Low density lipoprotein as a carrier of cytostatics in cancer chemotherapy: study of stability of drug-carrier complexes in blood.
Several solid tumour and leukemia cell types have a higher low density lipoprotein (LDL) uptake than the corresponding normal cells. We are investigating the possibilities to use LDL as a drug carrier to increase the selectivity of antineoplastic drugs in cancer chemotherapy. We have developed a method to incorporate lipophilic cytotoxic agents without interfering with the in vitro and in vivo properties of LDL. In this study, we examined the stability of some drug-LDL complexes in blood and plasma as this is an important prerequisite to achieve a selective therapy. The in vitro dialysis of N-trifluoroacetyl-adriamycin-14-valerat-LDL (AD-32-LDL) against plasma revealed a slow dissociation of the complex. The same method showed a fast and total leakage of paclitaxel from paclitaxel-LDL into the plasma chamber. The dissociation of paclitaxel was confirmed by an autoradiographic study of the distribution of paclitaxel-LDL in tumour-bearing mice. In patients with leukemia the rapid plasma dissociation of AD-32 from LDL illustrated a much higher in vivo instability of this complex. With this method, cholesteryl-linoleate only could be incorporated into LDL in a stable manner as shown by dialysis and autoradiography results. The incorporation of cytotoxic drug derivatives, containing lipophilic anchors, is now under study in order to obtain LDL complexes with better plasma stability.
Department of Medicine, Division of Clinical Pharmacology, Karolinska Institute and Hospital, S-171-76 Stockholm, Sweden. mich@comnet.se
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D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood* / Q000627:therapeutic use; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D004337:Drug Carriers; D005260:Female; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000188:drug therapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood; D015470:Leukemia, Myeloid, Acute / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D017239:Paclitaxel / Q000097:blood* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008077:Lipoproteins, LDL; C016163:valrubicin; D004317:Doxorubicin; D017239:Paclitaxel