Journal
JOURNAL OF NANOBIOTECHNOLOGY
Volume 19, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12951-021-01139-1
Keywords
Ovarian cancer; Multidrug resistance; PTX; miR let-7a; Co-delivery nanosystem
Funding
- National Natural Science Foundation of China [815 725 74]
- China Postdoctoral Science Foundation [2019M652541]
- Innovation Scientists and Technicians Troop Construction Projects of Henan Province [192101510001]
- Young Core Instructor Program in Higher Education Institution of Henan province [2018 GGJS 067]
- Henan Province medical science and technology research project jointly built by the Ministry and province [SB201901073]
- Basic Research Project of Key Scientific Research Projects in Henan Province [20zx011]
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In this study, a novel nano targeted co-delivery system modified by hyaluronic acid (HA) was developed to overcome multidrug resistance in ovarian cancer by delivering hydrophobic chemotherapy drug Paclitaxel (PTX) and lethal-7a (let-7a) microRNA. The nanosystem demonstrated effective cell uptake and enhanced tumor site permeability, leading to downregulation of P-glycoprotein, PTX release, and apoptosis induction. Additionally, mTOR-mediated signaling pathways played a crucial role in reversing drug resistance and inducing apoptosis, providing a model for overcoming PTX resistance in ovarian cancer.
Background: Multidrug resistance (MDR) is the main challenge of successful chemotherapy for ovarian cancer patients, with 50% to 75% of ovarian cancer patients eventually relapsed due to it. One of the effective strategies for treating MDR and improving therapeutic efficiency of ovarian cancer is to use nanotechnology-based targeted drug delivery systems. In this study, a novel nano targeted co-delivery system modified by hyaluronic acid (HA) was developed by using gold nanorods coated with functionalized mesoporous silica nanoparticles (HA-PTX/let-7a-GNR@MSN) for combined delivery of hydrophobic chemotherapy drug Paclitaxel (PTX) and lethal-7a (let-7a), a microRNA (miR), to overcome MDR in ovarian cancer. Furthermore, we also analyzed the molecular mechanism of this nanotherapeutic system in the treatment of ovarian cancer. Results: HA-modified nanocomplexes can specifically bind to the CD44 receptor, which is highly expressed in SKOV3/SKOV3m cells, achieving effective cell uptake and 150% enhancement of tumor site permeability. The nanosystem realized the stable combination and protective transportation of PTX and miRs. Analysis of drug-resistant SKOV3(TR) cells and an SKOV3(TR) xenograft model in BALB/c-nude mice showed significant downregulation of P-glycoprotein in heterogeneous tumor sites, PTX release, and subsequent induction of apoptosis. More importantly, this nanosystem could synergistically inhibit the growth of ovarian tumors. Further studies suggest that mTOR-mediated signaling pathways play an important role in reversing drug resistance and inducing apoptosis. Conclusions: To sum up, these data provide a model for overcoming PTX resistance in ovarian cancer.
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