Increased bone marrow toxicity of doxorubicin bound to nanoparticles.
The in vivo myelosuppressive effects of free and polyalkylcyanoacrylate-bound doxorubicin were compared in a mouse model. After intravenous administration of 11 mg/kg body weight of doxorubicin either free or bound to polyisobutyl (doxo-PIBCA) or polyisohexylcyanoacrylate (doxo-PIHCA) nanoparticles, we studied the total and differential counts of blood, bone marrow and spleen cells; the number of granulocyte progenitors (CFU-GM) was determined by culture. Doxorubicin concentrations were measured with an HPLC method in the bone marrow and the spleen. Doxo-PIHCA nanoparticles showed the highest and longest myelosuppressive effects which correlated well with a high concentration of the drug in the bone marrow and the spleen. Moreover, it was found that PIHCA nanoparticles induced the release of colony stimulating factors, which might account for the observed increase of toxic effects of doxorubicin on bone marrow progenitors. These data also indicate that a more precise evaluation of the myelosuppressive effects of targeted formulations of anticancer drugs is needed, which may be attained by studies on bone marrow progenitors.
Gibaud
S
S
Laboratoire de Pharmacie Galénique, U.R.A. CNRS 1218, France.
Andreux
J P
JP
Weingarten
C
C
Renard
M
M
Couvreur
P
P
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D003115:Colony-Stimulating Factors / Q000097:blood; D003487:Cyanoacrylates; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D004337:Drug Carriers; D004659:Enbucrilate; D005269:Femur / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010976:Platelet Count / Q000187:drug effects; D011108:Polymers; D013154:Spleen / Q000187:drug effects
D003115:Colony-Stimulating Factors; D003487:Cyanoacrylates; D004337:Drug Carriers; D011108:Polymers; C057532:polyisohexylcyanoacrylate; D004317:Doxorubicin; D004659:Enbucrilate