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Chelation, formulation, encapsulation, retention, and in vivo biodistribution of hydrophobic nanoparticles labelled with 57Co-porphyrin: Oleylamine ensures stable chelation of cobalt in nanoparticles that accumulate in tumors.

Publication ,  Journal Article
Hervella, P; Dam, JH; Thisgaard, H; Baun, C; Olsen, BB; Høilund-Carlsen, PF; Needham, D
Published in: Journal of controlled release : official journal of the Controlled Release Society
December 2018

While small molecules can be used in cancer diagnosis there is a need for imageable diagnostic NanoParticles (NPs) that act as surrogates for the therapeutic NPs. Many NPs are composed of hydrophobic materials so the challenge is to formulate hydrophobic imaging agents. To develop individualized medical treatments based on NP, a first step should be the selection of patients who are likely responders to the treatment as judged by imaging tumor accumulation of NPs. This requires NPs with the same size and structure as the subsequent therapeutic NPs but labelled with a long-lived radionuclide. Cobalt isotopes are good candidates for NP labelling since 55Co has half-life of 17.5 h and positron energy of 570 keV while 57Co (t1/2 271.6 d) is an isotope suited for preclinical single photon emission tomography (SPECT) to visualize biodistribution and pharmacokinetics of NPs. We used the hydrophobic octaethyl porphyrin (OEP) to chelate cobalt and to encapsulate it inside hydrophobic liquid NPs (LNPs). We hypothesized that at least two additional hydrophobic axial ligands (oleylamine, OA) must be provided to the OEP-Co complex in order to encapsulate and retain Co inside LNP.1. Cobalt chelation by OEP and OA. The association constant of cobalt to OEP was 2.49 × 105 M-1 and the formation of the hexacoordinate complex OEP-Co-4OA was measured by spectroscopy. 2. NP formulation and characterization: LNPs were prepared by the fast ethanol injection method and were composed of a liquid core (triolein) surrounded by a lipid monolayer (DSPC:Cholesterol:DSPE-PEG2000). The size of the LNPs loaded with the cobalt complex was 40 ± 5 nm, 3. Encapsulation of OEP-Co-OA: The loading capacity of OEP-Co-OA in LNP was 5 mol%. 4. Retention of OEP-57Co-4OA complex in the LNPs: the positive effect of the OA ligands was demonstrated on the stability of the OEP-57Co-4OA complex, providing a half-life for retention in PBS of 170 h (7 days) while in the absence of the axial OA ligands was only 22 h. 5 Biodistribution Study: the in vivo biodistribution of LNP was studied in AR42J pancreatic tumor-bearing mice. The estimated half-life of LNPs in blood was about 7.2 h. Remarkably, the accumulation of LNPs in the tumor was as high as 9.4% ID/g 24 h after injection with a doubling time for tumor accumulation of 3.22 h. The most important result was that the nanoparticles could indeed accumulate in the AR42J tumors up to levels greater than those of other NPs previously measured in the same tumor model, and at about half the values reported for the molecular agent 57Co-DOTATATE.The additional hydrophobic chelator OA was indeed needed to obtain a stable octahedral OEP-Co-4OA. Cobalt was actually well-retained inside LNP in the OEP-Co-4OA complex. The method described in the present work for the core-labelling of LNPs with cobalt is now ready for labeling of NPs with 55Co, or indeed other hexadentate radionuclides of interest for preclinical in vivo PET-imaging and radio-therapeutics.

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Published In

Journal of controlled release : official journal of the Controlled Release Society

DOI

EISSN

1873-4995

ISSN

0168-3659

Publication Date

December 2018

Volume

291

Start / End Page

11 / 25

Related Subject Headings

  • Tomography, Emission-Computed, Single-Photon
  • Tissue Distribution
  • Porphyrins
  • Pharmacology & Pharmacy
  • Neoplasms
  • Nanoparticles
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice
  • Male
 

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Hervella, P., Dam, J. H., Thisgaard, H., Baun, C., Olsen, B. B., Høilund-Carlsen, P. F., & Needham, D. (2018). Chelation, formulation, encapsulation, retention, and in vivo biodistribution of hydrophobic nanoparticles labelled with 57Co-porphyrin: Oleylamine ensures stable chelation of cobalt in nanoparticles that accumulate in tumors. Journal of Controlled Release : Official Journal of the Controlled Release Society, 291, 11–25. https://doi.org/10.1016/j.jconrel.2018.09.027
Hervella, Pablo, Johan Hygum Dam, Helge Thisgaard, Christina Baun, Birgitte Brinkmann Olsen, Poul Flemming Høilund-Carlsen, and David Needham. “Chelation, formulation, encapsulation, retention, and in vivo biodistribution of hydrophobic nanoparticles labelled with 57Co-porphyrin: Oleylamine ensures stable chelation of cobalt in nanoparticles that accumulate in tumors.Journal of Controlled Release : Official Journal of the Controlled Release Society 291 (December 2018): 11–25. https://doi.org/10.1016/j.jconrel.2018.09.027.
Hervella P, Dam JH, Thisgaard H, Baun C, Olsen BB, Høilund-Carlsen PF, et al. Chelation, formulation, encapsulation, retention, and in vivo biodistribution of hydrophobic nanoparticles labelled with 57Co-porphyrin: Oleylamine ensures stable chelation of cobalt in nanoparticles that accumulate in tumors. Journal of controlled release : official journal of the Controlled Release Society. 2018 Dec;291:11–25.
Hervella, Pablo, et al. “Chelation, formulation, encapsulation, retention, and in vivo biodistribution of hydrophobic nanoparticles labelled with 57Co-porphyrin: Oleylamine ensures stable chelation of cobalt in nanoparticles that accumulate in tumors.Journal of Controlled Release : Official Journal of the Controlled Release Society, vol. 291, Dec. 2018, pp. 11–25. Epmc, doi:10.1016/j.jconrel.2018.09.027.
Hervella P, Dam JH, Thisgaard H, Baun C, Olsen BB, Høilund-Carlsen PF, Needham D. Chelation, formulation, encapsulation, retention, and in vivo biodistribution of hydrophobic nanoparticles labelled with 57Co-porphyrin: Oleylamine ensures stable chelation of cobalt in nanoparticles that accumulate in tumors. Journal of controlled release : official journal of the Controlled Release Society. 2018 Dec;291:11–25.
Journal cover image

Published In

Journal of controlled release : official journal of the Controlled Release Society

DOI

EISSN

1873-4995

ISSN

0168-3659

Publication Date

December 2018

Volume

291

Start / End Page

11 / 25

Related Subject Headings

  • Tomography, Emission-Computed, Single-Photon
  • Tissue Distribution
  • Porphyrins
  • Pharmacology & Pharmacy
  • Neoplasms
  • Nanoparticles
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice
  • Male