The application of stimuli to improve the efficacy of therapeutic agents delivered by nanocarriers has received considerable attention in recent years. Stimuli-responsive nanocarriers have been developed to compensate for the shortcomings of conventional nanocarrier-based chemotherapy [8]. The delivery of therapeutic agents responsive to stimuli is based on both internal (endogenous) and external (exogenous) stimuli (Figure 3).

Various internal stimuli are used for nanocarrier-based anti-cancer agent delivery to increase therapeutic efficacy and suppress adverse effects. Internal stimuli used with nanocarriers in breast cancer chemotherapy include pH, redox, and enzymatic stimuli [15]. pH-responsive nanocarriers are internalized and dissociate, causing protonation and extracellular drug release. Subsequently, the nanoparticle is detached, which promotes endocytosis of nanocarriers and release of the drug [24]. The redox-responsive nanocarrier system is the S–S bond that is chemically cross-linked as a gating or capping molecule on the surface of the nanoparticle and is cleaved upon the addition of agents, causing rapid drug release to the tumor cells [25]. Drug release from NPs in an enzyme-responsive manner originates from specific enzyme-catalyzed chemical reactions that lead to the degradation, dissociation, or morphological transitions of the parent NPs [14].

External stimuli originate from outside of the body to initiate anti-cancer agent delivery. External stimuli used in breast cancer chemotherapy include magnetic fields, ultrasound, and light [26]. In contrast to the internal stimuli, the external stimuli would introduce contrast agents to the image—that of nanoparticles located in the target tissues, cells, or organelles. This further triggers nanocarriers from outside the body through particular stimuli at a specific time. Magnetic systems are widely utilized for targeting and imaging [27]. As magnetic-responsive nanotherapeutics are non-invasive signals, an externally applied magnetic field can damage the moving particles and increase the accumulation of therapeutic agents in tumors. A magnetic field could be employed for in vivo applications, and could have greater advantages for targeted cancer therapy as compared with intrinsic stimuli-responsive nanotherapeutics. Ultrasound is one of the most commonly used exogenous stimuli in cancer therapy [28]. The unique advantages of ultrasound responsiveness include safety, non-invasiveness, and deeper penetration into the tissue. Many exogenous stimuli are used for drug delivery systems, among which temperature-responsive drug delivery systems offer potential advantages compared to other counterparts. This is due to their flexible design, regulation of phase transition temperatures, and passive targeting capability. The localized hyperthermia from 42.5 to 43.5 °C helps to evade cancer cells by inducing high temperatures in tumor tissues. However, these hyperthermic stimuli would enlarge the blood vessels and modify the perforation of tumor cell membranes, thereby enhancing anti-tumor drug delivery [29].

Both internal and external stimuli have their own advantages and disadvantages, as presented in Table 1. Internal stimuli are safe and provide efficient and controllable drug release without compromising cell and site specificity. Internal stimuli have the disadvantage of not being controlled manually. External stimuli have the advantage of being manually controlled and modulated based on individual requirement making it vital in personalized treatment. They also provide upgraded site-specific drug delivery and enable regulated and payload release. However, external stimuli need more sophisticated equipment and normal cell injury may happen. Nevertheless, compared to internal stimuli, external stimuli are preferred for nanocarrier based chemotherapy.

Therapeutic agents are chemical substances that are delivered to the body for the treatment or mitigation of disease conditions or ailments. These substances can be drugs, proteins, genes, compounds, or other pharmaceutically active ingredients. As the human genome has been sequenced and genetic technology has advanced, there is a growing body of knowledge on genetic changes, initiation and proliferation, therapeutic mechanisms, and novel treatment targets for cancer therapy. Understanding the pathophysiology of the disease, human gene sequences, and discovery of novel molecular targets is the core of modern medicine to conquer cancer therapy. Numerous noteworthy advances have been made in the development of targeted therapy. These targeted therapies are designed to attack cancer cells while causing less damage to normal healthy cells. Targeted therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules or targets that are involved in the growth, spread, and progression of cancer. Targeted therapies are currently at the center of anti-cancer drug development; hence, they are the cornerstone of precision medicine. Similarly, in breast cancer, many drugs are being developed and integrated with nanocarriers. Table 3 lists some of the drugs used in breast cancer treatment along with nanocarriers responsive to ultrasound.