Melanin-covered nanoparticles for protection of bone marrow during radiation therapy of cancer.
OBJECTIVE
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
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.
Schweitzer
Andrew D
AD
Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Revskaya
Ekaterina
E
Chu
Peter
P
Pazo
Valeria
V
Friedman
Matthew
M
Nosanchuk
Joshua D
JD
Cahill
Sean
S
Frases
Susana
S
Casadevall
Arturo
A
Dadachova
Ekaterina
E
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000528:radiation effects; D004337:Drug Carriers / Q000138:chemical synthesis / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D008543:Melanins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008545:Melanoma / Q000378:metabolism / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D016499:Radioimmunotherapy / Q000009:adverse effects
D004337:Drug Carriers; D008543:Melanins; D011837:Radiation-Protective Agents