SYNTHESIS, CONTROLLED-RELEASE PROPERTIES AND ANTITUMOR-ACTIVITY OF ALGINATE-CIS-ACONITYL-DAUNOMYCIN CONJUGATES

Covalent conjugates of alginate and the antitumour agent daunomycin (D NM) were synthesized to be stable in the circulation and allow release of the drug in the acidic milieu of the endosomal and lysosomal compa rtments of tumour cells or the slightly acidic extracellular fluid of some solid tumours. Alginates containing primary amine groups were fir st prepared by reacting alginate with excess ethylenediamine. DNM was first reacted with cis-aconitic anhydride to produce N-cis-aconityl-DN M and then subsequently bound to the amino-modified alginate using the water-soluble carbodiimide 1-ethyl-3-(3-dimethylaminopropyl) carbodii mide (EDC). High (M(w) = 250000) and low (M(w) = 61000) molecular weig ht alginate-DNM conjugates were prepared. In vitro release studies sho wed that DMN was released from the conjugates (approx. 22-60%/48 h) un der acidic conditions (pH 5 and 6) with minimal release occurring at n eutral pH (approx. 2-4%/48 h). Reverse-phase HPLC confirmed that DNM w as the only product released from high molecular weight alginate-DNM c onjugate (22% released/48 h at pH 5), but the low molecular weight alg inate-DNM liberated in addition a DNM derivative (approx. 60% released (total)/48 h at pH 5). Ina preliminary experiment to investigate the antitumour activity of alginate-DNM conjugate in vivo, administration of a single intraperitoneal injection of low molecular weight alginate -DNM (equivalent to 5 mg/kg DNM) to mice bearing B16 subcutaneous tumo urs resulted in a small, but significant delay in the growth of the tu mour.