Some materials used to construct the acid-sensitive micelles are intrinsically sensitive to pH changes [74, 75], whereas others are introduced with functional groups that are known to be neutral at physiological pH and ionizable in an acidic environment (Fig. 26.2a). Poly(β-amino ester) is commonly used to construct acid-sensitive micelles [76, 77]. The advantage of poly(β-amino ester) is that it responds abruptly to pH changes. Given that the tertiary amino groups in the hydrophobic amino ester can be protonated (with a pK_b of 6.5) in an acidic environment, the polymers can become hydrophilic. Subsequently, the micelles lose stability (dissociate) and release the encapsulated drug contents rapidly. For example, camptothecin was encapsulated in the micelles assembled from PEG and poly(β-amino ester) copolymers. The resulting micelles can be activated inside the endosomes and the lysosomes to release the drug contents [78]. Protoporphyrin IX (PpIX) is a photosensitizer that has been loaded into the pH-responsive MPEG-poly(β-amino ester) polymeric micelles [79]. The resulting micelles could be delivered to the tumors by the EPR effect and, subsequently, destabilized to release the PpIX. Upon laser irradiation, the PpIX generated near-infrared (NIR) fluorescence for tumoral imaging and, simultaneously, singlet oxygen for photodynamic therapy (Fig. 26.2b and c). In another study, to synthesize an acid-sensitive magnetic resonance imaging (MRI) probe, iron oxide (Fe₃O₄) nanoparticles were encapsulated inside an acid-sensitive micelle composed of copolymers of PEG, poly(β-amino ester), and poly(amido amine). This MRI probe released the Fe₃O₄ nanoparticles at a lower pH to image the ischemic area of the brain [80]. Other acid-sensitive micelles were also created by introducing polyhistidine or poly-4-vinylpyridine to the polymeric constructs (Fig. 26.2a) [81, 82].

Certain inorganic materials, such as calcium phosphate (CaPO₄), are insoluble in physiological pH, but can be completely dissolved at pH <6.5. Thus, pH-sensitive delivery systems have been designed either by encapsulating hydrophobic drug molecules inside the particles made up of inorganic materials [83] or by adsorbing the drugs onto the particle surfaces [84]. For instance, CaPO₄ has been used to form a deposit layer on a polymer micelle through the mineralization process [85]. Doxorubicin molecules were securely trapped inside the micelle in physiological pH and were readily released after rapid dissolution of the CaPO₄ layer (Fig. 26.3a). In another design, zinc oxide (ZnO) quantum dots were employed to seal the nanopores of mesoporous silica nanoparticles [86]. The dots were decomposed in an acidic environment, which caused the pores to open to promote the release of the drug contents (Fig. 26.3b).

Some therapeutic agents such as doxorubicin have potential metal-binding sites [87]. They can be adsorbed onto the surfaces of inorganic particles, including titanium dioxide (TiO₂), magnesium oxide (MnO), and ZnO via electrostatic and hydrophobic interactions [88–92]. Despite the fact that the exact drug release mechanism is not completely understood, it can be explained as the protonation of the chemisorbed doxorubicin molecules under an acidic condition and lead to a reduction in binding to particles. Some inorganic nanoparticles, such as MnO, have been described as T₁ MRI contrast agents [93]. When loaded with doxorubicin, these particles can also be theranostic agents [89, 90].

Acid-sensitive microgels are composed of polymeric materials that can undergo phase transition (swelling) in response to pH [94]. At low pH, the protonation of certain functional groups, such as amino groups, generates positive charges that cause swelling. As a result, the gel permeability increases and leads to the release of drug content. Chitosan is one of the most commonly used acid-sensitive polymers for preparing microgels because it is also biocompatible. A chitosan derivative, N-[(2-hydroxy-3-trimethylammonium)propyl]chitosan chloride, has been employed to prepare acid-sensitive microgels for the delivery of methotrexate into HeLa cells [95]. The polymer has also been copolymerized with a variety of polymers, such as PEG, poly(methacrylic acid), and poly(N-isopropylacrylamide) (PNIPAM), for the delivery of other chemotherapeutic agents including 5-fluorouracil, temozolomide, and oridonin [96–98].

Aberration of enzyme activity or protein concentration occurs in most diseases. In the past, therapeutic agents were developed with the goal of inhibiting the action of a particular enzyme or protein. Enzyme-sensitive motifs can be incorporated into different nanoparticles, which can be readily activated by the disease-associated enzyme to release a payload at the target site [99]. The advantage of this approach is that the target enzyme behaves similarly to a self-propelled machine, where one enzyme can potentially activate hundreds to thousands of delivery systems. Further, enzyme-activatable agents can also act as substrate inhibitors. Therefore, numerous enzyme-activatable agents have been proposed for the purpose of drug delivery, therapy, and imaging in recent years [100]. To ensure the success of an enzyme-activatable agent, it is essential to have a profound understanding of the mechanism of the target enzymes (Fig. 26.4) and the heterogeneity between the disease and normal states.

In certain medical conditions such as hyperpyrexia, body temperature can be elevated up to 41.5 °C. In other disease states, including cancer, the microenvironment of tumors is slightly hyperthermic. In the past, numerous thermo-activatable agents have been developed for drug delivery with the aim of enhancing local drug release and cellular uptake. Another advantage of applying additional heat [i.e., hyperthermia therapy (HT)] to the tumor is that it can sensitize the cancer cells when responding to radiation and chemotherapy; therefore, HT has been proposed as an adjunctive therapy [222–226]. Many micelles have been assembled from thermo-responsive polymers (Table 26.4). In particular, PNIPAM has been widely used as the thermo-activatable polymer. It has a lower critical solution temperature (LCST) of 32 °C and can be dissolved at temperature below 32 °C. When the temperature is above the LCST, the polymer can undergo phase transition to form a gel. Thus, PNIPAM has been used in combination with other hydrophobic constructs. The resulting copolymers were able to assemble into a micelle consisting a thermo-responsive coating (Fig. 26.8). Furthermore, therapeutic agents, such as doxorubicin, could be encapsulated inside micelles. Upon heating, the coatings collapsed and resulted in the release of drug contents and/or enhanced cell attachment [227, 228]. Docetaxel has been loaded into micelles assembled from copolymer, poly(N-isopropylacrylamide-co-acrylamide)-b-poly(DL-lactide). The cytotoxicity of the micelles was significantly increased with hyperthermia therapy (Fig. 26.9) [229]. In vivo study using human BCG gastric tumor-implanted nude mice demonstrated that HT could significantly enhance the tumor inhibition of the docetaxel-loaded micelles compared to animals without hyperthermia treatment (82 vs. 32 %) (Fig. 26.9) [230]. Other newer types of polymers have also been used to generate thermo-activatable particles or micelles [231–233]. However, their performance still needs to be confirmed in vivo.