(T1330-08-50) Thermo-Responsive F127-BUM as a Platform for Drug Delivery Innovation

Purpose: Smart polymers, also known as stimuli-responsive or intelligent polymers, can change their properties in response to external stimuli like temperature, pH, light, electric or magnetic fields, and biological signals. These polymers are characterized by their responsive, tunable behavior and biocompatibility. The triggers for smart polymers can be physical, chemical, or biological. In this synthesis, the main trigger is temperature, a physical trigger, leading to the development of thermos-responsive smart polymers. These polymers exhibit responses such as swelling, solubility changes, and aggregation. The synthesis of smart polymers involves incorporating responsive monomers to undergo chemical reactions. The goal is to develop the F127-BUM polymer, a block copolymer made by combining two types of monomers: Pluronic F127 and 2-isocyanatoethyl methacrylate (BUM). Pluronic F127, also known as poloxamer 407, is a triblock copolymer consisting of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) blocks. 2-isocyanatoethyl methacrylate (IEM) is a monomer with both isocyanate and methacrylate groups. DBTL is used as a catalyst for the reaction between isocyanate and polyol groups to synthesize the F127-IEM block copolymer. The primary aim is to achieve the thermo-responsive behavior of Pluronic F127, which exhibits a lower critical solution temperature (LCST) behavior, meaning it undergoes a reversible phase transition from a sol to a gel at a specific temperature. This property makes F127 useful in thermos-responsive hydrogels, which can gelate at body temperature, allowing for minimally invasive administration and sustained drug release.

Methods: Following trial-and-error experimentation with different compositions, a single optimized formulation was used to synthesize F127-BUM in two batches, as illustrated in Figure 1. Various characterization techniques were employed to test the synthesized polymer. Solubility studies were performed by dissolving 1 g of each batch in 5 mL of deionized (DI) water at 4 °C overnight, followed by observation of gelation behavior at 30 °C, 45 °C, and 60 °C. Rheological evaluations were conducted using an Anton Paar Rheometer. Solutions of 20%, 25%, and 30% (w/v) concentrations were prepared from Pluronic F127 and both F127-BUM batches. Viscosity changes were monitored across increasing temperatures to determine sol–gel transition behavior. FTIR spectroscopy was used to confirm chemical modification by tracking the disappearance of the isocyanate peak and the formation of urethane and methacrylate functionalities. Further structural validation was performe d using ¹H NMR and ¹³C NMR spectroscopy, assessing peak shifts, disappearance of hydroxyl signals, and appearance of methacrylate protons.

Results: All powder samples showed excellent solubility at 4 °C with no visible gelation. At 30 °C, Pluronic F127 showed partial gelation, whereas both F127-BUM batches remained in solution, indicating a delayed response due to BUM conjugation. At 45 °C, Pluronic F127 fully gelled, while F127-BUM Batch 1 partially gelled and Batch 2 remained mostly fluid. At 60 °C, all samples gelled, though F127-BUM batches exhibited slower kinetics. Rheological data confirmed that increasing concentration and temperature led to higher viscosity, with Pluronic F127 undergoing a sharp sol–gel transition between 30–37 °C. In contrast, F127-BUM batches displayed delayed and broader gelation behavior, confirming that BUM modification modulates micelle formation and transition temperature. Batch 2 consistently demonstrated a more delayed gelation response compared to Batch 1. FTIR spectra confirm successful chemical modification of F127 with BUM. The FTIR spectrum of 2-IEM shows characteristic peaks for –NCO stretching (~2250 cm⁻¹) and C=C (~1635 cm⁻¹). Pure F127 shows ether C–O–C stretching near 1100 cm⁻¹. The physical mixture exhibits additive peaks without new bond formation. F127-BUM Batches 1, 2, and 3 all show: Disappearance of the isocyanate peak (~2250 cm⁻¹), New peaks corresponding to urethane linkage (–NH stretching around 3300 cm⁻¹ and C=O around 1700 cm⁻¹), Retained C=C peaks (~1635 cm⁻¹). These confirm successful conjugation of 2-IEM to Pluronic F127 via urethane linkage, forming methacrylated F127-BUM. The ^1H-NMR spectrum of 2-IEM displays vinyl proton resonances at 5.5–6.5 ppm and methylene signals near 4.2 ppm. In the spectrum of unmodified Pluronic F127, the characteristic PEO and PPO peaks appear at approximately 3.6 ppm and 1.1 ppm, respectively. The physical mixture of F127 and 2-IEM shows both sets of signals without any chemical shift or integration changes. After conjugation, all F127-BUM batches (1–3) exhibit loss of the F127 –OH signal at ~4.7 ppm, indicating end-group modification, along with new methacrylate vinyl peaks at ~5.6 ppm and ~6.1 ppm, confirming successful incorporation. Integration of these vinyl resonances reveals a similar degree of substitution across batches, although Batch 2 shows slightly lower intensity, suggesting marginally reduced functionalization compared to Batches 1 and 3. These NMR findings align with the FTIR data and validate the methacrylation of F127.

Conclusion: Both batches of F127-BUM were successfully synthesized and thoroughly characterized. Solubility studies, rheological measurements, FTIR, and NMR analyses confirmed the successful chemical modification of Pluronic F127 and the retention of its thermo-responsive behavior. These findings support the potential of F127-BUM as a smart polymer platform for future biomedical applications.

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NMR spectrum of Monomer (2-IEM), Pluronic F127, Physical Mixture (F127+ 2-IEM), F127-BUM Batch 1, and Batch 2

FTIR spectrum of Pluronic F127, Monomer (2-IEM), Physical Mixture (F127+ 2-IEM), F127-BUM Batch 1, and Batch 2

Solubility of Plutonic F17, Batch1 and 2 at 4°C, 30°C, 45°C, 60°C