Liposomal delivery of doxorubicin to hepatocytes in vivo by targeting heparan sulfate.
Previous work demonstrated that liposomes, containing an amino acid sequence that binds to hepatic heparan sulfate glycosaminoglycan, show effective targeting to liver hepatocytes. These liposomes were tested to determine whether they can deliver doxorubicin selectively to liver and hepatocytes in vivo. Fluid-phase liposomes contained a lipid-anchored 19-amino acid glycosaminoglycan targeting peptide. Liposomes were loaded with doxorubicin and were non-leaky in the presence of serum. After intravenous administration to mice, organs were harvested and the doxorubicin content extracted and measured by fluorescence intensity and by fluorescence microscopy. The liposomal doxorubicin was recovered almost entirely from liver, with only trace amounts detectable in heart, lung, and kidney. Fluorescence microscopy demonstrated doxorubicin preferentially in hepatocytes, also in non-parenchymal cells of the liver, but not in cells of heart, lung or kidney. The doxorubicin was localized within liver cell nuclei within 5 min after intravenous injection. These studies demonstrated that liposomal doxorubicin can be effectively delivered to hepatocytes by targeting the heparan sulfate glycosaminoglycan of liver tissue. With the composition described here, the doxorubicin was rapidly released from the liposomes without the need for an externally supplied stimulus.
Longmuir
Kenneth J
KJ
Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA 92697, USA.
Haynes
Sherry M
SM
Baratta
Janie L
JL
Kasabwalla
Natasha
N
Robertson
Richard T
RT
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D004317:Doxorubicin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D006497:Heparan Sulfate / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D007275:Injections, Intravenous; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D053758:Nanoparticles; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D004337:Drug Carriers; D006497:Heparan Sulfate; D008081:Liposomes; D010446:Peptide Fragments; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan