(Bio)degradation in response to external stimuli (stimuli-responsive degradation, SRD) is a desired property in constructing novel nanostructured materials. For polymer-based multifunctional drug delivery applications, the degradation enables fast and controlled release of encapsulated therapeutic drugs from delivery vehicles in targeted cells. It also ensures the clearance of the empty device after drugs are delivered to the body. This review summarizes recent development of various strategies to the design and synthesis of self-assembled micellar aggregates based on novel amphiphilic block copolymers having different numbers of stimuli-responsive cleavable elements at various locations. These cleavable linkages including disulfide, acid-labile, and photo-cleavable linkages are incorporated into micelles, and then are cleaved in response to cellular triggers such as reductive reaction, light, and low acid. The well-designed SRD micelles have been explored as controlled/enhanced delivery vehicles of drugs and genes. For future design and development of effective stimuli-responsive degradable micelles toward tumor-targeting delivery applications in vivo, a high degree of control over degradation for tunable release of encapsulated anticancer drugs as well as bioconjugation for active tumor-targeting is required.

A novel graphene quantum dot (GQD)-based nanocarrier labeled with Herceptin (HER) and β-cyclodextrin (β-CD) was developed as a promising theranostic candidate for the treatment of breast cancer. Each component of this nanocarrier plays a critical role in providing multiple functions to achieve enhanced anticancer activities. HER provides active targeting to HER2-overexpressed breast cancer to enhance accumulation in the cancer cells. β-CD provides a site for loading of a hydrophobic anticancer drug, doxorubicin (DOX), via “host–guest” chemistry. The nanocarriers also provide diagnostic effects due to the blue-color emission of the GQDs. In response to the acidic environment of cancer cells, the GQD-complex degraded rapidly and the DOX was released in a controlled manner to inhibit proliferation of cancer cells. This multi-functional drug delivery system leads to a synergistically enhanced anticancer strategy which provides treatment and diagnosis. The intracellular trafficking results, along with cell viability and confocal laser scanning microscopy, suggest that the GQD-complex offers a viable strategy for HER2-overexpressed breast cancer-targeting drug delivery applications.

Dual stimuli-responsive degradable carbon-based nanoparticles (DS-CNPs) conjugated with Herceptin (HER) and polyethylene glycol (PEG) have been designed for the treatment of HER2-positive breast cancer. Each component has been linked through disulfide linkages that are sensitive to glutathione in a cancer microenvironment. β-cyclodextrin (β-CD) on the surface of DS-CNPs formed an inclusion complex (DL-CNPs) with doxorubicin (DOX) at a high loading capacity of 5.3 ± 0.4%. In response to a high level of glutathione (GSH) and low pH in a tumor environment, DL-CNPs were rapidly degraded and released DOX in a controlled manner via disruption of host–guest inclusion. These novel DL-CNPs exhibited high cellular uptake with low toxicity, which induced the efficient inhibition of antitumor activity both in vitro and in vivo. Cell viability, confocal laser scanning microscopy, and animal studies indicate that DL-CNPs are a great platform with a synergistically enhanced antitumor effect from the dual delivery of HER and DOX in DL-CNPs.