## 4 Drug Delivery
### pH-Responsive Drug Delivery
This suggests that naproxen would be retained under gastric conditions and released in the intestine, making the micelles suitable for oral administration. A miktoarm star with 8 arms, A\({}_{2}\)B\({}_{6}\) (A = PCL, B = PMMA-_co_-PMMA was prepared using D-(-)-salicin (a \(\beta\)-glucoside) as a heterofunctional initiator [63]. It was functionalized with six bromoester groups and two hydroxyl groups, and the miktoarm star was constructed using ROP of caprolactone and ATRP of tert-butyl methacrylate (tBMA)/MMA, initiated by the hydroxyl and bromoester groups, respectively. The t-butyl groups were then removed through acidosis to give PCL\({}_{2}\)(PMMA-_co_-PMMA)\({}_{6}\) stars. Upon self-assembly, the CMC was reported to be as low as 15 mg/L, yet in some samples, an additional higher point was found at 411 mg/L. TEM micrographs revealed the presence of dandelion-shaped superstructures with coronae surrounding dark spheres above the CMC. Two anticancer drugs, DOX and camptothecin (CPT), were loaded into the micellar structures with encapsulation efficiencies of up to 60% and 6%, respectively, and the drug-loaded micelles were found to be larger than 200 nm in diameter. Due to the pH sensitivity of PMAA, the release rates of both drugs were slower at pH 7.4 than pH 5.0, at which point the chains became ionized and caused micelle swelling. Another example of a miktoarm star drug delivery system using PMAA as a pH-responsive unit had the composition of AB\({}_{2}\) (A = PEG, B = P(MAA-_co_-MMA) [62]. The polymer was synthesized by conjugating a bromoisobutyrate ATRP initiator to a dihydroxy benzoic acid core, followed by mPEG-OH coupling, and ATRP of MMA and tBMA. Acidolysis with TFA afforded the PEG-P(MAA-_co_-MMA)\({}_{2}\) miktoarm star polymer. The MAA content of the hydrophobic block was carefully controlled during copolymerization to tune the pH-sensitivity of miktoarm stars and two PEG-P(MMA\({}_{9}\)_co_-MAA\({}_{35}\))\({}_{2}\) and PEG-P(MMA\({}_{24}\)_co_-MAA\({}_{25}\))\({}_{2}\) miktoarm stars were synthesized. Higher MMA content led to higher (82.3%) encapsulation of methotrexate (MTX), an antineoplastic agent with significant chemotherapeutic activity, and the micelles exhibited a greater pH-induced MTX release (98% release after 48 h at pH 1.2), compared to 33% at pH 7.4. Taking advantage of poly(2-vinylpyridine) (P2 VP), containing basic units with a pKa of roughly 5.9, a variety of pH-sensitive ABC-type (A = PEG, B = PCL, C = P2 VP) miktoarm stars were synthesized [28; 29; 30]. Due to the presence of P2 VP, these polymers formed micelles with positive  
Figure 7: Representation of PEG-PAA-PCL miktoarm polymer self-assembly and pH-responsive morphological changes. (+12.5 mV) zeta potentials upon aqueous self-assembly, thus indicating the presence of protonated P2 VP arms in the coronae alongside PEG. Deprotonation through NaOH addition resulted in a micelle diameter change from 54 to 37 nm, due to the collapse of P2 VP branches into micelle cores. This was attributed to the unique architecture of the star polymers, as well as the loss of electrostatically repelling chains in the corona (Figure 8). A titration indicated that the pKa was 5.0, corresponding closely to that for P2 VP, and was neutral at physiological pH [28]. In a follow-up study, P2 VP blocks were biotinylated so that, upon administration, the labelled ABC micelles would contain biotin in the core [29]. Exposure to low pH in a tumor environment would protonate P2 VP chains and shift conjugated biotin to the micellar corona, where it would aid in tumor targeting. Interestingly, the passive uptake effect of cationic micelles, due to electrostatic interactions with negatively charged cell surfaces is so effective that the inclusion of biotin was unnecessary for astrocyte and 9L cell internalization. Loading of micelles with Nile Red as a model hydrophobe verified their efficacy in drug delivery.