## 3 Controlled Antibiotic Delivery
### Endogenous Stimuli-Responsive Antibiotic Delivery
Topical treatment (twice daily) of the antibiotic-loaded micelles effectively attenuated biofilm virulence in a rodent dental caries disease model, while free antibiotic had no effect. Alternatively, pH-responsive behavior has also been used in the treatment of resistant intracellular infections, where bacteria are found in acidic intracellular compartments (endosomes pH 5-6 or lysosomes pH 4-5). For instance, by encapsulating the hydrophilic antibiotic drug ceftazidine in a pH-responsive polymersome system, [PERSON] et al. demon  
Figure 4: Examples of pH-responsive nanocarriers for antibiotic delivery. (**A**) (**1**) Schematic illustration of a pH-sensitive polyion nanocomplex for delivery of Polymyrin B (PMB). The NPs were prepared through electrostatic interaction of positively charged PMB and negatively charged 2,3–dimethyl maleic anhydride (DA)-grafted dithioligosaccharide (CS). (**2**) Schematics of in vivo drug safety, different from free PMB and CS-DA/PMB, and the mechanism of antibacterial activity of CS-DA/PMB (reprinted with permission from [48], copyright 2020 John Wiley and Sons). (**B**) The self-assembly structure and mode of action acidic pH-sensitive micelles in delivering antibacterial in cariogenic dental biofilms (adapted with permission from (19), copyright 2015 ACS). (**C**) Illustrations of the physical structures of chitosan/heparin pH-sensitive NPs, an application in the treatment of _H. pylori_ infection (reprinted with permission from [49], copyright 2009 Elsevier). strated that antibiotics were effectively retained within the polymersomes until endosomal acidification caused spontaneous disassembly resulting in burst drug release as well as endosomal disruption [50]. Treatment with the ceftazidime-loaded polymersomes significantly reduced the number of intracellular _Burkholderia thailandensis_ bacteria in RAW 264.7 cells compared to the free antibiotics (undetectable levels at 0.2 mg mL\({}^{-1}\) loaded ceftazidime). Similarly, [PERSON] et al. recently described a novel formulation based on the manosylated polymeric NPs, in which antibiotics were covalently linked via a pH-responsive hydrazone bond (poly(diacetone acrylamide-hydrazzone-isoniazid)) [51]. This drug delivery agent exhibited an increased macrophage uptake and enabled the on-demand release of antibiotics upon exposure to the acidic phagolysosome. The in vitro treatment of these antibiotic-loaded NPs was shown to effectively kill intracellular mycobacteria, whose resistance mechanisms arise from the poor intracellular delivery of a range of antibiotics. In contrast to the examples above, treatment of _Helicobacter pylori_ gastric infections is a special case, which requires a dosage form with pH-stimulated release in the opposite direction. _H. pylori_ is a spiral microorganism and mainly resides in the gastric mucosa or at the interface with the mucus layer. It can secrete urease enzymes, hydrolyzing urea to ammonia and bicarbonate to neutralize the acidic pH around them. To successfully eliminate _H. pylori_ infections, the oral antibiotic must have good stability in the gastric acid (pH 1 to 3) before reaching its target site, where the pH is close to 7.4 [52; 53]. By taking advantage of this limitation, [PERSON] et al. developed stable chitosan/heparin nanocarriers, allowing them to protect active compounds from destructive gastric acids (Figure 4C) [49]. In addition, the nanosystem could adhere to the gastric mucosa (thanks to the excellent mucoadhesive properties of chitosan), increasing the gastric residence time and infiltrating the mucus layer. However, upon contact with _H. pylori_ in the gastric mucosa at neutral pH, chitosan (pKa 6.5) is deprotonated, causing the collapse of the NPs and the release of antibiotics. Although no animal studies have yet been conducted to examine this hypothesis, the transformable biomaterials-based nanocarriers were expected to enable specific accumulation of antibiotics in the infectious site, resulting in an enhanced binding capability and killing efficacy toward _H. pylori_.