Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy
Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy...
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2021
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oai:doaj.org-article:b894e70ce2bf48af9114ce5fabad732e2021-11-25T18:30:31ZSmart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy10.3390/nano111128752079-4991https://doaj.org/article/b894e70ce2bf48af9114ce5fabad732e2021-10-01T00:00:00Zhttps://www.mdpi.com/2079-4991/11/11/2875https://doaj.org/toc/2079-4991Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy are urgently required. In this study, for effective pancreatic cancer therapy, a novel mitochondria-targeted and ROS-triggered drug delivery nanoplatform was developed from the TPP-TK-CPI-613 (<b>TTCI</b>) prodrug, in which the ROS-cleave thioketal functions as a linker connecting mitochondrial targeting ligand TPP and anti-mitochondrial metabolism agent CPI-613. DSPE-PEG2000 was added as an assistant component to increase accumulation in the tumor via the EPR effect. This new nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability, and robust therapeutic performances. With active mitochondrial targeting, the formulated nanoparticles (<b>TTCI</b> NPs) demonstrate much higher accumulation in mitochondria, facilitating the targeted delivery of CPI-613 to its acting site. The results of in vitro antitumor activity and cell apoptosis revealed that the IC<sub>50</sub> values of <b>TTCI</b> NPs in three types of pancreatic cancer cells were around 20~30 µM, which was far lower than those of CPI-613 (200 µM); 50 µM <b>TTCI</b> NPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy.Yi-Mei ZhangMeng XiaRui AoLi-Xia GaoYan TangJiu-Hong HuangYa-Fei LuoZhong-Zhu ChenBo-Chu WangZheng HuangMDPI AGarticlemitochondria-targetingROS-responsivedrug deliverynanoparticlespancreatic cancer therapyCPI-613ChemistryQD1-999ENNanomaterials, Vol 11, Iss 2875, p 2875 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
mitochondria-targeting ROS-responsive drug delivery nanoparticles pancreatic cancer therapy CPI-613 Chemistry QD1-999 |
| spellingShingle |
mitochondria-targeting ROS-responsive drug delivery nanoparticles pancreatic cancer therapy CPI-613 Chemistry QD1-999 Yi-Mei Zhang Meng Xia Rui Ao Li-Xia Gao Yan Tang Jiu-Hong Huang Ya-Fei Luo Zhong-Zhu Chen Bo-Chu Wang Zheng Huang Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy |
| description |
Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy are urgently required. In this study, for effective pancreatic cancer therapy, a novel mitochondria-targeted and ROS-triggered drug delivery nanoplatform was developed from the TPP-TK-CPI-613 (<b>TTCI</b>) prodrug, in which the ROS-cleave thioketal functions as a linker connecting mitochondrial targeting ligand TPP and anti-mitochondrial metabolism agent CPI-613. DSPE-PEG2000 was added as an assistant component to increase accumulation in the tumor via the EPR effect. This new nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability, and robust therapeutic performances. With active mitochondrial targeting, the formulated nanoparticles (<b>TTCI</b> NPs) demonstrate much higher accumulation in mitochondria, facilitating the targeted delivery of CPI-613 to its acting site. The results of in vitro antitumor activity and cell apoptosis revealed that the IC<sub>50</sub> values of <b>TTCI</b> NPs in three types of pancreatic cancer cells were around 20~30 µM, which was far lower than those of CPI-613 (200 µM); 50 µM <b>TTCI</b> NPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy. |
| format |
article |
| author |
Yi-Mei Zhang Meng Xia Rui Ao Li-Xia Gao Yan Tang Jiu-Hong Huang Ya-Fei Luo Zhong-Zhu Chen Bo-Chu Wang Zheng Huang |
| author_facet |
Yi-Mei Zhang Meng Xia Rui Ao Li-Xia Gao Yan Tang Jiu-Hong Huang Ya-Fei Luo Zhong-Zhu Chen Bo-Chu Wang Zheng Huang |
| author_sort |
Yi-Mei Zhang |
| title |
Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy |
| title_short |
Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy |
| title_full |
Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy |
| title_fullStr |
Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy |
| title_full_unstemmed |
Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy |
| title_sort |
smart design of mitochondria-targeted and ros-responsive cpi-613 delivery nanoplatform for bioenergetic pancreatic cancer therapy |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/b894e70ce2bf48af9114ce5fabad732e |
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