Journal
JOURNAL OF NANOBIOTECHNOLOGY
Volume 15, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s12951-017-0316-z
Keywords
Gult-1; Redox-responsive polymer; Nanomicelles; Multidrug resistance; Cancer therapy
Funding
- National Science Foundation of China (NSFC) [81402023, 51403043]
- National Science Foundation of Guangdong [2014A030310022]
- Scientific Research Projects of Guangzhou [201510010212, 201707010329]
- Guangdong university innovation and enhancement project [Q17024031]
- College Students Cultivate Special Science and Technology Innovation Project of Guangzhou Medical University [GMUC2017b0408]
- College Students Cultivate Special Science and Technology Innovation Project of Guangdong Province [GMUC2017b0408]
Ask authors/readers for more resources
Background: Chemotherapeutic drugs used for cancer therapy frequently encounter multiple-drug resistance (MDR). Nanoscale carriers that can target tumors to accumulate and release drugs intracellularly have the greatest potential for overcoming MDR. Glucose transporter-1 (GLUT-1) and glutathione (GSH) overexpression in cancer cells was exploited to assemble aminoglucose (AG)-conjugated, redox-responsive nanomicelles from a single disulfide bond-bridged block polymer of polyethylene glycol and polylactic acid (AG-PEG-SS-PLA). However, whether this dual functional vector can overcome MDR in lung cancer is unknown. Results: In this experiment, AG-PEG-SS-PLA was synthetized successfully, and paclitaxel (PTX)-loaded AG-PEG-SS-PLA (AG-PEG-SS-PLA/PTX) nanomicelles exhibited excellent physical properties. These nanomicelles show enhanced tumor targeting as well as drug accumulation and retention in MDR cancer cells. Caveolin-dependent endocytosis is mainly responsible for nanomicelle internalization. After internalization, the disulfide bond of AG-PEG-SS-PLA is cleaved in the presence of high intracellular glutathione levels, causing the hydrophobic core to become a polar aqueous solution, which subsequently results in nanomicelle disassembly and the rapid release of encapsulated PTX. Reduced drug resistance was observed in cancer cells in vitro. The caspase-9 and caspase-3 cascade was activated by the AG-PEG-SS-PLA/PTX nanomicelles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the anti-apoptotic protein Bcl-2, thereby increasing apoptosis. Furthermore, significantly enhanced tumor growth inhibition was observed in nude mice bearing A549/ADR xenograft tumors after the administration of AG-PEG-SS-PLA/PTX nanomicelles via tail injection. Conclusions: These promising results indicate that AG-PEG-SS-PLA/PTX nanomicelles could provide the foundation for a paradigm shift in MDR cancer therapy.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available