Postpolymerization Modification Using Less Cytotoxic Activated Ester Polymers for the Synthesis of Biological Active Polymers

Abstract

Activated ester polymers, pioneered by Ferruti and Ringsdorf in the 1970s, are attractive polymeric materials because they can easily be converted into functional polymers by reacting with amine nucleophiles. In the present study, methyl salicylate acrylate, salicyl acrylate, and tert-butyl salicylate acrylate monomers were polymerized yielding three novel reactive precursors suitable for the postpolymerization modification with primary and secondary amines. The reactivities of poly(pentafluorophenyl acrylate), poly(methyl salicylate acrylic ester), and poly(salicyl acrylate) toward amines were compared by kinetic studies and revealed the practical applicability of salicylic acid based derivatives for efficient postpolymerization modifications. In addition, in vitro cytotoxicity of water-soluble leaving groups, pentafluorophenol and salicylic acid, as well as water-soluble polymers containing the respective activated ester groups were investigated using HeLa cells. In short, compared to the frequently used poly(pentafluorophenyl acrylate), poly(salicyl acrylate) activated ester feature a lower reactivity, but exhibit less cytotoxicity. In this respect, poly(salicyl acrylate) as reactive precursor polymers may become alternative routes for the synthesis of functional polyacrylamides when it comes to advanced applications in vivo.

Preparation of dual stimuli-responsive block copolymers based on different activated esters with distinct reactivities

“…As reported in our previous study [25], PFPA has a much higher reactivity towards hexylamine than methyl salicylate acrylate [25]. This motivated us to further explore the reactivity difference of these two esters.…”

“…Our previous work also demonstrated that the reactivity of PFPA ester is higher than activated esters derived from salicylate derivatives [25]. These positive features motivated us to investigate the difference in amine reactivity, especially aliphatic amines, between PFPA and methyl salicylate acrylate.…”

“…Azobisisobutyronitrile (AIBN) was recrystallized from methanol prior to use. Pentafluorophenyl acrylate (PFPA) [29] and methyl salicylate acrylate (MSA) [25] were synthesized according to previous reports.…”

“…Among these chemistry tools, activated ester-amine chemistry has many characteristics of click type chemistries, especially featuring metal free and mild reaction conditions [25]. The advantages of this chemistry are (i) precursor polymers are easy to synthesize and purify, (ii) reactive components including activated ester polymers and amine species are inert to air, providing a facile way in terms of storing, (iii) the aminolysis reaction is easy to be monitored by FT-IR spectroscopy, (iv) numerous functional amines are commercially available, (v) the compatibility of activated ester based monomer with modern controlled radical polymerization methods, such as reversible addition fragmentation chain transfer (RAFT) polymerization and nitroxide-mediated polymerization (NMP) [ [3].…”

“…Among these activated ester building blocks, the latest reported activated esters [25] based on salicylate derivatives, featuring the characteristics of lower cytotoxicity and cheap prices, are of great interest, especially when it comes to biological applications. Our previous work also demonstrated that the reactivity of PFPA ester is higher than activated esters derived from salicylate derivatives [25].…”