In vitro and in vivo data have indicated that tumor cells actively internalize the low-density lipoprotein (LDL) from the circulation. A family of 2-(aminomethyl) acrylophenones (AMA) possesses an in vitro antileukemic activity but is devoid of any in vivo antineoplastic activity, because the compounds are actively captured by proteins in solution in the blood. In order to achieve a selective delivery of these drugs via the LDL pathway, we have incorporated an AMA drug, 2-morpholinomethyl-2',3',4'- trimethoxy acrylophenone hydrochloride (ILE) into LDL particles. ILE spontaneously associated with LDL to produce an LDL-ILE complex containing 200 +/- 100 molecules of drug per LDL particle. The LDL-ILE complex was highly electronegative as detected by electrophoresis. Further, this complex presented an immunologically detected over expression of the ligand-binding domain to the LDL receptor. In spite of these modifications, the LDL receptor processing bound, internalized, and degraded the LDL-ILE complex. Nevertheless, these biological properties were reduced by 32, 20, and 40%, respectively, in comparison to native LDL. Despite its high electronegativity, the LDL-ILE complex was not recognized by the macrophagic scavenger receptor. The LDL-ILE complex showed specific LDL receptor mediated in vitro cytotoxicity as judged from the growth inhibition of neoplastic A549 cells and of normal fibroblasts, but no activity on defective LDL receptor cells. Further, the pharmacological activity of the complex against A549 cells has been demonstrated to be equally potent as that of the free drug (median inhibitory dose, 5 microM). It is suggested that LDL drug targeting of AMA molecules could specifically deliver active molecules to cancer cells, avoiding their entrapment by other blood proteins and their rapid clearance by the reticuloendothelial system.