The invention pertains to soluble and biodegradable copolymers which are activated for bonding of biologically active compounds.
Biologically active compounds bonded on soluble synthetic polymers have been proposed during recent years as suitable types of so called "prodrugs" for medical applications. Such bonded compounds enable, for example, longer excretion halftimes for active components, affects at active sites in the body, combining several activities, etc. Poly(aspartic acid) and poly(glutamic acid) and their derivatives are prospective polymers for such applications. Reactive functional groups must to be introduced into the polymers to bond chosen compounds. Poly(succinimide) is usually used for the synthesis, of poly(aspartic acid) as the reactive intermediate which is allowed to react with a reactive amine carrying a suitable functional group. However, this procedure always affords the racemic polymer which, moreover, contains both .alpha. and .beta. peptide bonds in the main chain and, consequently, the resulting polymer is biodegradable with great difficulty.
The biodegradable derivatives of activated poly(aspartic acid) may be obtained by the polymerization of N-carboxyanhydrides of the .beta.-monoester of the pertinent amino acid by deprotection of the carboxylic group through ester cleavage, and the subsequent activation of carboxylic group, e.g. with carbodiimide or formic esters. A disadvantage of this procedure is the complicated multistep synthesis, low yield, possible accumulation of undesirable side reactions, and incomplete conversion in the individual steps. In addition to this, polyanions with free carboxylic groups are not very suitable for practical medical application, and it is more convenient to prepare non-ionogenic derivatives with hydroxyl groups in the side chain. This requires, indeed, further reaction with aminoalcohols after bonding of a biologically active compound.
Preparation of poly(N-hydroxyethylglutamine) carrying 1-.beta.-D-arabinofuranosylcytosine (ara-C) in the side chain may serve as an example of this procedure: Poly(.gamma.-benzyl glutamate) was transferred to poly(glutamic acid) and ara-C and then aminoethanol were incorporated by means of isobutyrylcarbonyl chloride (Kato et al., Cancer Res. 44, 25 (1984)). The copolymer of glutamic acid and glutamic acid hydrazide was also prepared from poly(glutamic acid) by the reaction with tert-butyl carbazate by means of N-ethyloxycarbonyl-2-ethoxy-1,2-dihydroquinoline. The tert-butyl group was split off after reaction. This copolymer was employed for bonding of adriamycin by means of an acylhydrazone bond (Heeswijk et al., Rec. Adv. Drug Delivery Systems, Anderson Kim ed., Plenum Publishing Corporation, 1984, p. 77-100).
If the copolymer of hydroxyalkylglutamine and glutamic acid is prepared from polyalkylglutamate by an incomplete aminolysis of the ester groups followed by the hydrolysis, the carboxylic groups thus formed cannot be simply activated for the reaction with a biologically active compound without the parallel undesirable reaction between the hydroxyl groups of hydroxyalkylglutamine and carboxylic groups.