Tissue distribution of doxorubicin associated with polyisohexylcyanoacrylate nanoparticles

Abstract

The body distribution of i.v. doxorubicin depends mainly on the physicochemical characteristics of the molecule. However, entrapment of that cytostatic drug inside polyalkylcyanoacrylate nanoparticles has been shown to modify its distribution profoundly in the mouse. Polysiohexylcyanoacrylate nanoparticles loaded with [14C]-doxorubicin were studied in comparison with free drug, with emphasis on their distribution pattern in mouse tissue after i.v. administration. An autoradiographic study showed that most of the radioactivity was found in the reticuloendothelial system as soon as a few minutes after i.v. administration of the doxorubicin-loaded nanoparticles. Quantitative determinations by liquid scintillation counting in fresh tissue (spleen, heart, kidneys, liver, lungs, bone marrow) and blood samples confirmed these observations. When the drug was linked to nanoparticles, doxorubicin blood clearance was reduced during the first few minutes after administration, whereas heart and kidney concentrations were substantially decreased. Assays of doxorubicin and doxorubicinol by a specific HPLC analytical method gave results very similar to those obtained by scintillation counting.

Etoposide Loaded PLGA and PCL Nanoparticles II: Biodistribution and Pharmacokinetics after Radiolabeling with Tc-99m

“…When associated with nanoparticles, drugs concentrate mainly in the liver and spleen and are precluded from exerting their acute toxicity in other organs. This was demonstrated earlier in mice treated with doxorubicin incorporated into poly-(isohexylcyanoacrylate) (PI-HCA) nanospheres, (Verdun et al 1990). Such affinity of MPS macrophages for endocytosis/phagocytosis provides an opportunity to deliver therapeutic agents efficiently to these cells, using polymeric conventional nanoparticles.…”

Drug transport to brain with targeted nanoparticles

“…17 Lacking stealth properties, poly(alkylcyanoacrylate) nanoparticles administered intravenously are rapidly cleared from the blood stream by the monuclear phagocyte system (MPS) and mainly accumulate in liver and spleen, 18 -20 together with the entrapped compounds. [21][22][23] Only pegylated polyalkylcyanoacrylate nanoparticles have lower MPS uptake and prolonged blood circulation in vivo. 24 Brain delivery with PBCA nanoparticles Adsorbed onto polysorbate 80-coated PBCA nanoparticles administered intravenously compounds with poor brain diffusion as diverse as doxorubicin, 25,26 loperamide, 27 tubocurarine, 28 the hexapeptide dalargin 6,7 were successfully delivered to the brain, where they induced a pharmacological effect (for review, see Kreuter 29 ).…”

“…11,12 As an evidence of this desorption, blood pharmacokinetic profiles of drugs adsorbed onto polysorbate 80-coated PBCA nanoparticles administered intravenously were actually similar to free solutions, 25,34,35 and not at all typical of drugs associated to nonstealth colloidal drug carriers. 21,22,23,36 Therefore, as an alternative to the brain uptake of nanoparticles, we hypothesized a nanoparticle-induced nonspecific BBB permeabilization. 11 It has been known for a long time that polysorbate 80 causes BBB disturbance at intravenous systemic doses as low as 3 mg/kg 37 (25-100 mg/kg polysorbate 80 doses were used in brain targeting experiments 7,25,27 ).…”

Conventional Chemotherapeutic Drug Nanoparticles for Cancer Treatment

“…Another study found higher concentrations of doxorubicin in mice liver, spleen and lungs with doxorubicin incorporated into poly(isohexyl cyanoacrylate) than in mice treated with free doxorubicin. At the same time, the concentration of doxorubicin in heart and kidneys of the mice were lower than when free doxorubicin was used [18]. Tissue pharmacokinetic studies showed that the underlying mechanism responsible for the increased therapeutic efficacy of the nanoparticle formulation was a transfer of doxorubicin from the healthy hepatic tissue, acting as a drug reservoir, to the malignant cells.…”

“…Moreover, encapsulation of doxorubicin within nanoparticles reduces its cardiotoxicity by reducing the amount of drug that reaches the myocardium with a significant increase of drug concentrations in the liver. In one study this was not associated with any overall toxicity [18] while another study, using unloaded nanoparticles, observed a reversible decline in the phagocytic capacity of the liver after prolonged dosing, as well as a slight inflammatory response [19]. Accumulation of drug nanoparticles in the liver may also influence its elimination, since this organ is the site of metabolism and biliary excretion.…”