Thermogelling Multiblock Poloxamer Aqueous Solutions with Closed‐Loop Sol–Gel–Sol Transitions on Increasing pH

Abstract

The thermogelling properties of aqueous polymer solutions have been hot topics of research due to their potential biomedical applications as well as to interest in understanding sol±gel transition mechanisms.[1] In particular, poloxamer, a triblock copolymer of poly(ethylene glycol)±poly(propylene glycol)±poly(ethylene glycol), and its derivatives, such as poloxamer-g-poly(acrylic acid) (Smart Gel), 3,4-dihydroxyphenylalanine (DOPA)-conjugated poloxamers, and biodegradable multiblock poloxamers, have been investigated.[2]Aqueous solutions of the above polymers are free-flowing sols at low temperature, whereas they turn into gels at physiological temperature by a heat-induced sol-to-gel transition. Therefore, aqueous polymer solutions containing drugs or cells have been proposed as injectable reservoir systems.[3] However, small-tissue adhesion and blockage of a long needle, especially a catheter, by gelation during injection of the formulation of the drug or cell limits their application. In addition, the pH in our body varies from 1±8 depending on the site as well as pathological condition. For example, vaginal pH is 3.7±5.5 and tumoral pH is~5.7±7.4. [4,5] Considering the above facts, we designed a multiblock poloxamer (MBP) with carboxylic acids and investigated the gelation characteristics as a function of pH and temperature. The synthetic route (Scheme 1) of the MBP shows that two moles of carboxylic acid groups are generated by one mole of terephthalic anhydride in the coupling reaction.Dynamic rheological analysis showed that the MBP aqueous solution (30 wt.-%) did not undergo appreciable change in dynamic viscosity (g¢) as the temperature was increased to 45 C at pH 7.4, indicating that the sol-to-gel transition did not occur. The increased hydrophilicity of the ionized carboxylic acid groups solubilize the MBP at pH 7.4. To see the effect of pH change on gelation, the viscosity of MBP (30 wt.-%) was measured as a function of pH and temperature (Fig. 1). The abrupt increase in viscosity at 25±30 C indicates the sol-to-gel transition of the MBP aqueous solution in a pH range of 4±6. Interestingly, the gel phase is observed in a specific pH range of 4±6 at 37 C. At low pH (< 3) and high pH (> 7.4), an appreciable increase in viscosity, that is, a solto-gel transition, was not observed.pH-and temperature-sensitive polymers such as poly(N-isopropylacrylamide-co-acrylic acid); poly(styrene-co-maleic anhydride) (SMA) grafted to poly(ethylene glycol) (PEG) (SMAg-PEG); and poly(N-vinylcaprolactam-co-methacrylic acid) have been reported.[6±8] They form gels at low pH and high temperature. However, there is no report of a polymer with a closed-loop gel phase, where the gel exists at a certain pH range and becomes a sol phase in both low-and high-pH regions.To get some idea of the closed-loop pH-dependent behavior, we hypothesized two opposing forces. First, as the pH increases, carboxylic acid (±COOH) is ionized to its conjugate carboxylate anion (±COO ± ), which increases the hydrophilicity of the MBP and makes th...

Multifunctional Stimuli Responsive ABC Terpolymers: From Three‐Compartment Micelles to Three‐Dimensional Network

“…The viscosity exhibits a maximum at pH 6-7 and gradually decreases at elevated pH to finally demonstrate a closed loop sol-gelsol behavior, analogous to that recently observed for a multiblock-poloxamer (30 wt.-%) aqueous system. [14] It should be noted here that the sol-gel-sol behavior illustrated in Figure 3a is concentration dependent and was observed at relatively low concentrations. For instance, the zero shear viscosity of a 10 wt.-% polymer concentration at pH 4 is 3 Â 10 4 Pa Á s.…”

“…At high pH, the above structure is transformed into a three-dimensional transient network constituted of hydrophobic domains interconnected with negatively charged bridging chains (PAA chains). At even higher pH (14) the network is disrupted and finally exhibits a closed loop solgel-sol behavior.…”

Temperature/pH‐Sensitive Hydrogels Prepared from Pluronic Copolymers End‐Capped with Carboxylic Acid Groups via an Oligolactide Spacer

“…It was previously shown that the solubility of hydrophilic PEO decreases with increasing pH, especially above pH 8. [21] Thus, at the higher pH condition, the reduced PEO solubility made the PEO shell layer dehydrated, leading to the formation of more compact micellar packing even though terminal carboxylic acid groups were ionized. This would lead to the gel-to-sol transition observed at pH ¼ 8.…”

“…The terminal -CH 2 protons produced by reaction with SA were confirmed at 2.62 ppm in the 1 H NMR spectrum of the polymer. [21] The degree of substitution was almost 100%. …”

Reverse Thermal Organogel

“…[15] From the intrinsic viscosity, the relative size (r/r 10 ) of the polymer at any temperature to the size at 10°C can be calculated by the equations of hydrodynamic volume (V h ) = 4pr [ 16] c and r are the polymer concentration (g dm -1 ) and radius (nm), respectively. From the polymer concentration (1.0 wt %) and the average radius (17 nm) of a micelle from the TEM image, M is calculated to be 168 500 g mol -1 .…”