Interactions of carboplatin with fibrin(ogen), implications for local slow release chemotherapy.
The effect of carboplatin (CPt) on fibrin(ogen) clot formation and the possible use of this combination for local slow release chemotherapy were examined. CPt significantly reduced thrombin-induced fibrin clotting time (CT) and increased clot turbidity in a concentration-dependent manner. When CPt was mixed with physiological levels of fibrinogen (>1 mg/ml), electron-dense nanoparticles (3 nm) were formed, as demonstrated by both optical particle counter and transmission electron microscopy (TEM). Upon thrombin-induced coagulation, the CPt nanoparticles were trapped within the fibrin mesh. At higher fibrinogen levels (>5 mg/ml), the 3-nm CPt nanoparticles aggregated, so that approximately 2% and approximately 0.5% of the CPt on the fibrinogen appeared as larger particles of 10 and 50 nm, respectively. Dialysis experiments showed that 60-70% of the CPt was released from the fibrin clot within one hour as a non-particulate soluble form, while approximately 30% of particulate CPt were retained. Up to 5 mg/ml this portion of firmly attached CPt was dependent of the initial drug level. CPt released from the fibrin by either diffusion or by fibrinolysis exhibited cytotoxic activity towards retinoblastoma (RB) cell lines (Y-79 and Weri RB1) equivalent to free drug. Our study indicates that CPt enhances fibrin clot formation and suggests the use of fibrin with high dose CPt for slow release chemotherapy against localized tumors such as retinoblastoma.
Gorodetsky
Raphael
R
Biotechnology and Radiobiology Laboratory, Sharett Institute of Oncology, Hadassah University Hospital, Hadassah-Hebrew University Medical Center, P.O.B. 12000, Jerusalem 91120, Israel. Rafi@Hadassah.org.il
Peylan-Ramu
Nili
N
Reshef
Avraham
A
Gaberman
Elena
E
Levdansky
Lilia
L
Marx
Gerard
G
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D016190:Carboplatin / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D010316:Particle Size
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D005340:Fibrinogen; D016190:Carboplatin