Amphoteric linear poly(amido-amine)s as endosomolytic polymers: Correlation between physicochemical and biological properties

Five poly(amido amine)s (PAAs) carrying two ter-amino groups and one carboxyl group per repeating unit were prepared by hydrogen-transfer polyaddition of a-methylpiperazine (ISA 23), 1,2-bis(N-methylamino)ethane (DMEDA-BAC), 1,2-bis(N-ethylamino)ethane (DEEDA-BAC, 1,3-bis(N-methylamino)propane (DMEPDA-BAC), or 1,6-bis(N-methylamino)hexane (DMEXA-BAC), in each case to 2,2-bis(acrylamido)acetic acid (BAC). The resultant PAAs had an M-n in the range 7 985-24 980 g/mole and an M-w in the range 11 420-42 710 g/mole. Considerable differences were observed in the basicity of the amino groups present (log K(1)degrees = 7.5-9.5; log K(2)degrees = 3.2-8.4), whereas the log K(3)degrees value (2-3) of the carboxyl groups was consistent with that of a fairly strong acid. DEEDA-BAC, DMEDA-BAC, and ISA 23 were nontoxic (IC50 > 5 mg/mL). Those PAAs with the highest log K(2)degrees values were more cytotoxic (IC50 = 3.55 mg/mL for DMEPDA-BAC, and IC50 = 0.23 m/mL for DMEXA-BAC). All the PAAs displayed pH-dependent haemolysis (most lytic at pH 5.5), consistent with their proposed use as endosomolytic polymers.