Skip to main content
SpringerLink
Log in

Thermal Behavior of 19F Nuclear Magnetic Resonance Signal of 19F-Containing Compound in Lipid Nano-Emulsion for Potential Tumor Diagnosis

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

We developed carriers of a 19F magnetic resonance imaging (19F MRI) agent, capable of responding to the temperature difference for cancer diagnosis. The carriers were based on high melting point (mp) neutral lipids, namely, tripalmitin (TPT) and tristearin (TSR) and triarachidin (TAC). Lipid nano-emulsions (LNEs) containing a fluorine compound, i.e., a modified α-tocopherol (19F-TP), were respectively prepared as TPT-LNE, TSR-LNE, TAC-LNE1, and TAC-LNE2 and studied by 19F NMR spectroscopy. In LNE prepared with soybean oil as a control, the full width at half maximum (FWHM) values of the 19F NMR signal of 19F-TP remained constant at 25, 37, and 42°C, while those of the LNEs prepared from a neutral lipid with a high mp showed a sharp decrease between 25 and 37°C. The magnitude of the decrease followed the order: TPT-LNE < TSR-LNE < TAC-LNE1. However, TAC-LNE2, for which the amount of encapsulated 19F-TP was one third less than that of TAC-LNE1, showed a sharp decline in the FWHM between 37 and 42°C. To examine these changes, the 19F spin-lattice (T1) and spin-spin (T2) relaxation times of 19F-TP were measured. TAC-LNE2 in particular showed a substantial change in its T2 value between 37 and 42°C compared with the change of its T1 value. This result was attributed to activation of the molecular motion of 19F-TP in TAC-LNE2 from 37 to 42°C. Thus, TAC-LNE showed potential for use as a carrier for cancer diagnosis using 19F MRI.

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

Similar content being viewed by others

References

  1. Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium (III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev. 1999;99:2293–352.

    Article  PubMed  CAS  Google Scholar 

  2. Kobayashi H, Brechbiel MW. Nano-sized MRI contrast agents with dendrimer cores. Adv Drug Deliv Rev. 2005;57:2271–86.

    Article  PubMed  CAS  Google Scholar 

  3. Dechent JF, Buljubasich L, Schreiber LM, Spiess HW, Munnemann K. Proton magnetic resonance imaging with parahydrogen induced polarization. Phys Chem Chem Phys. 2012;14:2346–52.

    Article  PubMed  CAS  Google Scholar 

  4. Ruiz-Cabello J, Barnett BP, Bottomley PA, Bulte JWM. Fluorine (19F) MRS and MRI in biomedicine. NMR Biomed. 2011;24:114–29.

    Article  PubMed  CAS  Google Scholar 

  5. Knight JG, Edwards PG, Paisey SJ. Fluorinated contrast agents for magnetic resonance imaging; a review of recent developments. RSC Adv. 2011;1:1415–25.

    Article  CAS  Google Scholar 

  6. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res. 1986;46:6387–92.

    PubMed  CAS  Google Scholar 

  7. Seki J, Sasaki H, Doi M, Yoshikawa H, Takahashi Y, Yamane S, et al. Lipid nano-sphere (LNS), a protein-free analogue of lipoproteins, as a novel drug carrier for parenteral administration. J Control Release. 1994;28:352–3.

    Article  CAS  Google Scholar 

  8. Miyamoto M, Hirano K, Ichikawa H, Fukumori Y, Akine Y, Tokuuye K. Preparation of gadolinium-containing emulsions stabilized with phosphatidylcholine-surfactant mixtures for neutron-capture therapy. Chem Pharm Bull. 1999;47:203–8.

    Article  CAS  Google Scholar 

  9. Ahmed N, Jaafar-Maalej C, Mohamed M, Fessi H, Elaissari A. New oil-in-water magnetic emulsion as contrast agent for in vivo magnetic resonance imaging (MRI). J Biomed Nanotechnol. 2013;9:1579–85.

    Article  PubMed  CAS  Google Scholar 

  10. Sigg SJ, Santini F, Najer A, Richard PU, Meier WP, Palivan CG. Nanoparticle-based highly sensitive MRI contrast agents with enhanced relaxivity in reductive milieu. Chem Commun. 2016;52:9937–40.

    Article  CAS  Google Scholar 

  11. Bouchoucha M, van Heeswijk RB, Gossuin Y, Kleitz F, Fortin M–A. Fluorinated mesoporous silica nanoparticles for binuclear probes in 1H and 19F magnetic resonance imaging. Langmuir. 2017;33:10531–42.

    Article  PubMed  CAS  Google Scholar 

  12. Takegami S, Kitamura K, Kawada H, Matsumoto Y, Kitade T, Ishida H, et al. Preparation and characterization of a new lipid nano-emulsion containing two cosurfactants, sodium palmitate for droplet size reduction and sucrose palmitate for stability enhancement. Chem Pharm Bull. 2008;56:1097–102.

    Article  PubMed  CAS  Google Scholar 

  13. Takegami S, Takara K, Tanaka S, Yamamoto K, Hori M, Yokoyama T, et al. Characterization, in vitro cytotoxicity and cellular accumulation of paclitaxel-loaded lipid nano-emulsions. J Microencapsul. 2010;27:453–9.

    Article  PubMed  CAS  Google Scholar 

  14. Takegami S, Kitamura K, Ohsugi M, Konishi A, Kitade T. 19F nuclear magnetic resonance spectrometric determination of the partition coefficients of flutamide and nilutamide (antiprostate cancer drugs) in a lipid nano-emulsion and prediction of its encapsulation efficiency for the drugs. AAPS PhamSciTech. 2016;17:1500–6.

    Article  CAS  Google Scholar 

  15. Takegami S, Katsumi H, Asai K, Fujii D, Fujimoto T, Kawakami H, et al. Application of 19F NMR spectroscopy using a novel α-tocopherol derivative as a 19F NMR probe for a pharmacokinetic study of lipid nano-emulsions in mice. Pharm Anal Acta. 2015;6:339.

    Google Scholar 

  16. Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol. 1984;2:343–66.

    Article  PubMed  CAS  Google Scholar 

  17. Gerweck LE, Seetharaman K. Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res. 1996;56:1194–8.

    PubMed  CAS  Google Scholar 

  18. Oishi M, Sumitani S, Nagasaki Y. On-off regulation of 19F magnetic resonance signals based on pH-sensitive PEGylated nanogels for potential tumor-specific smart 19F MRI probes. Bioconjug Chem. 2007;18:1379–82.

    Article  PubMed  CAS  Google Scholar 

  19. Wang K, Peng H, Thurecht KJ, Puttick S, Whittaker AK. pH-responsive star polymer nanoparticles: potential 19F MRI contrast agents for tumor-selective imaging. Polym Chem. 2013;4:4480–9.

    Article  CAS  Google Scholar 

  20. Monti M, Brandt L, Ikomi-Kumm J, Olsson H. Microcalorimetric investigation of cell metabolism in tumour cells from patients with non-Hodgkin lymphoma (NHL). Scand J Haematol. 1986;36:353–7.

    Article  PubMed  CAS  Google Scholar 

  21. Okabe K, Inada N, Gota C, Harada Y, Funatsu T, Uchiyama S. Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy. Nat Commun. 2012;3:705.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Zhu X, Chen S, Luo Q, Ye C, Liu M, Zhou X. Body temperature sensitive micelles for MRI enhancement. Chem Commun. 2015;51:9085–8.

    Article  CAS  Google Scholar 

  23. Araki T, Murayama S, Usui K, Shimada T, Aoki I, Karasawa S. Self-assembly behavior of emissive urea benzene derivatives enables heat-induced accumulation in tumor tissue. Nano Lett. 2017;17:2397–403.

    Article  PubMed  CAS  Google Scholar 

  24. Davis RM, Viglianti BL, Yarmolenko P, Park J-Y, Stauffer P, Needham D, et al. A method to convert MRI images of temperature change into images of absolute temperature in solid tumours. Int J Hyperth. 2013;29:569–81.

    Article  CAS  Google Scholar 

  25. Langereis S, Keupp J, van Velthoven JLJ, de Roos IHC, Burdinski D, Pikkemaat JA, et al. A temperature-sensitive liposomal 1H CEST and 19F contrast agent for MR image-guided drug delivery. J Am Chem Soc. 2009;131:1380–1.

    Article  PubMed  CAS  Google Scholar 

  26. Yamaoka K, Tanigawara Y, Nakagawa T, Uno T. A pharmacokinetic analysis program, (multi) for microcomputer. J Pharmacobio-Dyn. 1981;4:879–85.

    Article  PubMed  CAS  Google Scholar 

  27. Rotenberg M, Rubin M, Bor A, Meyuhas D, Talmon Y, Lichtenberg D. Physico-chemical characterization of Intralipid™ emulsions. Biochim Biophys Acta. 1991;1086:265–72.

    Article  PubMed  CAS  Google Scholar 

  28. Sotirhos N, Herslöf B, Kenne L. Quantitative analysis of phospholipids by 31P-NMR. J Lipid Res. 1986;27:386–92.

    PubMed  CAS  Google Scholar 

  29. Calculated using advanced chemistry development (ACD/Labs) software V1.02 (©1994–2017 ACD-Labs).

  30. Unruh T, Bunjcs H, Westesen K, Koch MHJ. Investigations on the melting behaviour of triglyceride nanoparticles. Colloid Polym Sci. 2001;279:398–403.

    Article  CAS  Google Scholar 

  31. Povey MJW, Hindle SA, Aarflot A, Hoiland H. Melting point depression of the surface layer in n-alkane emulsions and its implications for fat destabilization in ice cream. Cryst Growth Des. 2006;6:297–301.

    Article  CAS  Google Scholar 

  32. Awad TS, Helgason T, Kristbergsson K, Weiss J, Decker EA, McClements DJ. Temperature scanning ultrasonic velocity study of complex thermal transformations in solid lipid nanoparticles. Langmuir. 2008;24:12779–84.

    Article  PubMed  CAS  Google Scholar 

  33. Friebolin H. Basic one- and two-dimensional NMR spectroscopy, Third revised edition, Wiley-Vch, 1998.

  34. Farrar TC, Becker ED. Pulse and Fourier transform NMR, Academic Press, 1971

Download references

Funding

This work was partly supported by a subsidy (Grant Number S1311035) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT)-supported Program for the Strategic Research Foundation at Private Universities, 2013–2018.

Author information

Authors and Affiliations

  1. Department of Analytical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchicho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan

    Risa Iima, Shigehiko Takegami, Atsuko Konishi, Shiori Tajima, Nao Minematsu & Tatsuya Kitade

Authors
  1. Risa Iima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shigehiko Takegami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Atsuko Konishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shiori Tajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nao Minematsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tatsuya Kitade
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shigehiko Takegami.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Electronic Supplementary Material

ESM 1

(DOCX 173 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iima, R., Takegami, S., Konishi, A. et al. Thermal Behavior of 19F Nuclear Magnetic Resonance Signal of 19F-Containing Compound in Lipid Nano-Emulsion for Potential Tumor Diagnosis. AAPS PharmSciTech 19, 2679–2686 (2018). https://doi.org/10.1208/s12249-018-1102-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-018-1102-4

KEY WORDS

Search

Navigation