Polyamidoamines as Drug Carriers: Synthesis of Polymers Featuring Extrachain-type Primary Amino Groups as Drug-anchoring Sites

Abstract

The versatile polymerization of bisacrylamides with mono- and difunctional amines, first investigated and greatly expanded in Ferruti’s laboratory,^1–3 is utilized in the present project for the synthesis of  macromolecular drug carriers. Specifically, we report on the preparation of linear polyamidoamines possessing primary amino groups as terminals of short side chains, designed to function as drug  attachment sites. In the first reaction step, performed in aqueous medium, methylenebisacrylamide  (MBA) is copolymerized with two types of comonomer: (1) primary amines bearing solubilizing  functionality, such as tert-amine or hydroxyl groups, and (2) a variety of mono-N-Boc-protected primary diamines (Boc = tert-butoxycarbonyl). In other reactions, MBA is allowed to react with a mono-N-protected diamine to give a macromonomer, which is polymerized with an oligo- or poly(ethylene oxide) terminated at both ends by a primary amino group. The intermediary polymers so obtained, as yet featuring N-protected amino side groups, are treated with trifluoroacetic acid for deprotection. Further work-up by aqueous dialysis (25 000 mwco tubing) and freeze-drying affords the target polymers as water- and methanol-soluble solids in ultimate yields of 10–25%. 1H NMR spectroscopy serves to confirm the structural assignments 1–12. In order to demonstrate the drug-carrying potential of these polymers, an exemplifying polyamidoamine (11) is allowed to react with an active ester of 4-ferrocenylbutanoic acid in methanolic solution. A water-soluble conjugate (11-Fc) is thus obtained, in which 93% of available primary amine side-chain terminals are acylated by the ferrocenylation agent.

KEYWORDS: Polyamidoamines., methylenebisacrylamide, macromolecular drug carriers, primary amine side functionality, 4-ferrocenylbutanoic acid.