title: Activity of doxorubicin covalently bound to a novel human serum albumin microcapsule.
abstract: Doxorubicin is widely used in the treatment of human malignancies, however is associated with significant cardiac, bone marrow and gastro-intestinal toxicity. Delivery systems may ameliorate this toxicity and increase treatment specificity by increasing the proportion of drug delivered to sites of disease. We have developed a novel preparation of doxorubicin (Dox) covalently linked to a heat stabilised human serum albumin microparticle (HSAM) carrier (median particle diameter of 4 microm) and assessed its activity in 4 malignant cell lines.
  
  
  METHODS
  Doxorubicin microcapsules were compared with free doxorubicin in the rat carcinoma cell line, WRC256, and the human lines, OVCAR3, MCF7 and the Dox resistant MCF7/Dox, using a cell counting technique. IC50 were calculated from regression analysis of the resulting survival curves. Endocytosis of the microcapsules by cells in culture was observed. The rate of microcapsule uptake was assessed using dual wavelength filtered fluorescence microscopy and flow cytometry.
  
  
  RESULTS
  The mean IC50 following incubation with the Dox microcapsules was around 5 times greater than Dox for WRC256 (p < 0.001), MCF7 (p < 0.01) and for OVCAR3 (p < 0.01). MCF7/Dox was significantly more sensitive to Dox microcapsules than free Dox (p = 0.034). A negative correlation between the rate of microcapsule uptake and the IC50 values for each cell line in culture exists (r = -0.96, p = 0.04).
  
  
  CONCLUSIONS
  We conclude that: 1) Doxorubicin microcapsules retain activity in vitro and appear to overcome p-glycoprotein mediated Dox resistance. 2) The observed activity of Dox microcapsules correlates with the rate of particle uptake. Further studies in animal tumour models are in progress.
authors.affiliation: Department of Medical Oncology, Glasgow Royal Infirmary NHS Trust, UK.
authors.forename: M
authors.initials: M
authors.lastname: Eatock
authors.forename: N
authors.initials: N
authors.lastname: Church
authors.forename: R
authors.initials: R
authors.lastname: Harris
authors.forename: W
authors.initials: W
authors.lastname: Angerson
authors.forename: C
authors.initials: C
authors.lastname: McArdle
authors.forename: R
authors.initials: R
authors.lastname: French
authors.forename: C
authors.initials: C
authors.lastname: Twelves
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002214:Capsules / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D008856:Microscopy, Fluorescence; D051381:Rats; D012044:Regression Analysis; D012709:Serum Albumin / Q000008:administration & dosage*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002214:Capsules; D004337:Drug Carriers; D012709:Serum Albumin; D004317:Doxorubicin