively inhibit tumor cell proliferation by inducing apoptosis. Therefore, the system developed can enhance the delivery of anticancer drugs to cancer cells and thereby reduce their toxic effects on normal cells.

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Folate Receptor Targeting and Cathepsin B-Sensitive Drug Delivery System for Selective Cancer Cell Death and Imaging

Cited by 35 publications

References 40 publications

Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy

Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy

Spatio-Temporal Autophagy Tracking with a Cell-Permeable, Water-Soluble, Peptide-Based, Autophagic Vesicle-Targeted Sensor

Antitumor Activity of a Novel Double-Targeted System for Folate Receptor-Mediated Delivery of Mitomycin C

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