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Synergetic therapy of glioma mediated by a dual delivery system loading ?-mangostin and doxorubicin through cell cycle arrest and apoptotic pathways.

ABSTRACT: Two of the biggest hurdles in the deployment of chemotherapeutics against glioma is a poor drug concentration at the tumor site and serious side effects to normal tissues. Nanocarriers delivering different drugs are considered to be one of the most promising alternatives. In this study, a dual delivery system (methoxy poly(ethylene glycol)-poly(?-caprolactone) (MPEG-PCL)) loaded with ?-mangostin (?-m) and doxorubicin (Dox) was decorated and constructed by self-assembly to determine its ability to treat glioma. Molecular dynamics simulations showed that MPEG-PCL could provide ideal interaction positions for both ?-m and Dox, indicating that the two drugs could be loaded into MPEG-PCL. Based on the in vitro results, MPEG-PCL loaded with ?-m and Dox (?-m-Dox/M) with a size of 25.68?nm and a potential of -1.51?mV was demonstrated to significantly inhibit the growth and promote apoptosis in Gl261, C6 and U87 cells, and the effects of the combination were better than each compound alone. The mechanisms involved in the suppression of glioma cell growth were blockage of the cell cycle in S phase by inhibition of CDK2/cyclin E1 and promotion of apoptosis through the Bcl-2/Bax pathway. The synergetic effects of ?-m-Dox/M effectively inhibited tumor growth and prolonged survival time without toxicity in mouse glioma models by inducing glioma apoptosis, inhibiting glioma proliferation and limiting tumor angiogenesis. In conclusion, a codelivery system was synthesized to deliver ?-m and Dox to the glioma, thereby suppressing the development of glioma by the mechanisms of cell cycle arrest and cellular apoptosis, which demonstrated the potential of this system to improve the chemotherapy response of glioma.

SUBMITTER: Nie W

PROVIDER: S-EPMC7595144 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Synergetic therapy of glioma mediated by a dual delivery system loading α-mangostin and doxorubicin through cell cycle arrest and apoptotic pathways.

Nie Wen W Zan Xin X Yu Ting T Ran Mengni M Hong Zehua Z He Yihong Y Yang Tingting T Ju Yan Y Gao Xiang X

Cell death & disease 20201028 10

Two of the biggest hurdles in the deployment of chemotherapeutics against glioma is a poor drug concentration at the tumor site and serious side effects to normal tissues. Nanocarriers delivering different drugs are considered to be one of the most promising alternatives. In this study, a dual delivery system (methoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL)) loaded with α-mangostin (α-m) and doxorubicin (Dox) was decorated and constructed by self-assembly to determine its ability t ...[more]

PMID: 33116114

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Project description:Extracellular vesicles (EVs) have great potential as drug delivery vehicles. While mesenchymal/stromal stem cell (MSC) conditioned medium (CM) and milk are potentially safe and scalable sources of EVs for this purpose, the suitability of MSC EVs and milk EVs as drug delivery vehicles has never been compared and so was the objective of this study. Here EVs were separated from MSCs' CM and from milk and were characterised by nanoparticle tracking analysis, transmission electron microscopy, total protein quantification, and immunoblotting. An anti-cancer chemotherapeutic drug, doxorubicin (Dox), was then loaded into the EVs by one of three methods: by passive loading or by active loading by either electroporation or sonication. Dox-loaded EVs were analysed by fluorescence spectrophotometer, high-performance liquid chromatography (HPLC), and imaging flow cytometer (IFCM). Our study showed that EVs were successfully separated from the milk and MSC CM, with significantly (p < 0.001) higher yields of milk EVs/mL starting material compared to MSC EVs/mL of starting material. Using a fixed amount of EVs for each comparison, electroporation achieved significantly more Dox loading when compared to passive loading (p < 0.01). Indeed, of 250 µg of Dox made available for loading, electroporation resulted in 90.1 ± 12 µg of Dox loading into MSC EVs and 68.0 ± 10 µg of Dox loading into milk EVs, as analysed by HPLC. Interestingly, compared to the passive loading and electroporation approach, after sonication significantly fewer CD9+ EVs/mL (p < 0.001) and CD63+ EVs/mL (p < 0.001) existed, as determined by IFCM. This observation indicates that sonication, in particular, may have detrimental effects on EVs. In conclusion, EVs can be successfully separated from both MSC CM and milk, with milk being a particularly rich source. Of the three methods tested, electroporation appears to be superior for achieving maximum drug loading while not causing damage to EV surface proteins.

Project description:Doxorubicin (DOX) is one of the most commonly used antineoplastic agents, but its clinical application is oftentimes coupled with severe side effects. Selective delivery of DOX to tumors via nanosized drug carrier represents an attractive approach to this problem. Previously, we developed a dual functional nanomicellar carrier, PEG5K-embelin2 (PEG5K-EB2), which was able to deliver paclitaxel (PTX) selectively to tumors and to achieve an enhanced therapeutic effect. In the present study, we examined the utility of PEG5K-EB2 to deliver DOX to tumors. In addition, folic acid (FA) was coupled to the surface of the PEG5K-EB2 micelles (FA-PEG5K-EB2) to further improve the selective targetability of the system. DOX-loaded PEG5K-EB2 micelles were uniformly spherical particles with a diameter of approximately 20 nm. Incorporation of FA had minimal effect on the size of the particles. The DOX loading efficiency was as high as 91.7% and 93.5% for PEG5K-EB2 and FA-PEG5K-EB2, respectively. DOX formulated in PEG5K-EB2 micelles (with or without FA decoration) demonstrated sustained kinetics of DOX release compared to free DOX. FA-PEG5K-EB2 significantly facilitated the intracellular uptake of DOX over free DOX and PEGylated liposomal DOX (Doxil) in breast cancer cells, 4T1.2, and drug resistant cells, NCI/ADR-RES. P-gp ATPase assay showed that PEG5K-EB2 significantly inhibited the function of the P-gp efflux pump. The maximum tolerated dose of DOX-loaded PEG5K-EB2 micelles was 15 mg/kg in mice, which was 1.5-fold greater than that for free DOX. Pharmacokinetics (PK) and biodistribution studies showed that both types of DOX-loaded micelles, especially FA-PEG5K-EB2, were able to significantly prolong the blood circulation time of DOX and facilitate its preferential accumulation at the tumor tissue. Finally, DOX/PEG5K-EB2 mixed micelles demonstrated significantly enhanced tumor growth inhibitory effect with minimal toxicity in comparison to free DOX and Doxil and the antitumor activity was further enhanced after the decoration by folic acid. Our data suggest that FA-PEG5K-EB2 micelles represent a promising DOX delivery system that warrants more study in the future.

Dataset Information

Synergetic therapy of glioma mediated by a dual delivery system loading ?-mangostin and doxorubicin through cell cycle arrest and apoptotic pathways.

Publications

Synergetic therapy of glioma mediated by a dual delivery system loading α-mangostin and doxorubicin through cell cycle arrest and apoptotic pathways.

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