Skip to main content

Advertisement

SpringerLink
Log in

Ceramide and N,N,N-Trimethylphytosphingosine-Iodide (TMP-I)-Based Lipid Nanoparticles for Cancer Therapy

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the anti-tumor effect of ceramide or trimethylphytosphingosine-iodide (TMP-I) containing solid lipid nanoparticles (SLNs) prepared using trymyristin, phosphatidylcholine (PC), and Pluronic P85 (P85) for intravenous delivery of docetaxel.

Methods

Docetaxel-loaded SLNs using ceramide or TMP-I at 3.22% (w/w) with a mean diameter of 89–137 nm were successfully prepared by high pressure homogenization. The prepared nanoparticles were characterized by particle size, zeta potential, drug content, and TEM analysis. Cellular uptake and cytotoxicity were studied using adriamycin-resistant breast cancer (MCF-7/ADR) cells. The optimized formulation’s dissolution profile, pharmacokinetics, and antitumor effect in mice tumor model were compared with that of control (Taxotere®).

Results

The drug release rate of docetaxel from SLNs was lower than that of control (Taxotere®). The prepared SLNs showed higher cellular uptake of docetaxel compared to that of Taxotere® in MCF-7/ADR cell lines, which was further confirmed by the confocal laser scanning microscopy (CLSM) study using coumarin 6 (C6). Prepared SLNs exhibited significantly increased antitumor efficacy, compared to Taxotere®, in MCF-7/ADR cells. In vivo pharmacokinetic study in rats (at 10 mg/kg dose) showed that the SLNs significantly reduced in vivo clearance of drug than Taxotere®. Interestingly, ceramide and TMP-I SLNs efficiently inhibited the tumor growth compared to Taxotere® in MCF-7/ADR tumor xenografted mouse model.

Conclusion

This work showed that TMP-I and ceramide SLNs not only significantly enhanced systemic exposure of drug, but also increased antitumor efficacy compared to Taxotere® and control SLN.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AUC:

Area Under the Curve

BA:

Bioavailability

BCRP:

Breast cancer resistance protein

BSA:

Bovine serum albumin

C6:

Coumarin 6

CL:

Clearance

CLSM:

Confocal laser scanning microscopy

DMS:

N,N-dimethylphytosphingosine

DW:

Distilled water

ELS:

Electrophoretic light scattering

HPLC:

High performance liquid chromatography

LLOQ:

Lower limit of quantitation

MDR:

Multidrug resistance

MMS:

N-monomethylphytosphingosine

MRP:

Multidrug resistance-associated protein

MRT:

Mean residence time

P85:

Pluronic P85

PBS:

Phosphate-buffered saline

PC:

Phosphatidylcholine

P-gp:

P-glycoprotein

RBC:

Refrigerated bath circulator

ROS:

Reactive oxygen species

S1P:

Sphingosine-1-phosphate

SD:

Sprague Dawley

SDS:

Sodium dodecyl sulfate

SK1:

Sphingosine kinase-1

SLNs:

Solid lipid nanoparticles

TEM:

Transmission electron microscopy

TMP-I:

Trimethylphytosphingosine-iodide

TMS:

N,N,N-trimethylsphingosine

References

  1. Baker J, Ajani J, Scotte F, Winther D, Martin M, Aapro MS, et al. Docetaxel-related side effects and their management. Eur J Oncol Nurs. 2009;13(1):49–59.

    Article  PubMed  Google Scholar 

  2. Persohn E, Canta A, Schoepfer S, Traebert M, Mueller L, Gilardini A, et al. Morphological and morphometric analysis of paclitaxel and docetaxel-induced peripheral neuropathy in rats. Eur J Cancer. 2005;41(10):1460–6.

    Article  PubMed  CAS  Google Scholar 

  3. Immordino ML, Brusa P, Arpicco S, Stella B, Dosio F, Cattel L. Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing docetaxel. J Control Release. 2003;91(3):417–29.

    Article  PubMed  CAS  Google Scholar 

  4. Yin YM, Cui FD, Mu CF, Choi MK, Kim JS, Chung SJ, et al. Docetaxel microemulsion for enhanced oral bioavailability: preparation and in vitro and in vivo evaluation. J Control Release. 2009;140(2):86–94.

    Article  PubMed  CAS  Google Scholar 

  5. Mi Y, Liu Y, Feng SS. Formulation of Docetaxel by folic acid-conjugated d-alpha-tocopheryl polyethylene glycol succinate 2000 (Vitamin E TPGS(2k)) micelles for targeted and synergistic chemotherapy. Biomaterials. 2011;32(16):4058–66.

    Article  PubMed  CAS  Google Scholar 

  6. Cho HJ, Yoon HY, Koo H, Ko SH, Shim JS, Lee JH, et al. Self-assembled nanoparticles based on hyaluronic acid-ceramide (HA-CE) and Pluronic® for tumor-targeted delivery of docetaxel. Biomaterials. 2011;32(29):7181–90.

    Article  PubMed  CAS  Google Scholar 

  7. Nabekura T. Overcoming multidrug resistance in human cancer cells by natural compounds. Toxins. 2010;2(6):1207–24.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Wong HL, Bendayan R, Rauth AM, Li Y, Wu XY. Chemotherapy with anticancer drugs encapsulated in solid lipid nanoparticles. Adv Drug Deliv Rev. 2007;59(6):491–504.

    Article  PubMed  CAS  Google Scholar 

  9. zur Muhlen A, Schwarz C, Mehnert W. Solid lipid nanoparticles (SLN) for controlled drug delivery--drug release and release mechanism. Eur J Pharm Biopharm. 1998;45(2):149–55.

    Article  PubMed  Google Scholar 

  10. Mehnert W, Mader K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2012.

  11. Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur J Pharm Biopharm. 2000;50(1):161–77.

    Article  PubMed  CAS  Google Scholar 

  12. Woodcock J. Sphingosine and ceramide signalling in apoptosis. IUBMB Life. 2006;58(8):462–6.

    Article  PubMed  CAS  Google Scholar 

  13. Spiegel S, Milstien S. Sphingosine 1-phosphate, a key cell signaling molecule. J Biol Chem. 2002;277(29):25851–4.

    Article  PubMed  CAS  Google Scholar 

  14. Petremand J, Widmann C. Lipid metabolism: sphingolipids- from membrane constituents to signaling molecules that control cell-to-cell communications. Curr Opin Lipidol. 2008;19(6):620–1.

    Article  PubMed  CAS  Google Scholar 

  15. Endo K, Igarashi Y, Nisar M, Zhou QH, Hakomori S. Cell membrane signaling as target in cancer therapy: inhibitory effect of N, N-dimethyl and N, N, N-trimethyl sphingosine derivatives on in vitro and in vivo growth of human tumor cells in nude mice. Cancer Res. 1991;51(6):1613–8.

    PubMed  CAS  Google Scholar 

  16. Park MT, Kang JA, Choi JA, Kang CM, Kim TH, Bae S, et al. Phytosphingosine induces apoptotic cell death via caspase 8 activation and Bax translocation in human cancer cells. Clin Cancer Res. 2003;9(2):878–85.

    PubMed  CAS  Google Scholar 

  17. Kim BM, Choi YJ, Han Y, Yun YS, Hong SH. N, N-dimethyl phytosphingosine induces caspase-8-dependent cytochrome c release and apoptosis through ROS generation in human leukemia cells. Toxicol Appl Pharmacol. 2009;239(1):87–97.

    Article  PubMed  CAS  Google Scholar 

  18. Devalapally H, Duan Z, Seiden MV, Amiji MM. Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin Cancer Res. 2008;14(10):3193–203.

    Article  PubMed  CAS  Google Scholar 

  19. van Vlerken LE, Duan Z, Seiden MV, Amiji MM. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res. 2007;67(10):4843–50.

    Article  PubMed  Google Scholar 

  20. Werle M. Natural and synthetic polymers as inhibitors of drug efflux pumps. Pharm Res. 2008;25(3):500–11.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Mu CF, Balakrishnan P, Cui FD, Yin YM, Lee YB, Choi HG, et al. The effects of mixed MPEG-PLA/Pluronic copolymer micelles on the bioavailability and multidrug resistance of docetaxel. Biomaterials. 2010;31(8):2371–9.

    Article  PubMed  CAS  Google Scholar 

  22. Yan YD, Kim DH, Sung JH, Yong CS, Choi HG. Enhanced oral bioavailability of docetaxel in rats by four consecutive days of pre-treatment with curcumin. Int J Pharm. 2010;399(1–2):116–20.

    Article  PubMed  CAS  Google Scholar 

  23. Lee MK, Lim SJ, Kim CK. Preparation, characterization and in vitro cytotoxicity of paclitaxel-loaded sterically stabilized solid lipid nanoparticles. Biomaterials. 2007;28(12):2137–46.

    Article  PubMed  CAS  Google Scholar 

  24. Song CK, Balakrishnan P, Shim CK, Chung SJ, Kim DD. Enhanced in vitro cellular uptake of P-gp substrate by poloxamer-modified liposomes (PMLs) in MDR cancer cells. J Microencapsul. 2011;28(6):575–81.

    Article  PubMed  CAS  Google Scholar 

  25. Goppert TM, Muller RH. Protein adsorption patterns on poloxamer- and poloxamine-stabilized solid lipid nanoparticles (SLN). Eur J Pharm Biopharm. 2005;60(3):361–72.

    Article  PubMed  Google Scholar 

  26. Shirahama T, Sweeney EA, Sakakura C, Singhal AK, Nishiyama K, Akiyama S, et al. In vitro and in vivo induction of apoptosis by sphingosine and N, N-dimethylsphingosine in human epidermoid carcinoma KB-3-1 and its multidrug-resistant cells. Clin Cancer Res. 1997;3(2):257–64.

    PubMed  CAS  Google Scholar 

  27. Song CK, Lee JH, Jahn A, Choi MJ, Namgoong SK, Hong SS, et al. In vitro and in vivo evaluation of N, N, N-trimethylphytosphingosine-iodide (TMP) in liposomes for the treatment of angiogenesis and metastasis. Int J Pharm. 2012;434(1–2):191–8.

    Article  PubMed  CAS  Google Scholar 

  28. Yang SC, Lu LF, Cai Y, Zhu JB, Liang BW, Yang CZ. Body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on brain. J Control Release. 1999;59(3):299–307.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURE

This research was supported by the National Research Foundation of Korea (NRF), funded by the Korean government (MSIP) (No. NRF-2015R1A1A1A05027671).

Author information

Authors and Affiliations

  1. College of Pharmacy, Hanyang University, Ansan, 426-791, Republic of Korea

    Prabagar Balakrishnan

  2. Institute of Nano Science and Technology, Hanyang University, Seoul, 133-791, Republic of Korea

    Chung Kil Song

  3. Department of Bio-Chemical Engineering, Graduate School, Dongseo University, Busan, 617-716, Republic of Korea

    Alexander Jahn

  4. College of Pharmacy, Kangwon National University, Chuncheon, 200-701, Republic of Korea

    Hyun-Jong Cho

  5. School of Medicine, Stony Brook University, HSC, Stony Brook, NY, 11794, USA

    Prabagar Balakrishnan

Authors
  1. Prabagar Balakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chung Kil Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander Jahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyun-Jong Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Prabagar Balakrishnan or Hyun-Jong Cho.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Balakrishnan, P., Song, C.K., Jahn, A. et al. Ceramide and N,N,N-Trimethylphytosphingosine-Iodide (TMP-I)-Based Lipid Nanoparticles for Cancer Therapy. Pharm Res 33, 206–216 (2016). https://doi.org/10.1007/s11095-015-1780-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-015-1780-5

KEY WORDS

Search

Navigation