Exploring heart lymphatics in local drug delivery.
BACKGROUND
Local intramyocardial delivery (IMD) is under active clinical investigation for cell therapies to treat congestive heart failure, and gene therapies to induce revascularization of ischemic myocardium in coronary artery disease. Locally delivered agents can migrate away from the site of delivery through pathways that include lymphatics. Postdelivery redistribution can be observed using fluorescent tracers of different physical geometries. This approach provides a means to characterize these pathways and to delineate their importance in local cardiovascular drug delivery.


RESULTS
The left ventricular wall of rats (N = 83) received injections of fluorescent microspheres with mean diameters ranging from 20 nm to 15,000 nm. Fluorescent microscopy was used to observe and image the patterns of migration from the epicardial surface. The animals were sacrificed after delivery. The microspheres with diameters smaller than 200 nm were widely distributed within the lymphatic network on the epicardial surface of the rat heart and through the ventricular wall at the injection site. Cardiac lymph nodes were identified with 20 nm and 100 nm deliveries, but could not be identified in any deliveries 200 nm or larger. The 15000 nm microspheres did not migrate.


CONCLUSIONS
Tortuous lymphatic pathways are apparent in the images of fluorescent sphere migration from the intramyocardial site of delivery. These images suggest a lymphatic role in the formation of native collaterals that may implicate potential advantages to IMD in therapeutic angiogenesis. Distribution postdelivery also suggests that IMD may provide a means to administer hydrophilic agents to the periadventitial zone of the arterial wall to limit restenosis. The lack of redistribution of the 15,000 nm microspheres supports the potential for cell therapies to remain localized over an extended time frame.
Altman
Peter A
PA
BioCardia, Inc, South San Francisco, California 94080, USA. paltman@biocardia.com
Sievers
Richard
R
Lee
Randall
R
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes / Q000494:pharmacology; D006321:Heart / Q000502:physiology; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008198:Lymph Nodes / Q000502:physiology*; D042601:Lymphatic Vessels / Q000502:physiology*; D008856:Microscopy, Fluorescence; D008863:Microspheres; D008953:Models, Anatomic; D008954:Models, Biological; D009206:Myocardium / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010496:Pericardium / Q000473:pathology; D051381:Rats; D013997:Time Factors
D005456:Fluorescent Dyes