Enhanced brain tumor selectivity of cationic magnetic polysaccharide microspheres.
A novel cationic delivery system composed of magnetic aminodextran microspheres (MADM) 1-2 microm in diameter was evaluated along with neutral magnetic dextran microspheres (MDM) for their ability to target intracerebral rat glioma-2 (RG-2) tumors in vivo. The tissue distribution of the microspheres was determined following intraarterial injection (25 mg/kg) over 2 min in male Fisher 344 rats bearing RG-2 tumors as well as normal animals with a magnetic field of 0 or 0.6 T applied to the brain for 30 min. Animals were sacrificed at 30 min or 6 h post-injection after which the microspheres were recovered from various tissues and analyzed for magnetite (Fe3O4) content by atomic absorption. Overall, administration of cationic MADM and neutral MDM particles in normal animals resulted in low brain tissue concentrations with the highest concentrations observed in lung and spleen tissue. In contrast, studies in brain tumor bearing animals resulted in cationic MADM particles concentrating in brain tumor at levels significantly higher than neutral MDM particles (p = 0.0111). Cationic particles were also retained in brain tissue over a longer period of time compared to neutral particles (p = 0.0161) with MADM tumor concentrations decreasing only 4% after 6h compared with a 32% decrease for MDM. Application of a magnetic field failed to produce any significant effect on tissue distribution due to high variability in these groups, but generally resulted in increased brain concentrations and decreased non-target tissue concentrations. TEM analysis of brain tissue sections in tumor animals also revealed differences in particle distribution with MADM particles observed in the interstitial space and MDM particles trapped in the vasculature. In summary, particle charge, state of the vascular endothelium and time significantly influenced particle distribution contributing to the ability of MADM to selectively target brain tumor and supports further investigation of magnetic cationic microspheres as a targeted drug delivery system for brain tumors.
Pulfer
S K
SK
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Gallo
J M
JM
D000704:Analysis of Variance; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D002412:Cations; D003911:Dextrans / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005910:Glioma / Q000378:metabolism*; D007269:Injections, Intra-Arterial; D008280:Magnetics; D008297:Male; D017348:Microscopy, Electron, Scanning Transmission; D008863:Microspheres; D011134:Polysaccharides / Q000008:administration & dosage; D051381:Rats; D011916:Rats, Inbred F344; D013054:Spectrophotometry, Atomic; D014018:Tissue Distribution
D002412:Cations; D003911:Dextrans; D011134:Polysaccharides