## 4 Drug Delivery
### pH-Responsive Drug Delivery  
The design of drug delivery nanocarriers often involves careful tailoring of polymer constituents for enhanced micellar stability, and the introduction of endogenous stimuli-responsive functional groups. For example, there is a considerable variation of pH in the blood, tissue, stomach (1.5-3.5), the small intestine (5.5-6.8), the colon (6.4-7.0), as well as in the intracellular endosomal (5.5-6.0) and lysosomal (4.5-5.0) environments. One could use pH stimulus in drug delivery, and the constituent polymers must be resistant to degradation in these environments, and must have a pKa adapted to targeted delivery [135]. Polymers used for pH-responsive drug delivery, such as PDEAEMA or poly(methacrylic acid) (PMAA), are often weakly basic. It should also be noted that, while not inherent to nano-delivery systems, acidic conditions can also increase drug release from miktoarm polymers, due to drug protonation, resulting in increased aqueous solubility [72]. An A\({}_{3}\)(BC)\({}_{3}\) (A = PCL, B = PDEAEMA, C = poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA)) miktoarm polymer was synthesized by combining ROP of caprolactone, and sequential ARGET-ATRP of DEAEMA and PEGMA, using a multifunctional dipentaerythnitol core [51]. PCL was the biocompatible hydrophobic block that would form the core of self-assembled micelles, PDEAEMA was the pH-responsive entity, which at a pH lower than 6.9 became protonated, leading to hydrophilic/hydrophobic switch. The PPEGMA block provided a hydrophilic shell, which imparted biological stability. At pH > 8, the PDEAEMA chains were found to be completely deprotonated, and as a result, collapsed to form the hydrophobic core with PCL. A decrease in pH to 4 led to a gradual increase in micelle size, due to both PDEAEMA chain expansion upon becoming soluble, and electrostatic repulsion between the now positively charged chains. At pH of 7.4, 6.5, and 5.0, TEM micrographs showed that micelles had diameters of 100-180, 250-350, and >500 nm, respectively. DOX-loaded A\({}_{3}\)(BC)\({}_{3}\) star-based micelles with an encapsulation efficiency of 42-71%, showed steady drug release curves, culminating in 27-40% over 96 h. Decreasing the pH of the release medium to 6.5 and 5.0 increased the cumulative release to 44-59% and 85-100%, respectively. Generally, micelles with larger PDEAEMA fractions showed a greater response to pH, as one would expect. A\({}_{2}\)(BC)\({}_{2}\) (A = PCL, B = PDEAEMA, C = PPEGMA) stars were also synthesized by the same group, and these polymers self-assembled to slightly smaller (63 nm) micelles [50]. Drug release at pH = 7.4, 6.5, and 5.0 showed cumulative DOX release of 82%, 50%, and 36%, respectively. While the cytotoxicity of unloaded micelles was negligible, DOX-loaded micelles exhibited similar anti-tumor efficiencies to free DOX in HepG2 cancer cells. A series of ABC (A = PEG, B = PCL, C = PAA) star polymers that would assemble into micelles with hydrophobic cores and mixed PEG/PAA hydrophilic coronae with pH sensitivity imparted by PAA (Figure 7), have also been synthesized [56]. At low pH, the COOH group on the backbone of PAA arms became increasingly protonated and resulted in hydrogen-bonding complexation with PEG arms in micellar coronae, and a decrease in micelle size. In the pH range from 6 to 10, PAA arms became progressively ionized, and formed larger swollen micelles, from the loss of PEG/PAA corona complexation and repulsive forces between adjacent PAA arms. The average particle size increasedfrom 51 to 154 nm at pH 2.2 to 10. The ABC miktoarm polymers had 58-73% encapsulation of naproxen, a model hydrophobic drug, and its cumulative release from the ABC miktoarm star micelles was 65-89% over 24 h, at pH 7.4. Adjusting the pH to 2.2, and therefore, compressing the micelles, resulted in greater drug retention, with cumulative naproxen release coming to roughly 35-50%.