(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.

Reduction-responsive degradation based on disulfide-thiol chemistry is highly desirable in the development of self-assembled block copolymer nanocarriers for multifunctional polymer-based drug delivery applications. Most conventional approaches involve the incorporation of disulfide linkages at a single location. Herein, we report a new dual disulfide located degradable polylactide (PLA)-based block copolymer (DL-ssABP) synthesized by a combination of ring opening polymerization, facile coupling reactions, and controlled radical polymerization. The amphiphilic design of the DL-ssABP enables the formation of self-assembled micelles having disulfides positioned both in the hydrophobic PLA core and at the core/corona interface. The reductive response to glutathione as a cellular trigger results in the cleavage of the disulfide linkage at the interface shedding hydrophilic coronas as well as the disulfides in the PLA core causing disintegration of PLA cores. Such dual disulfide degradation process leads to a synergistically enhanced release of encapsulated anticancer drugs in cellular environments. These results, combined with flow cytometry and confocal laser scanning microscopy (CLSM) as well as cell viability measurements, suggest that DL-ssABP offers versatility in tumor-targeting controlled/enhanced drug delivery applications.

A novel graphene quantum dot (GQD)-based nanocarrier labeled with Herceptin (HER) and b-cyclodextrin (b-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. b-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.

A biocompatible silk fibroin‐based carbon quantum dot (SF‐CQD) is first synthesized under microwave irradiation for a short time. This fast and environmentally safe technique produce well‐defined nanosized SF‐CQDs. The SF‐CQDs have good crystallinity, a strong emission peak in the blue‐color region, high quantum yield, and the potential for modification with various functional groups on the surface. These SF‐CQDs demonstrate stable emission, good water dispersity, low toxicity, and good biocompatibility. These properties show the great potential of these SF‐CQDs for use in biomedical applications including bioimaging, biosensing, and drug delivery systems.

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A new method to synthesize a variety of well-controlled polylactide (PLA)-based block copolymers having disulfide linkages at block junctions (PLA-ss-PATRPs) was investigated. The method uses a combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP) that initiates the synthesis of a new disulfide-labeled double-head initiator having both terminal OH and Br groups (HO-ss-iBuBr). The amount of tin catalyst and polymerization time significantly influenced the control of ROP initiated with HO-ss-iBuBr. A series of ATRP of various methacrylates as well as acrylate and styrene in the presence of the resulting PLA-ss-iBuBr macroinitiators proceeded in a living manner. These well-controlled PLA-ss-PATRPs were further characterized for thermal properties using differential scanning calorimetry and thiol-responsive degradation upon the cleavage of disulfide linkages.We have recently developed a new method that centers on the synthesis of a new disulfide-labeled double-head initiator Additional Supporting Information may be found in the online version of this article.

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