## 4 Drug Delivery
### pH-Responsive Drug Delivery
While 24% sustained release was seen after 6 h at pH 7, an acidic pH 5, mimicking the endosomal environment, caused burst release with a cumulative release of 64% after 6 h.  
Rather than using intrinsically pH-responsive polymers, linear and miktoarm star polymers of AB and AB\({}_{2}\) compositions, respectively (A = PEG, B = PGA), were prepared with DOX conjugated via an acid-labile hydrazone linker [52]. To achieve this, ROP of benzyl-L-glutamate was carried out on mPEG with either one or two primary amino groups. This was followed by the ester-amide exchange aminolysis of the benzyl protecting groups on the PGA blocks, and then the linker was conjugated to neutralized DOX. The micelles were also loaded with DOX, and it was observed that miktoarm star polymers had nearly twice the drug loading, as compared to their linear analogues. This may be related to the increased number of sites in the PGA blocks for the association. pH-dependent DOX release was seen in both AB and AB\({}_{2}\) polymer micelles as a result of acid-catalyzed hydrazone linker cleavage. While all micelles showed a similar 45% cumulative release within 72 h at pH 7.4, AB\({}_{2}\) micelles showed 15% faster release compared to AB micelles at pH 5.0, and 25% faster release than micelles at physiological pH. These DOX release rates also contributed to a larger tumor-suppressive effect when micelles were incubated with HeLa cells. Another use of the pH-responsive hydrazone functional group was in linking the constituents of an AB\({}_{2}\) (A = oleic acid (OA), B = PEG) miktoarm star for antibacterial drug delivery [77]. The hydrazone linker itself was formed from the combination of a hydrazide functionalized G1 oleodendrimer with PEG-CHO, and its efficient hydrolysis was initially confirmed via incubation of the AB\({}_{2}\) star in phosphate-buffered saline at pH 6.0. It resulted in fragmentation, observed using ESI, which showed peaks related to the cleaved oleic acid segment. The miktoarm star polymers self-assembled into 130 nm micelles with 6 mg/L CMC, and were used to load vancomycin, an antibiotic, with an encapsulation efficiency of 39.6%, showing good compatibility with the micellar core. Drug release experiments showed the benefit of the hydrazone linker, as the cumulative release of drug-loaded micelles reached 100% at pH 6.0 in 48 h, due to hydrazone linker cleavage (and subsequent micellar disassembly),  
Figure 8: Schematic representation of the effect of (**a**) physiological pH and (**b**) acidic pH on the morphology of self-assembled PEG-PCL-P2 VP micelles. Reprinted with permission from reference [29]. Copyright 2012 Elsevier. as opposed to 86% release at pH 7.4. It allowed for antibacterial activity for 52 h when tested against _S. aureus_, while unloaded vancomycin was only effective for 18 h. The nanocarriers were also shown to be more effective in depleting bacterial growth in a skin infection model. AB\({}_{2}\) (A = PEG, B = PHis) type pH-sensitive miktoarm star polymers for self-assembly into polymersomes were prepared [43]. Using a 150 mM NaCl solution, it was found that the miktoarm star effectively buffers in a pH range of 5-7, with an effective pK\({}_{a}\) of 6, which is in the endolysosomal pH range. Shifting pH from physiological pH at 7.4 down to 6.8, 6.0, and 5.0 was also associated with morphological transitions to cylindrical micelles, spherical micelles, and finally, soluble unimers. The polymersomes showed encapsulation of 5(6)-carboxyfluorescein, a fluorescent hydrophilic dye, similar to that for liposomes, and a drug release profile indicating about 70% release in 72 h. Decreasing the pH below 6.8, and thus triggering structural changes, resulted in a complete burst release within a few hours, and it showed good sensitivity to the endosomal pH range.