New FTY720-docetaxel Nanoparticle Therapy Overcomes FTY720-induced Lymphopenia and Inhibits Metastatic Breast Tumour Growth

Overview

Journal Breast Cancer Res Treat

Specialty Oncology

Date 2017 Jul 12

PMID 28695300

Citations 14

Authors

Heba Alshaker

Qi Wang

Shyam Srivats

Yimin Chao

Colin Cooper

Dmitri Pchejetski

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Enhancing Lung Recovery: Inhaled Poly(lactic--glycolic) Acid Encapsulating FTY720 and Nobiletin for Lipopolysaccharide-Induced Lung Injury, with Advanced Inhalation Tower Technology.

Zhang H, Kuo W, Tu P, Lee C, Wang H, Huang Y ACS Nano. 2025; 19(8):7634-7649.

PMID: 39965088 PMC: 11887484. DOI: 10.1021/acsnano.3c12532.

Synergistic Action of Benzyl Isothiocyanate and Sorafenib in a Nanoparticle Delivery System for Enhanced Triple-Negative Breast Cancer Treatment.

Wang Q, Cheng N, Wang W, Bao Y Cancers (Basel). 2024; 16(9).

PMID: 38730647 PMC: 11083210. DOI: 10.3390/cancers16091695.

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer.

Nagahashi M, Miyoshi Y Int J Mol Sci. 2024; 25(6).

PMID: 38542328 PMC: 10970081. DOI: 10.3390/ijms25063354.

Emerging Roles of Ceramides in Breast Cancer Biology and Therapy.

Pal P, Atilla-Gokcumen G, Frasor J Int J Mol Sci. 2022; 23(19).

PMID: 36232480 PMC: 9569866. DOI: 10.3390/ijms231911178.

Anti-rheumatic effect of quercetin and recent developments in nano formulation.

Guan F, Wang Q, Bao Y, Chao Y RSC Adv. 2022; 11(13):7280-7293.

PMID: 35423269 PMC: 8695102. DOI: 10.1039/d0ra08817j.

References

Paraskar A, Soni S, Chin K, Chaudhuri P, Muto K, Berkowitz J . Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy. Proc Natl Acad Sci U S A. 2010; 107(28):12435-40. PMC: 2906605. DOI: 10.1073/pnas.1007026107. View

Maruyama K . Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects. Adv Drug Deliv Rev. 2010; 63(3):161-9. DOI: 10.1016/j.addr.2010.09.003. View

Parhi P, Sahoo S . Trastuzumab guided nanotheranostics: A lipid based multifunctional nanoformulation for targeted drug delivery and imaging in breast cancer therapy. J Colloid Interface Sci. 2015; 451:198-211. DOI: 10.1016/j.jcis.2015.03.049. View

Sauer L, Nunes J, Salunkhe V, Skalska L, Kohama T, Cuvillier O . Sphingosine kinase 1 inhibition sensitizes hormone-resistant prostate cancer to docetaxel. Int J Cancer. 2009; 125(11):2728-36. DOI: 10.1002/ijc.24640. View

Ibrahim N, Desai N, Legha S, Soon-Shiong P, Theriault R, Rivera E . Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res. 2002; 8(5):1038-44. View

Simberg D, Duza T, Park J, Essler M, Pilch J, Zhang L . Biomimetic amplification of nanoparticle homing to tumors. Proc Natl Acad Sci U S A. 2007; 104(3):932-6. PMC: 1783417. DOI: 10.1073/pnas.0610298104. View

Pchejetski D, Bohler T, Brizuela L, Sauer L, Doumerc N, Golzio M . FTY720 (fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1. Cancer Res. 2010; 70(21):8651-61. DOI: 10.1158/0008-5472.CAN-10-1388. View

Gradishar W, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P . Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005; 23(31):7794-803. DOI: 10.1200/JCO.2005.04.937. View

Korotcov A, Ye Y, Chen Y, Zhang F, Huang S, Lin S . Glucosamine-linked near-infrared fluorescent probes for imaging of solid tumor xenografts. Mol Imaging Biol. 2011; 14(4):443-51. PMC: 3288187. DOI: 10.1007/s11307-011-0520-4. View

10.

Treuel L, Jiang X, Nienhaus G . New views on cellular uptake and trafficking of manufactured nanoparticles. J R Soc Interface. 2013; 10(82):20120939. PMC: 3627074. DOI: 10.1098/rsif.2012.0939. View

11.

Zong Y, Wu J, Shen K . Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: a systematic review and meta-analysis. Oncotarget. 2017; 8(10):17360-17372. PMC: 5370046. DOI: 10.18632/oncotarget.14477. View

12.

Pchejetski D, Golzio M, Bonhoure E, Calvet C, Doumerc N, Garcia V . Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res. 2005; 65(24):11667-75. DOI: 10.1158/0008-5472.CAN-05-2702. View

13.

Adachi K, Chiba K . FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology. Perspect Medicin Chem. 2009; 1:11-23. PMC: 2754916. View

14.

Kappos L, Radue E, OConnor P, Polman C, Hohlfeld R, Calabresi P . A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010; 362(5):387-401. DOI: 10.1056/NEJMoa0909494. View

15.

Ohotski J, Long J, Orange C, Elsberger B, Mallon E, Doughty J . Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor-negative breast cancer. Br J Cancer. 2012; 106(8):1453-9. PMC: 3326679. DOI: 10.1038/bjc.2012.98. View

16.

Azuma H, Horie S, Muto S, Otsuki Y, Matsumoto K, Morimoto J . Selective cancer cell apoptosis induced by FTY720; evidence for a Bcl-dependent pathway and impairment in ERK activity. Anticancer Res. 2003; 23(4):3183-93. View

17.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun M . Cancer statistics, 2009. CA Cancer J Clin. 2009; 59(4):225-49. DOI: 10.3322/caac.20006. View

18.

Basu S, Chaudhuri P, Sengupta S . Targeting oncogenic signaling pathways by exploiting nanotechnology. Cell Cycle. 2009; 8(21):3480-7. DOI: 10.4161/cc.8.21.9851. View

19.

Ernsting M, Murakami M, Undzys E, Aman A, Press B, Li S . A docetaxel-carboxymethylcellulose nanoparticle outperforms the approved taxane nanoformulation, Abraxane, in mouse tumor models with significant control of metastases. J Control Release. 2012; 162(3):575-81. DOI: 10.1016/j.jconrel.2012.07.043. View

20.

Misra R, Das M, Sahoo B, Sahoo S . Reversal of multidrug resistance in vitro by co-delivery of MDR1 targeting siRNA and doxorubicin using a novel cationic poly(lactide-co-glycolide) nanoformulation. Int J Pharm. 2014; 475(1-2):372-84. DOI: 10.1016/j.ijpharm.2014.08.056. View