Biodegradable microspheres containing a colchicine analogue inhibit DNA synthesis in vascular smooth muscle cells

K. L. March, S. Mohanraj, P. P K Ho, R. L. Wilensky, D. R. Hathaway

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Local application of agents capable of modulating vascular responses, including smooth muscle cell proliferation, has been achieved, but difficulty in maintaining active levels locally has been a factor limiting the efficacy of such approaches. One strategy to maintain adequate levels is the local delivery of microspheres that release active agents over sustained time periods. Methods and Results: We incorporated a colchicine analogue into biodegradable microspheres composed of a lactic acid/glycolic acid copolymer and characterized their drug release behavior as well as their effects on bovine aortic smooth muscle cells (BASMCs) in culture. Drug release was evaluated by spectrophotometric assay. Drug effects on DNA synthesis were measured by thymidine incorporation after addition of serum to subconfluent cells synchronized by serum withdrawal as well as in asynchronous cell populations. Polymeric microspheres incorporating 10% to 17% drug by weight and averaging 6 μm in size were found to release the colchicine analog in buffered saline solutions over more than several weeks. Drug-loaded particles inhibited DNA synthesis completely, with EC50 values ranging from 0.001 to 0.005 g% (wt/wt). Morphological changes suggesting microtubule depolymerization were observed after drug particle treatment, with similar EC50 values. Microspheres allowed to contact the cell surface demonstrated effects similar to those seen with microspheres suspended in the nutrient medium by porous polycarbonate filters, at EC50 values approximately fivefold lower. In contrast, control microspheres composed only of polymer with no incorporated active drug demonstrated no observable toxicity to BASMCs and <40% inhibition of thymidine incorporation even in suspensions containing up to 0.5 g% particles. Conclusions: Biodegradable microspheres were fashioned that release a colchicine analogue and inhibit DNA synthesis in smooth muscle cells. Drug-loaded polymeric particles are candidates for local delivery at sites of arterial injury to decrease restenosis.

Original languageEnglish
Pages (from-to)1929-1933
Number of pages5
JournalCirculation
Volume89
Issue number5
StatePublished - May 1994

Fingerprint

Colchicine
Microspheres
Vascular Smooth Muscle
Smooth Muscle Myocytes
DNA
Pharmaceutical Preparations
polycarbonate
glycolic acid
Thymidine
Cell Proliferation
Vascular System Injuries
Serum
Angioplasty
Sodium Chloride
Microtubules
Blood Vessels
Lactic Acid
Suspensions
Polymers
Cell Culture Techniques

Keywords

  • cells
  • colchicine
  • muscle, smooth
  • stenosis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

March, K. L., Mohanraj, S., Ho, P. P. K., Wilensky, R. L., & Hathaway, D. R. (1994). Biodegradable microspheres containing a colchicine analogue inhibit DNA synthesis in vascular smooth muscle cells. Circulation, 89(5), 1929-1933.

Biodegradable microspheres containing a colchicine analogue inhibit DNA synthesis in vascular smooth muscle cells. / March, K. L.; Mohanraj, S.; Ho, P. P K; Wilensky, R. L.; Hathaway, D. R.

In: Circulation, Vol. 89, No. 5, 05.1994, p. 1929-1933.

Research output: Contribution to journalArticle

March, KL, Mohanraj, S, Ho, PPK, Wilensky, RL & Hathaway, DR 1994, 'Biodegradable microspheres containing a colchicine analogue inhibit DNA synthesis in vascular smooth muscle cells', Circulation, vol. 89, no. 5, pp. 1929-1933.
March KL, Mohanraj S, Ho PPK, Wilensky RL, Hathaway DR. Biodegradable microspheres containing a colchicine analogue inhibit DNA synthesis in vascular smooth muscle cells. Circulation. 1994 May;89(5):1929-1933.
March, K. L. ; Mohanraj, S. ; Ho, P. P K ; Wilensky, R. L. ; Hathaway, D. R. / Biodegradable microspheres containing a colchicine analogue inhibit DNA synthesis in vascular smooth muscle cells. In: Circulation. 1994 ; Vol. 89, No. 5. pp. 1929-1933.
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abstract = "Background: Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Local application of agents capable of modulating vascular responses, including smooth muscle cell proliferation, has been achieved, but difficulty in maintaining active levels locally has been a factor limiting the efficacy of such approaches. One strategy to maintain adequate levels is the local delivery of microspheres that release active agents over sustained time periods. Methods and Results: We incorporated a colchicine analogue into biodegradable microspheres composed of a lactic acid/glycolic acid copolymer and characterized their drug release behavior as well as their effects on bovine aortic smooth muscle cells (BASMCs) in culture. Drug release was evaluated by spectrophotometric assay. Drug effects on DNA synthesis were measured by thymidine incorporation after addition of serum to subconfluent cells synchronized by serum withdrawal as well as in asynchronous cell populations. Polymeric microspheres incorporating 10{\%} to 17{\%} drug by weight and averaging 6 μm in size were found to release the colchicine analog in buffered saline solutions over more than several weeks. Drug-loaded particles inhibited DNA synthesis completely, with EC50 values ranging from 0.001 to 0.005 g{\%} (wt/wt). Morphological changes suggesting microtubule depolymerization were observed after drug particle treatment, with similar EC50 values. Microspheres allowed to contact the cell surface demonstrated effects similar to those seen with microspheres suspended in the nutrient medium by porous polycarbonate filters, at EC50 values approximately fivefold lower. In contrast, control microspheres composed only of polymer with no incorporated active drug demonstrated no observable toxicity to BASMCs and <40{\%} inhibition of thymidine incorporation even in suspensions containing up to 0.5 g{\%} particles. Conclusions: Biodegradable microspheres were fashioned that release a colchicine analogue and inhibit DNA synthesis in smooth muscle cells. Drug-loaded polymeric particles are candidates for local delivery at sites of arterial injury to decrease restenosis.",
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