A number of promising nano-sized particles (nanoparticles) have been developed to conquer the limitations of conventional chemotherapy. One of the most promising methods is stimuli-responsive nanoparticles because they enable the safe delivery of the drugs while controlling their release at the tumor sites. Different intrinsic and extrinsic stimuli can be used to trigger drug release such as temperature, redox, ultrasound, magnetic field, and pH. The intracellular pH of solid tumors is maintained below the extracellular pH. Thus, pH-sensitive nanoparticles are highly efficient in delivering drugs to tumors compared to conventional nanoparticles. This review provides a survey of the different strategies used to develop pH-sensitive nanoparticles used in cancer therapy.

Doxorubicin (DOX) is one of the most widely used anthracycline anticancer drugs due to its high efficacy and evident antitumoral activity on several cancer types. However, its effective utilization is hindered by the adverse side effects associated with its administration, the detriment to the patients’ quality of life, and general toxicity to healthy fast-dividing cells. Thus, delivering DOX to the tumor site encapsulated inside nanocarrier-based systems is an area of research that has garnered colossal interest in targeted medicine. Nanoparticles can be used as vehicles for the localized delivery and release of DOX, decreasing the effects on neighboring healthy cells and providing more control over the drug’s release and distribution. This review presents an overview of DOX-based nanocarrier delivery systems, covering loading methods, release rate, and the cytotoxicity of liposomal, micellar, and metal organic frameworks (MOFs) platforms.

Temperature excursions within a biological milieu can be effectively used to induce drug release from thermosensitive drug-encapsulating nanoparticles. Oncological hyperthermia is of particular interest, as it is proven to synergistically act to arrest tumor growth when combined with optimally-designed smart drug delivery systems (DDSs). Thermoresponsive DDSs aid in making the drugs more bioavailable, enhance the therapeutic index and pharmacokinetic trends, and provide the spatial placement and temporal delivery of the drug into localized anatomical sites. This paper reviews the fundamentals of thermosensitive polymers, with a particular focus on thermoresponsive liposomal-based drug delivery systems.

Chemotherapeutic drugs are highly effective in treating cancer. However, the side effects associated with this treatment lower the quality of life of cancer patients. Smart nanocarriers are able to encapsulate these drugs to deliver them to tumors while reducing their contact with the healthy cells and the subsequent side effects. Upon reaching their target, the release of the encapsulated drugs should be carefully controlled to achieve therapeutic levels at the required time. Light is one of the promising triggering mechanisms used as external stimuli to trigger drug release from the light-responsive nanocarriers. Photo-induced drug release can be achieved at a wide range of wavelengths: UV, visible, and NIR depending on many factors. In this review, photo-induced release mechanisms were summarized, focusing on liposomes and micelles. In general, light-triggering mechanisms are based on one of the following: changing the hydrophobicity of a nanocarrier constituent(s) to make it more soluble, introducing local defects within a nanocarrier (by conformational transformation or photo-cleavage of its lipids/polymers chains) to make it more porous or concentrating heat for thermo-sensitive nanocarriers to release their payload. Several research studies were also presented to explore the potentials and limitations of this promising drug release triggering mechanism.

Quantum dots (QDs) are a promising tool to detect and monitor tumors. However, their small size allows them to accumulate in large quantities inside the healthy cells (in addition to the tumor cells), which increases their toxicity. In this study, we synthesized stealth liposomes encapsulating hydrophilic graphene quantum dots and triggered their release with ultrasound with the goal of developing a safer and well-controlled modality to deliver fluorescent markers to tumors. Our results confirmed the successful encapsulation of the QDs inside the core of the liposomes and showed no effect on the size or stability of the prepared liposomes. Our results also showed that low-frequency ultrasound is an effective method to release QDs encapsulated inside the liposomes in a spatially and temporally controlled manner to ensure the effective delivery of QDs to tumors while reducing their systemic toxicity.