Poly(N-isopropylacrylamide)-Based Polymer-Inducing Isothermal Hydrophilic-to-Hydrophobic Phase Transition via Detachment of Hydrophilic Acid-Labile Moiety

Abstract

The polymerization of N-isopropylacrylamide (NIPAAm) with ionizable monomers results in pH-responsive lower critical solution temperature (LCST) polymer which works in an ionization-dependent manner. However, gradual ionization of the comonomer occurs at a broad pH range due to the electrostatic field generated by the polymers, limiting the extent of LCST shift in response to pH change. Furthermore, excess introduction of comonomer may dull phase transition behavior. Here, we report the development of an ionization-independent LCST polymer that exerts a sharp isothermal hydrophilic-to-hydrophobic phase transition in response to slight pH change. Our polymer has a poly­(NIPAAm/2-aminoisoprpylacrylamide (AIPAAm)) (P­(NIPAAm/AIPAAm)) backbone that retains the continuous structural similarity of N-alkyl groups for preserving phase transition sensitivity, and primary amine for forming hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amide linkage. The PMM moiety improves the polymer’s hydrophilicity and drastically increases the LCST. Detachment of the PMM moiety in response to mild acidic condition (pH < 6.8) lowers the LCST to that of original P­(NIPAAm/AIPAAm), permitting isothermal pH-responsive phase transition. Utilizing this mechanism, P­(NIPAAm/AIPAAm) modified with PMM amide linkage exhibits a sharp hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C) and, strikingly, facilitates interaction with cultured cells. Most importantly, our polymer showed significantly higher accumulation within a solid tumor after systemic injection compared to conventional PNIPAAm, which may be due to its phase transition responding to slightly acidic tumor microenvironment. Thus, this study provides a novel polymer that offers delicate control of LCST and pH-responsiveness suitable for use in even fuzzy biological environments.

Sequentially Self-Assembled Nanoreactor Comprising Tannic Acid and Phenylboronic Acid-Conjugated Polymers Inducing Tumor-Selective Enzymatic Activity

“…Derived count rate of the β-Gal/TA complex solution (β-Gal: 185 nM) was measured for evaluation of the turbidity based on a previous study using Zetasizer Nano ZS (Malvern Instruments, Malvern, U.K.) …”

“…Derived count rate of the β-Gal/TA complex solution (β-Gal: 185 nM) was measured for evaluation of the turbidity based on a previous study using Zetasizer Nano ZS (Malvern Instruments, Malvern, U.K.). 15 Preparation of β-Gal/TA/PEG-P[Lys/Lys(FPBA)] Ternary Complexes. To purify β-Gal/TA complex ([TA]/[-Gal] = 1175), ultrafiltration (MWCO: 10 kDa, MilliporeSigma) was performed.…”

Anti‐cancer combination therapy by co‐delivery of hydrophilic and hydrophobic using dual temperature and pH‐responsive liposomes

“…To overcome this deficiency, polymer‐modified liposomes have been developed [5]. However, some applied hydrophilic polymers such as poly N ‐isopropylacrylamide (NIPAAm), which was added to supply both stability and modification [6] have been easily separate from the liposome, made them unstable. Cross‐linking of functional groups solved the problem and prevented the dissociation of polymer components which needs monomers with high‐functional‐group content [7].…”

Artificial Reactor with Alterable Tandem Channeling for the Formation of Self‐Screened Catalytic Ability

“…To that end, the first layer was fabricated with 4‐nitrophenyl acetate (NPA)‐imprinted poly( N ‐isopropylacrylamide‐ co ‐2‐acrylamido‐2‐methylpropanesulfonic acid) (PIAM), a negatively thermosensitive and acidic polymer capable of providing access at relatively low temperatures (i.e., the access only became available at relatively low temperatures due to the hydrophilic/hydrophobic transition , ). Such characteristics allowed the first layer to run with switchable access to the coupled middle layer and accordingly admitted/denied the catalytic hydrolysis of NPA.…”