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Published on: May 14, 2021
New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour
Heba Alshaker1,2, Qi Wang1, Shyam Srivats3
1School of Medicine, University of East Anglia, 2.53 BCRE, Norwich Research Park, Norwich, NR47UQ, UK.
Purpose:
Combining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity.
Methods:
Docetaxel, FTY and glucosamine were covalently conjugated to poly(lactic-co-glycolic acid) (PLGA). NPs were characterised by dynamic light scattering and electron microscopy. The cellular uptake, cytotoxicity and in vivo antitumor efficacy of CNPs were evaluated.
Results:
We show for the first time that in triple negative breast cancer cells FTY provides chemosensitisation to DTX, allowing a four-fold reduction in the effective dose. We have encapsulated both drugs in PLGA complex NPs (CNPs), with narrow size distribution of ~ 100 nm and excellent cancer cell uptake providing sequential, sustained release of FTY and DTX. In triple negative breast cancer cells and mouse breast cancer models, CNPs had similar efficacy to systemic free therapies, but allowed an effective drug dose reduction. Application of CNPs has significantly reversed chemotherapy side effects such as weight loss, liver toxicity and, most notably, lymphopenia.
Conclusions:
We show for the first time the DTX chemosensitising effects of FTY in triple negative breast cancer. We further demonstrate that encapsulation of free drugs in CNPs can improve targeting, provide low off-target toxicity and most importantly reduce FTY-induced lymphopenia, offering potential therapeutic use of FTY in clinical cancer treatment.
Insights
This study developed nanoparticle-encapsulated docetaxel and FTY720 to treat chemoresistant triple-negative breast cancer. The nanoparticles enhanced drug efficacy, reduced toxicity, and significantly mitigated FTY720-induced lymphopenia.
Area of Science:
- Oncology
- Nanomedicine
- Pharmacology
Background:
- Chemotherapy resistance in tumors necessitates novel therapeutic strategies.
- Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) exhibits anticancer potential but causes dose-limiting lymphopenia.
- Combining molecular therapies with chemotherapy may improve outcomes for chemoresistant cancers.
Purpose of the Study:
- To develop a nanoparticle (NP) formulation combining docetaxel (DTX) and FTY for enhanced anticancer effects.
- To achieve targeted tumor delivery and reduce systemic toxicity associated with FTY.
- To investigate the potential of FTY to chemosensitize docetaxel in chemoresistant cancers.
Main Methods:
- Docetaxel (DTX), FTY720 (FTY), and glucosamine were conjugated to poly(lactic-co-glycolic acid) (PLGA) to form complex nanoparticles (CNPs).
- CNPs were characterized for size and morphology using dynamic light scattering and electron microscopy.
- In vitro cellular uptake and cytotoxicity, and in vivo antitumor efficacy in mouse models were evaluated.
Main Results:
- FTY demonstrated chemosensitization to DTX in triple-negative breast cancer cells, enabling a four-fold reduction in effective dose.
- PLGA-based CNPs exhibited a narrow size distribution (~100 nm) and efficient cancer cell uptake, facilitating sustained release of FTY and DTX.
- CNPs showed comparable efficacy to free therapies in vitro and in vivo, while significantly reducing chemotherapy side effects including weight loss, liver toxicity, and lymphopenia.
Conclusions:
- FTY exhibits docetaxel chemosensitizing effects in triple-negative breast cancer, a novel finding.
- Encapsulation of DTX and FTY in CNPs improves tumor targeting and reduces off-target toxicity.
- This nanoparticle formulation effectively mitigates FTY-induced lymphopenia, suggesting potential for FTY's clinical application in cancer treatment.
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