Synthesis, Acid-Base Properties and Preliminary Cell Compatibility Evaluation of Amphoteric Poly(Amido-Hydrazine)s

Abstract

Amphoteric poly(amido-hydrazine)s (PAHYs) were obtained by hydrogen-transfer polyaddition of hydrazine, 1,2-dimethylhydrazine and 1,1-dimethylhydrazine to 2,2-bisacrylamidoacetic acid. These polymers were studied for biomedical applications, such as degradability in water solution, acid-base properties, and cell toxicity. They degraded rapidly in aqueous media under physiological conditions, their molecular weight was reduced to about one-fourth, that of the original polymer in less than two days. They exhibited a typical polyelectrolyte behavior with isoelectric points between 4 and 5 and are prevailingly anionic in the blood. In preliminary cell toxicity essays they proved to be remarkably biocompatible, comparable in this respect to amphoteric poly(amido-amine)s (PAAs), and much less toxic than poly-L-lysine and polyethylenimine.

Novel Therapeutic Agents for Bone Resorption. Part 1. Synthesis and Protonation Thermodynamics of Poly(amido-amine)s Containing Bis-phosphonate Residues

“…This protonation leads to the formation of a clustered zwitterionic species where the ionized oxygens forms H-bonded structures toward the onium ion, involving two seven-membered rings condensed with a sixmembered one of the bis-phosphonate moiety in the PAM. In the corresponding oligomer, the two additional amido-oxygens may further on contribute, with a six-chelate ring, to a more compact structure (Chart 6), as also evidenced in previously studied poly(amido-amine)s. 20,39 This hypothesis is well-supported by the very large -∆H°v alue and the corresponding very low ∆S°. OligoPAM showed lower basicity, even if greater than expected, and the lower enthalpy contribution being the basic nitrogen tertiary in nature.…”

“…In the case of ampholyte compounds, triethylamine was used to free the zwitterionic species of the amino-bis-phosphonate (BPs), and this allowed polyaddition to the bisacrylamide, even if the reaction was expected to become extremely sluggish . In fact, in both cases, we obtained oligomeric products with molecular weights lower than that of the amphoteric PAAs previously reported. , This may have the advantage of cytosolic access and to be pharmacologically competitive with the BPs action toward the bone resorption cells.…”

“…33 In fact, in both cases, we obtained oligomeric products with molecular weights lower than that of the amphoteric PAAs previously reported. 13,20 This may have the advantage of cytosolic access and to be pharmacologically competitive with the BPs action toward the bone resorption cells.…”

“…Therefore, if injected, they are bioeliminable . Despite their polycationic nature, the biocompatibility of some polyamphoteric PAAs is close to that of dextran and, after intravenous injection, they are not captured by the reticulo-endothelial system (stealth properties) but have a prolonged permanence in the blood circle and are passively concentrated in tumor tissues, if present, by the enhanced permeation and retention effect (EPR). − On the basis of many encouraging results experienced in studying this class of polymers, ,, we designed the synthesis of novel poly(ampholyte) PAAs incorporating the pamidronate and neridronate drugs to obtain new therapeutic agents in the polymeric form (Chart ) of short macromolecular chains.

1 Structure of the Monomer Unit of Oligomers

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