METABOLITE-DERIVED ARTIFICIAL POLYMERS DESIGNED FOR DRUG TARGETING, CELL PENETRATION AND BIORESORPTION

The use of poly(beta-malic acid) and poly(L-lysine citramide) carriers to transport doxorubicin (Dox) within K562 myeloblastic cells was stu died by taking advantage of laser microspectrofluorometry (L-MSF). Thi s technique provided a means to monitor and to quantify the penetratio n of Dox molecules in the cytoplasm and in the nucleus of Dox-sensitiv e and Dox-resistant cells. Comparison was made between polymer-drug co njugates more or less hydrophobised by C2, C7 and C12 aliphatic substi tuents and by the Dox attached to the polymer backbone as pendent chai ns. Furthermore, a method was proposed to introduce a cleavable non-pe ptidic spacer of the lactyllactyl-type between the poly(L-lysine citra mide) backbone and the drug. It is shown that: Dox was released from t he conjugates by a non-enzymatic route in the absence of cells, the Do x-uptake by cells was slower for the conjugates than for the free drug , and the hydrophobisation promoted the penetration of the released dr ug within the nucleus, even in the case of Dox-resistant cells. Howeve r, no reversion of the resistance was observed. (C) 1998 Elsevier Scie nce B.V.