Melanin-covered nanoparticles for protection of bone marrow during radiation therapy of cancer

Int J Radiat Oncol Biol Phys. 2010 Dec 1;78(5):1494-502. doi: 10.1016/j.ijrobp.2010.02.020. Epub 2010 Apr 24.

Abstract

Purpose: Protection of bone marrow against radiotoxicity during radioimmunotherapy and in some cases external beam radiation therapy such as hemi-body irradiation would permit administration of significantly higher doses to tumors, resulting in increased efficacy and safety of treatment. Melanin, a naturally occurring pigment, possesses radioprotective properties. We hypothesized that melanin, which is insoluble, could be delivered to the bone marrow by intravenously administrated melanin-covered nanoparticles (MNs) because of the human body's "self-sieving" ability, protecting it against ionizing radiation.

Methods and materials: The synthesis of MNs was performed via enzymatic polymerization of 3,4-dihydroxyphenylalanine and/or 5-S-cysteinyl-3,4-dihydroxyphenylalanine on the surface of 20-nm plain silica nanoparticles. The biodistribution of radiolabeled MNs in mice was done at 3 and 24 h. Healthy CD-1 mice (Charles River Laboratories International, Inc., Wilmington, MA) or melanoma tumor-bearing nude mice were given MNs intravenously, 50 mg/kg of body weight, 3 h before either whole-body exposure to 125 cGy or treatment with 1 mCi of (188)Re-labeled 6D2 melanin-binding antibody.

Results: Polymerization of melanin precursors on the surface of silica nanoparticles resulted in formation of a 15-nm-thick melanin layer as confirmed by light scattering, transmission electron microscopy, and immunofluorescence. The biodistribution after intravenous administration showed than MN uptake in bone marrow was 0.3% and 0.2% of injected dose per gram at 3 and 24 h, respectively, whereas pre-injection with pluronic acid increased the uptake to 6% and 3% of injected dose per gram, respectively. Systemic MN administration reduced hematologic toxicity in mice treated with external radiation or radioimmunotherapy, whereas no tumor protection by MNs was observed.

Conclusions: MNs or similar structures provide a novel approach to protection of bone marrow from ionizing radiation based on prevention of free radical formation by melanin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone Marrow / metabolism*
  • Bone Marrow / radiation effects
  • Drug Carriers / chemical synthesis
  • Drug Carriers / pharmacokinetics
  • Magnetic Resonance Spectroscopy
  • Melanins / administration & dosage
  • Melanins / chemical synthesis
  • Melanins / pharmacokinetics*
  • Melanoma / metabolism
  • Melanoma / radiotherapy
  • Mice
  • Mice, Nude
  • Microscopy, Electron, Transmission
  • Nanoparticles* / administration & dosage
  • Radiation Injuries, Experimental / prevention & control*
  • Radiation-Protective Agents / administration & dosage
  • Radiation-Protective Agents / chemical synthesis
  • Radiation-Protective Agents / pharmacokinetics*
  • Radioimmunotherapy / adverse effects

Substances

  • Drug Carriers
  • Melanins
  • Radiation-Protective Agents