Extracellular control of intracellular drug release for enhanced safety of anti-cancer chemotherapy

Qian Zhu,Zhen Huang,Haixia Qi,Shang Liu,Lei Dong,Ziyan Long,Chunming Wang,Junfeng Zhang

doi:10.1038/srep28596

Qian Zhu, Zhen Huang + Show 6 more

Open Access

https://doi.org/10.1038/srep28596

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Abstract

The difficulty of controlling drug release at an intracellular level remains a key challenge for maximising drug safety and efficacy. We demonstrate herein a new, efficient and convenient approach to extracellularly control the intracellular release of doxorubicin (DOX), by designing a delivery system that harnesses the interactions between the system and a particular set of cellular machinery. By simply adding a small-molecule chemical into the cell medium, we could lower the release rate of DOX in the cytosol, and thereby increase its accumulation in the nuclei while decreasing its presence at mitochondria. Delivery of DOX with this system effectively prevented DOX-induced mitochondria damage that is the main mechanism of its toxicity, while exerting the maximum efficacy of this anti-cancer chemotherapeutic agent. The present study sheds light on the design of drug delivery systems for extracellular control of intracellular drug delivery, with immediate therapeutic implications.

Highlights

Intracellular release rate of DOX, via simple addition of a small-molecule chemical in the cell medium
The formed intercalation generally exhibited the property of the RNA molecules[7], such that we could deliver it into cells by using common RNAdelivering vehicles, such as cationic polymers
We synthesised a segment of nucleic acid mimicking miR16, a miRNA that is stable under physiological conditions and abundant in serum and cytosol[8], to intercalate DOX

Summary

Introduction

Intracellular release rate of DOX, via simple addition of a small-molecule chemical in the cell medium. Control of DOX release from HSA/PEI/miR-16/DOX complex (HPMD) by ATA in vitro and in vivo. Confocal microscopic examination of the cells incubated with HPMD after 4 hours post transfection revealed that the highest DOX concentration was observed in the nucleus (Fig. 3G).

Results

Conclusion