# Automatic Detoxification Medicine Delivery by Thermo-Sensitive Poly(ethylene glycol)-Based Nanogels
## 3 Results and Discussion
### Thermo-Sensitive Behavior of PS@(MEO\({}_{2}\)MA-co-MEO\({}_{5}\)MA) Nanogels  
The PS@P(MEO\({}_{2}\)MA-co-MEO\({}_{5}\)MA) nanogels were synthesized by feeding MEO\({}_{2}\)MA (2.5 mmol) and MEO\({}_{5}\)MA (7.5 mmol) in 100 mL of 0.227 g L\({}^{-1}\) PS dispersion. Figure 2A shows the temperature-dependent average radius (\(R_{\rm h}\)) of the nanogel particles. It is clear that the \(R_{\rm h}\) of the nanogel decreases from 255 nm to 193 nm when the temperature increases from 30 \({}^{\circ}\)C to 40 \({}^{\circ}\)C. That is, the temperature of the dispersion medium can significantly influence the size of the PS@P(MEO\({}_{2}\)MA-co-MEO\({}_{5}\)MA) nanogels. The change in volume can be attributed to a thermo-sensitive nonlinear PEG-based gel shell, because the change in volume of the pure PS microspheres was not observed at the corresponding temperature range. Referring to [31], and using the method of corresponding Boltzmann fitting-differential curve, the volume phase transition temperature (VPTT) of the nanogels was determined to be 38.9 \({}^{\circ}\)C (Figure 2B). This is within the fluctuating temperature scale of drug addicts. Figure 2C shows the \(R_{\rm h}\) value change of the PS@P(MEO\({}_{2}\)MA-co-MEO\({}_{5}\)MA) nanogels experiencing five cycles of heating and cooling adjustment. The particle size was fully reproducible after repeated heating and cooling, indicating the particles can shrink and swell reversibly. This is due to the reversible thermo-responsive volume phase transition of the nonlinear PEG-based gel shell. The reversible change of the particles' size is critical for the nanogels to automatically release drugs upon environmental stimuli. Figure 2: (**A**) Temperature-dependent average radius (\(R_{\rm h}\)) value of PS@P(MEO\({}_{2}\)MA-co-MEO\({}_{5}\)MA) nanogels, (**B**) its corresponding Boltzmann fitting-differential curve, (**C**) Reversible \(R_{\rm h}\) value change of the hybrid nanogels after five cycles of repeated heating (40 \({}^{\circ}\)C) and cooling (30 \({}^{\circ}\)C). Figure 1: (**A**) SEM and (**B**) TEM images of the PS microspheres. (**C**) TEM image of PS@P(MEO\({}_{2}\)MA-co-MEO\({}_{5}\)MA) nanogel particles. (**D**) Single particle TEM image of PS@P(MEO\({}_{2}\)MA-co-MEO\({}_{5}\)MA). Why do the volumes of the nanogels change along with the ambient temperature? Let us take a look at the structure of the nonlinear poly(ethylene glycol)-based P(MEO\({}_{2}\)MA-_co_-MEO\({}_{5}\)MA) shell copolymer in Figure 3. For example, when the temperature of the dispersion medium is lower than 30 \({}^{\circ}\)C, the temperature of shell component P(MEO\({}_{2}\)MA-_co_-MEO\({}_{5}\)MA) is lower than its VPTT. A hydrogen bond may be formed between the oxygen atoms of the short oligo(ethylene glycol) side chain and the hydrogen atoms of the aqueous medium. This hydrogen bond impels water molecules to enter into the nanogel network. This finally leads to volume swelling of the whole nanogel. On the contrary, when the temperature of the dispersion medium is higher than its VPTT, the hydrogen bond is broken. Water molecules in the nanogel network may be squeezed out, resulting in the contraction of the entire nanogel. Figure 4 further shows the temperature-dependent average radius (\(R_{\text{h}}\)) of the PS@P(M-EO\({}_{2}\)MA-_co_-MEO\({}_{5}\)MA)-x (x = 1, 2, 3) nanogels synthesized with the same \(n\)(MEO\({}_{2}\)MA)/\(n\)(M-EO\({}_{5}\)MA) feeding molar ratio of 1:3 but with different initial feeding amounts of MEO\({}_{2}\)MA and MEO\({}_{5}\)MA (see details in Table 1). As can be seen from Figure 4, three samples still keep a tendency of volume contraction according to an increase in ambient temperature from 30 to 40 \({}^{\circ}\)C, which shows obvious temperature sensitive characteristics. Another fact is that the sizes of the nanogels become slightly smaller when the number of two-shell monomers increases at the corresponding temperature.