Increased intramural retention after local delivery of molecules with increased binding properties: Implications for regional delivery of pharmacologic agents

R. L. Wilensky, K. Mehdi, K. M. Sowinski, Hong Baek Sang Hong Baek, K. L. March

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Catheter-based local vascular delivery results in concentrated quantities of pharmaceutical agents or genes into focal areas of the arterial wall. However, intramural retention is short and has reduced the potential efficacy of this approach. It was postulated that agents that possess increased intramural binding would show increased intramural retention. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were models of agents with increased cellular and extracellular matrix binding properties. Methods and Results: The delivery efficiency and intramural retention of 2 mL of saline containing I125 labeled PDGF (n = 35 arteries) and bFGF (n = 24) were compared with albumin (n = 21) after local delivery into porcine coronary arteries. Animals were sacrificed at three or more prespecified timepoints: immediately after delivery, 1 day, or 3 days after delivery and if necessary at 5 or 7 days to document prolonged retention. Autoradiograms of the arterial sections were evaluated for the extent of delivery. Delivery efficiency, defined as the amount leaving the catheter and retrieved from the arterial wall, was 0.60% ± 0.42% for albumin, 1.98% ± 0.88% for PDGF (P = .001), and 0.31% ± 0.11% for bFGF. The calculated intramural half-life of albumin was 7.4 hours, 56.2 hours for PDGF, and 14.9 hours for bFGF (P = .0001 for PDGF). Infusate covering >50% of the medial area was observed in 85% of arteries immediately after delivery. Although myocardial delivery was similar for albumin, PDGF, and bFGF, myocardial retention was significantly longer for bFGF (P <.001). Conclusions: Molecules that exhibit preferential intramural binding show a longer intramural residence duration than solutes without such binding properties. In addition, delivery and subsequent prolonged retention in the myocardium can be obtained by local delivery via the arterial lumen of solutions with preferential binding properties.

Original languageEnglish (US)
Pages (from-to)103-112
Number of pages10
JournalJournal of Cardiovascular Pharmacology and Therapeutics
Volume4
Issue number2
StatePublished - 1999
Externally publishedYes

Fingerprint

Platelet-Derived Growth Factor
Fibroblast Growth Factor 2
Albumins
Catheters
Arteries
Extracellular Matrix
Blood Vessels
Half-Life
Coronary Vessels
Myocardium
Swine
Pharmaceutical Preparations
Genes

Keywords

  • Atherosclerosis
  • Gene therapy
  • Local drug delivery
  • Restenosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Increased intramural retention after local delivery of molecules with increased binding properties : Implications for regional delivery of pharmacologic agents. / Wilensky, R. L.; Mehdi, K.; Sowinski, K. M.; Sang Hong Baek, Hong Baek; March, K. L.

In: Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 4, No. 2, 1999, p. 103-112.

Research output: Contribution to journalArticle

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abstract = "Background: Catheter-based local vascular delivery results in concentrated quantities of pharmaceutical agents or genes into focal areas of the arterial wall. However, intramural retention is short and has reduced the potential efficacy of this approach. It was postulated that agents that possess increased intramural binding would show increased intramural retention. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were models of agents with increased cellular and extracellular matrix binding properties. Methods and Results: The delivery efficiency and intramural retention of 2 mL of saline containing I125 labeled PDGF (n = 35 arteries) and bFGF (n = 24) were compared with albumin (n = 21) after local delivery into porcine coronary arteries. Animals were sacrificed at three or more prespecified timepoints: immediately after delivery, 1 day, or 3 days after delivery and if necessary at 5 or 7 days to document prolonged retention. Autoradiograms of the arterial sections were evaluated for the extent of delivery. Delivery efficiency, defined as the amount leaving the catheter and retrieved from the arterial wall, was 0.60{\%} ± 0.42{\%} for albumin, 1.98{\%} ± 0.88{\%} for PDGF (P = .001), and 0.31{\%} ± 0.11{\%} for bFGF. The calculated intramural half-life of albumin was 7.4 hours, 56.2 hours for PDGF, and 14.9 hours for bFGF (P = .0001 for PDGF). Infusate covering >50{\%} of the medial area was observed in 85{\%} of arteries immediately after delivery. Although myocardial delivery was similar for albumin, PDGF, and bFGF, myocardial retention was significantly longer for bFGF (P <.001). Conclusions: Molecules that exhibit preferential intramural binding show a longer intramural residence duration than solutes without such binding properties. In addition, delivery and subsequent prolonged retention in the myocardium can be obtained by local delivery via the arterial lumen of solutions with preferential binding properties.",
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T1 - Increased intramural retention after local delivery of molecules with increased binding properties

T2 - Implications for regional delivery of pharmacologic agents

AU - Wilensky, R. L.

AU - Mehdi, K.

AU - Sowinski, K. M.

AU - Sang Hong Baek, Hong Baek

AU - March, K. L.

PY - 1999

Y1 - 1999

N2 - Background: Catheter-based local vascular delivery results in concentrated quantities of pharmaceutical agents or genes into focal areas of the arterial wall. However, intramural retention is short and has reduced the potential efficacy of this approach. It was postulated that agents that possess increased intramural binding would show increased intramural retention. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were models of agents with increased cellular and extracellular matrix binding properties. Methods and Results: The delivery efficiency and intramural retention of 2 mL of saline containing I125 labeled PDGF (n = 35 arteries) and bFGF (n = 24) were compared with albumin (n = 21) after local delivery into porcine coronary arteries. Animals were sacrificed at three or more prespecified timepoints: immediately after delivery, 1 day, or 3 days after delivery and if necessary at 5 or 7 days to document prolonged retention. Autoradiograms of the arterial sections were evaluated for the extent of delivery. Delivery efficiency, defined as the amount leaving the catheter and retrieved from the arterial wall, was 0.60% ± 0.42% for albumin, 1.98% ± 0.88% for PDGF (P = .001), and 0.31% ± 0.11% for bFGF. The calculated intramural half-life of albumin was 7.4 hours, 56.2 hours for PDGF, and 14.9 hours for bFGF (P = .0001 for PDGF). Infusate covering >50% of the medial area was observed in 85% of arteries immediately after delivery. Although myocardial delivery was similar for albumin, PDGF, and bFGF, myocardial retention was significantly longer for bFGF (P <.001). Conclusions: Molecules that exhibit preferential intramural binding show a longer intramural residence duration than solutes without such binding properties. In addition, delivery and subsequent prolonged retention in the myocardium can be obtained by local delivery via the arterial lumen of solutions with preferential binding properties.

AB - Background: Catheter-based local vascular delivery results in concentrated quantities of pharmaceutical agents or genes into focal areas of the arterial wall. However, intramural retention is short and has reduced the potential efficacy of this approach. It was postulated that agents that possess increased intramural binding would show increased intramural retention. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were models of agents with increased cellular and extracellular matrix binding properties. Methods and Results: The delivery efficiency and intramural retention of 2 mL of saline containing I125 labeled PDGF (n = 35 arteries) and bFGF (n = 24) were compared with albumin (n = 21) after local delivery into porcine coronary arteries. Animals were sacrificed at three or more prespecified timepoints: immediately after delivery, 1 day, or 3 days after delivery and if necessary at 5 or 7 days to document prolonged retention. Autoradiograms of the arterial sections were evaluated for the extent of delivery. Delivery efficiency, defined as the amount leaving the catheter and retrieved from the arterial wall, was 0.60% ± 0.42% for albumin, 1.98% ± 0.88% for PDGF (P = .001), and 0.31% ± 0.11% for bFGF. The calculated intramural half-life of albumin was 7.4 hours, 56.2 hours for PDGF, and 14.9 hours for bFGF (P = .0001 for PDGF). Infusate covering >50% of the medial area was observed in 85% of arteries immediately after delivery. Although myocardial delivery was similar for albumin, PDGF, and bFGF, myocardial retention was significantly longer for bFGF (P <.001). Conclusions: Molecules that exhibit preferential intramural binding show a longer intramural residence duration than solutes without such binding properties. In addition, delivery and subsequent prolonged retention in the myocardium can be obtained by local delivery via the arterial lumen of solutions with preferential binding properties.

KW - Atherosclerosis

KW - Gene therapy

KW - Local drug delivery

KW - Restenosis

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