M. Masquelier

Drug Targeting in Human Cancer Chemotherapy

Drug targeting aims to restrict the access of pharmacological agents to selected cells. Theoretically, such a method should on one hand, decrease unsuitable side effects resulting from an interaction of the drugs with non target cells and, on the other hand, enhance the pharmacological activity by increasing the proportion of the administered drug found within the target cells. Our conceptual approach to this problem consists in linking drugs through a covalent bond to macromolecular carriers which are recognized by receptors or antigens present at the cell surface of the target cells and thereafter endocytosed to allow the release of the drug after hydrolysis of the covalent linkage by lysosomal enzymes.

Targeting of Antitumour and Antiprotozoal Drugs by Covalent Linkage to Protein Carriers

The possibility of directing drugs selectively to their cellular targets was considered for the first time by Paul Ehrlich at the beginning of this century. It is, however, only since about twenty years that developments in biology and medicine have incited an increasing number of laboratories to try to translate this dream into reality. One of the most promising and most explored approaches is the linkage of very active but toxic pharmacological agents to carriers which will transport and target these selectively to sites of action.

DNA, Liposomes, and Proteins as Carriers for Antitumoral Drugs

The “drug-carrier” concept in cancer chemotherapy is discussed in view of the experience gained in developing and testing drug-carrier complexes composed of anthracyclines and vincristine associated with DNA, liposomes, or proteins.

Covalent Linkage of Anthracyclines to Macromolecular Carriers

Abstract Daunorubicin (DNR) and doxorubicin (DOX) have been covalently linked to protein carriers such as human serum albumin (SA), galactosylated serum albumin (gal SA) and antibodies. The drug is transformed into a succinylated tetrapeptide derivative and is linked to the amino group of the protein via an activated ester derivative. Molar drug to protein ratios of 4 to 12 have been reached in the drug albumin conjugates whereas in the drug antibodies conjugates its value never raised above 3. Monomeric conjugates were obtained in good yields with over 99.7% of the drug covalently attached to the carrier.

N-L-Leucyl Derivatives of Anthracyclines: Toxic and Chemotherapeutic Properties

Various N-aminoacids of daunorubicin (DNR) have been synthesized in an attempt to develop a method for linking DNR to protein carriers, which would enable DNR to be released intralysosomally after endocytosis of the drug-carrier conjugate by tumor cells (1,2,3). It rapidly becarne evident that these amino-acid derivatives could be interesting by themselves as potential prodrugs of DNR. It was assumed that these prodrugs could have proper pharmacokinetic properties and be activated into DNR either inside the tumor cells or in their vicinity by enzymatic hydrolysis.